An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0

An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy... Background: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. Methods: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. Results: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. Conclusion: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy. Keywords: Guidelines, Immunotherapy, Melanoma, Treatment * Correspondence: howardkaufman6@gmail.com; HLK12@mgh.harvard.edu Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 2 of 23 Background melanoma. SITC is a non-profit professional Cutaneous melanoma continues to be a serious public organization dedicated to improving cancer patient out- health threat with a slow, but steady increase in annual comes through the use of cancer immunotherapy. The incidence over the past four decades [1]. In 2017, there Task Force consisted of melanoma experts, including were an estimated 87,110 new cases and 9730 deaths physicians, nurses and patient advocates who met in per- due to melanoma in the United States. While melano- son and communicated through email to consider major mas detected early can often be treated by complete sur- issues and provide recommendations related to patient gical excision with good outcomes, the development of selection, toxicity management, treatment cessation and metastatic disease, which is associated with reduced sur- treatment sequencing. The panel published the first con- vival, is correlated with increasing stage and other sensus statement in 2013 [4], and this publication repre- high-risk features of the primary tumor [2]. Contempor- sents an update based on more recent assessment of the ary systemic therapeutic options for patients with meta- peer-reviewed literature and clinical experience of the static melanoma include cytotoxic chemotherapy, expert Task Force participants. These recommendations molecularly targeted therapy, and immunotherapy. Since are not intended to supplant sound clinical judgment 2011, the treatment landscape for patients with melan- but to provide clinicians who care for melanoma pa- oma has changed considerably with regulatory approval tients the most current thinking on how experts inte- of 11 new drugs and/or combination regimens [3]. Im- grate immunotherapy into the treatment munotherapy agents in particular have been associated armamentarium for patients with advanced cutaneous with durable long-term survival in responding patients melanoma. and have emerged as first-line treatment in most melan- oma populations [4]. Methods The immunotherapy agents approved for melanoma Consensus statement policy include cytokines, such as interferon α2b/pegylated SITC utilized the National Academy of Medicine interferon α2b for high-risk adjuvant therapy and (formerly Institute of Medicine) March 2011 Standards high-dose interleukin-2 (IL-2) for metastatic disease; ipi- for Developing Trustworthy Clinical Guidelines as a limumab and nivolumab, immune checkpoint inhibitors model for organizing and preparing this consensus state- targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) ment [13]. These standards include a transparent process and programmed cell death 1 (PD-1), respectively for for guideline development and funding, managing and high-risk adjuvant melanoma, and four T cell checkpoint reporting conflicts of interest, maintaining a multidiscip- inhibitors for metastatic melanoma, including ipilimu- linary and balanced group composition, establishing an mab (anti-CTLA-4), pembrolizumab (anti-PD-1), nivolu- evidence-based foundation for recommendations and rat- mab (anti-PD-1) and the combination of ipilimumab/ ing system to assess the strength of the evidence, report- nivolumab; finally, one gene-modified oncolytic virus, ing the results through a peer-reviewed publication and talimogene laherparepvec (T-VEC), has been approved publicly available website, and updating the statement as for intralesional therapy [5–12]. While the clinical trials changes in the field warrant revisions. supporting regulatory approvals have dramatically chan- The Melanoma Task Force was established through ged the melanoma treatment landscape and provided pa- SITC in 2011, with additional panel members added as tients and providers with several new options, there is necessary (Additional file 1). A Steering Committee led a relatively little data for evidence-based decisions in re- panel discussion to develop clinical treatment guidelines gard to optimal sequencing of these agents, methods or considering four basic issues for each immunotherapy biomarkers to select the right treatment for individual agent in current clinical practice: patient selection, toxicity patients, or rigorous information on how best to manage management, assessment of response, and therapy se- potential adverse events or indicators for optimal dur- quencing and combinations. The in-person meeting was ation of therapy. The availability of other therapeutic op- supplemented by email voting on several issues due to the tions, in particular targeted therapy for patients whose rapid development of new findings and drug approvals for melanoma harbors a mutation in BRAF, highlight the melanoma over the last 2 years. Full consensus recom- importance of having data or consensus agreement from mendations can be found on the SITC website [14]. experts in the field on how best to manage patients Owing to disparities in drug approval and availability in while waiting for new clinical and clinical trial data to some countries, this panel focused solely on drugs ap- help inform decision-making. proved by the U.S. Food and Drug Administration (FDA). To address the gap in evidence-based data, the Society An advance copy of this manuscript was submitted to the for Immunotherapy of Cancer (SITC) established a Mel- FDA for comment before submission for publication. The anoma Task Force to provide consensus recommenda- panel also recognized that the AJCC Cancer Staging Man- tions for clinical decision making for patients with ual, 8th Edition has been released but the clinical trial data Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 3 of 23 reviewed utilized earlier versions of AJCC staging; as such, independent searches, resulting in a final bibliography of the recommendations presented in this manuscript were 1643 manuscripts (see Additional file 3) catalogued using largely based on 7th edition staging criteria. However, rec- EndNote X5.0.1. The bibliography was supplemented with ommendations that extrapolate clinical trial data using additional literature identified by the panel, as appropriate. 7th edition staging criteria in the setting of completion Literature was graded into three levels of evidence, as pre- lymph node dissection (CLND), are made to the current viously described [4]. Level A evidence is based on strong era using the 8th edition staging system in the non-CLND supporting evidence, such as data derived from appropri- era where appropriate. ately powered prospective, randomized clinical trials or meta-analyses; Level B is based on moderate supporting Consensus panel and conflicts of interest data, such as uncontrolled, prospective clinical trials; and Potential panel members were solicited from the SITC Level C is based on weaker supporting data, such as retro- membership and supplemented with non-member mel- spective reviews and case reports. anoma multidisciplinary experts, clinicians and groups in the U.S. expected to be affected by the development Consensus recommendations of any recommendations, including patients, patient ad- The Task Force considered individual melanoma stages vocates and nurses. Panel members were screened for independently and provided the following consensus rec- conflicts of interest using the SITC disclosure form, ommendations described by stage of disease. These rec- which mandates full financial and other disclosures in- ommendations were based on data available for AJCC cluding relationships with commercial entities that version 7 staging guidelines; where appropriate, modifi- might reasonably be expected to have direct regulatory cations relevant for AJCC version 8, which became ac- or commercial impact resulting from the publication of tive in January 2018, are noted. The majority of the this statement. Disclosures of potential conflicts of inter- immunotherapy trials on which the following recom- est are noted in this manuscript. No commercial funding mendations are based included patients with ECOG Per- was used to support the consensus panel, literature re- formance Status 0 or 1. These guidelines are intended to view or preparation of the manuscript. assist clinicians in critical decision-making for patients The consensus panel convened in June 2016 in accord- with melanoma and should not supplant clinical judg- ance with the National Academy of Medicine and SITC ment for individual patient management. guidelines to review results from a previously distributed questionnaire collecting information on the participants’ Immunotherapy for stage II melanoma role in the care of patients with melanoma, primary clin- Initial assessment ical focus, experience with FDA-approved agents used Patients with stage II melanoma have an excellent over- for immunotherapy treatments, and current practices in all survival (OS) of 80% or better provided the primary the use or recommendation for use of such agents. Add- tumor is completely excised [2]. A subset of tumors, itional questionnaires were distributed electronically characterized as deep (Breslow thickness > 4 mm), and/ after the meeting to collect further information, includ- or with ulceration, and possibly those with a high tumor ing a final questionnaire in the late summer of 2017. mitotic rate (≥1 per mm ), are considered at higher risk The final consensus statement was made available to the for recurrence [15]. Practically speaking, using both entire SITC membership for open comment and these AJCC 7th and 8th additions, Stage IIB and IIC are con- comments were considered for the final manuscript and sidered higher risk. The panel discussed at length the are available in supplementary materials (see Add- changing landscape with respect to how to define high itional file 2) and online at the SITC website [14]. risk and when to consider further intervention with the goal of preventing tumor relapse. There was unanimous Literature review and rating system agreement that all stage II patients should have a com- A search of the scientific literature (using the MEDLINE prehensive diagnostic workup and be reviewed by a database) was conducted focusing on current therapeutic multidisciplinary team, including physicians with expert- approaches in humans. The search terms included “mel- ise in surgical oncology, medical oncology, dermatology anoma” and “interferon”, “interleukin-2”, “ipilimumab”, and dermatopathology to accurately determine tumor “vemurafenib,”“BRAF,”“dabrafenib, dacarbazine, temozo- stage and estimate the risk of melanoma recurrence for lomide”, “pembrolizumab”, “nivolumab”, “PD-1/PD-L1”, individual patients. This workup should include sentinel “combination”, “talimogene laherparepvec”, “adverse lymph node biopsy information, as appropriate [16]. event”,and “toxicity”. The search resulted in retrieval of nearly 2400 manuscripts, which were screened by Task Consensus management of stage II melanoma Force members to include only papers with clinically rele- The panel considered the therapeutic approach to stage vant information and removing duplicates from II melanoma should be based on an assessment of risk Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 4 of 23 for tumor recurrence or metastatic spread but recog- that high-risk patients be treated with standard 1-year nized that there is considerable controversy in how to high dose interferon-α2b, now a small majority (55%) determine risk stratification. Further, changes in the recommend enrollment onto a clinical trial - either un- AJCC staging system and emerging data using a variety selected or selected by a biomarker known to be associ- of histologic and molecular assays for risk assessment ated with either risk (prognostic) or responsiveness to have made firm recommendations challenging. For the the therapy (predictive) - as a preferred option for these purposes of our discussions, we defined high risk stage patients. Among panel members who did not recom- II as patients with tumors > 4 mm in depth (with or mend a clinical trial, twice as many recommended ob- without ulceration) or tumors > 2–4 mm with ulcer- servation (20%) as did the pursuit of standard of care ation. While this definition may change with further adjuvant interferon α-2b (10%). This is a reflection of a prospective data, the general approach to patient man- number of factors including: 1) improved systemic ther- agement can be considered based on clinical assessment apy for recurrent, metastatic disease [4]; 2) acknowledg- of higher versus lower risk. ment of the limitations of the AJCC staging system to There was general agreement that patients with lower identify those at high and low risk of recurrence (e.g., a risk stage I and IIA melanoma can be observed and that significant number of patients with low risk [by cur- there is no evidence that currently warrants treatment of rently available methods] melanoma will still die of dis- these patients (Fig. 1). The panel, however, was divided ease [15]); and 3) emerging, as yet non-validated on the role of immunotherapy for patients with biomarkers, which may better identify patients at great- higher-risk stage IIB-C melanoma (see Fig. 1) and recog- est risk of recurrence (e.g., ulceration, gene expression nized the limited Level A data available to inform clin- profile, circulating tumor DNA) [15, 17, 18]. None of the ical decision-making. The panel did consider emerging panel members recommended treatment with pegylated Level B data suggesting new recommendations are interferon-α2b for patients with stage II disease. needed for high-risk stage II melanoma patients. Patients with stage IIB or IIC melanoma who are Whereas before the majority of the panel recommended treated with interferon-α2b should have a good Fig. 1 Stage II melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate, and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) High-risk disease is defined as tumors > 4 mm in depth (with or without ulceration) or > 2–4 mm with ulceration. There is limited consensus on adjuvant therapy for this group with 10% of the panel recommending interferon-α2b, 20% recommending observation, 45 and 15% recommending therapeutic and/or biomarker-based clinical trial participation, respectively, and no panelists recommending pegylated-interferon-α2. (2) There is no evidence that immunotherapy is useful in patients with lower risk stage II melanoma, although the panel did recommend clinical trial participation, if available. Protocol-specific eligibility would need to be followed to select appropriate study candidates. (3) Patients should have a good performance status without evidence of significant depression, psychiatric history or underlying autoimmune disease to be considered for interferon-α2b. There are limited data available on interferon-α2b as treatment for stage II disease. (4) Clinical trials were the preferred treatment recommendation for patients with stage II disease associated with higher risk of tumor recurrence Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 5 of 23 performance status without evidence of significant de- believed that, in patients with microscopic metastasis to a pression or psychiatric history or underlying auto- single lymph node (stage N1a), especially when the node immune disease [4]. The data to support the use of has been excised by sentinel lymphadenectomy, cancer be- adjuvant, high-dose interferon-α2b are controversial and haves differently than in patients with more extensive many studies did not incorporate required sentinel lymph node involvement (stages N1b-3). In the updated lymph node biopsy into the study eligibility complicating recommendations, patients with N1a disease, in accord- the interpretation. In a prospective study, 499 patients ance with the AJCC 7th edition were considered as a dis- with melanoma Breslow thickness > 1.5 mm, and without tinct subset; management recommendations by nodal clinically detectable lymph node metastases, were ran- staging are shown in Fig. 2. With the recent publication domly assigned to 18 months of subcutaneous and adoption of the 8th edition of AJCC, which strived to interferon-α2b or observation [19]. Patients treated with identify a group of Stage III patients with significantly interferon-α2b demonstrated a significant improvement lower risk, the Task Force considered Stage IIIA (per AJJC in relapse-free survival (RFS) (P = 0.038) and a trend to- 8th Ed.) to have lower risk of tumor recurrence compared ward improved OS (P = 0.059). In another trial, 855 pa- to Stage IIIB-D. The management of stage III disease has tients were randomly assigned to observation or 4 weeks also been complicated by recent data showing that, while induction interferon-α2b followed by 1 or 2 years of immediate completion lymph node dissection was associ- interferon-α2b maintenance therapy [20]. The study in- ated with a decreased rate of lymph node basin recurrence vestigators reported an improvement in RFS for patients and increased disease-free survival in sentinel who received 1 year of maintenance interferon-α2b (haz- node-positive patients, there was no improvement in ard ratio [HR] 0.77, 95% Confidence interval [CI]: 0.63– melanoma-specific survival [27]. These findings along 0.96; P = 0.034), but no benefit in OS (HR 0.91, 95% CI: with the availability of more effective systemic treatment 0.74–1.10; P = 0.642). Several other prospective random- will change the management for sentinel node-positive pa- ized trials examined interferon-α2b at a variety of doses tients, although all of the reported clinical trials of adju- and treatment schedules in patients with stage II melan- vant therapy mandated completion lymph node dissection oma, but none has demonstrated a survival benefit [5, as a key eligibility criterion for study participation. Thus, 21–25]. A recently reported phase 3 randomized study the recommendations for stage III management should be in 1150 patients with resectable melanoma (T2bN0, considered carefully in light of these recent developments. T3a-bN0, T4a-bN0, and T1-4N1a-2a) who were ran- domly assigned to receive intravenous (IV) high-dose Initial assessment interferon-α2b for 5 days every week for 4 weeks or ob- In all patients with stage lll melanoma, a diagnostic workup servation, produced equivalent 5-year RFS rates between should be performed and reviewed by a multidisciplinary groups. Moreover, 4 weeks of IV interferon-α2b resulted team for patient and tumor characteristics. Complete in higher rates of treatment-related grade 3 and higher tumor staging information should be assessed, including toxicities (57.9% vs. 4.6%; P < .001) and worsened quality pathological features of the primary tumor and any in- of life [26]. These studies are complicated by a lack of a volved lymph nodes, as well as BRAF mutation testing. In standardized definition of ‘high risk for relapse’, 23 dif- addition, whole-body imaging (see Table 1)and perform- ferent interferon-α2b dosages/formulations/schedules ance status assessment should be completed prior to mak- were evaluated, and in some cases, the inclusion of other ing treatment decisions. Nodal status should be determined drugs in combination. Thus, the efficacy of interferon in based on physical examination and sentinel lymph node bi- sentinel node negative stage II melanoma patients re- opsy (SNB) with or without subsequent completion lymph- mains unresolved. To date, there are no data with ipili- adenectomy if SNB is positive. The consensus panel mumab, nivolumab, pembrolizumab, or BRAF-targeted identified five potential immunotherapy agents with poten- therapy (either single-agent BRAF inhibitors or com- tial clinical benefit in the adjuvant therapy of patients with bined BRAF/MEK inhibitor therapy) to justify the use of stage III melanoma: interferon-α2b, pegylated these agents/regimens in patients with stage II melan- interferon-α2b, ipilimumab, pembrolizumab, and nivolu- oma. However, data from planned clinical trials may pro- mab [6, 28–31]. Furthermore, the consensus panel noted vide additional information to guide the use of the that the combination of the BRAF and MEK inhibitors, anti-PD1 agent pembrolizumab in this setting. dabrafenib and trametinib, respectively, was recently shown to be superior to placebo in patients with stage III melan- Immunotherapy for stage III melanoma oma with BRAF V600E/K mutations; these data provide Stage III comprises a heterogeneous group of patients the first evidence for significant RFS and OS benefit of a with 5-year survival rates ranging from 30 to 80% [15]. targeted antitumor therapy that does not fit the putative While the previous consensus statement considered stage immunotherapy approach and can be considered for pa- III patients as a single group, the Task Force strongly tients with tumors harboring BRAF mutations [32]. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 6 of 23 Fig. 2 Stage III N1a (7th)/Stage IIIA (8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III patients should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone, which is anticipated to become more common. (2) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma independent of the volume of lymph node involvement or the number of lymph nodes involved. (3) Level A data supporting the use of nivolumab over ipilimumab was demonstrated in patients with Stage IIIB to IV resected melanoma and did not include patients with Stage IIIA (based on 7th) disease. Ipilimumab 10 mg/kg dosing was supported by a minority of panelists (10%), however, subset analysis suggests that the risk: benefit ratio for patients with Stage IIIA melanoma does not support its use in Stage IIIA patients at this time. (4) There are level A data that 1 year interferon-α2b is associated with improvement in RFS and, while this therapy was generally recommended by the consensus panel previously, only two panelists recommended considering this therapy. There are level B data to support a benefit in RFS for pegylated-interferon-α2b in patients with N1a disease and in patients with ulceration of the primary tumor site; however, no panelists considered this a reasonable option for these patients. Abbreviations: LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; RFS, recurrence-free survival Consensus management of microscopic single node disease There is one prospective randomized clinical trial dem- (stage N1a – AJCC 7th; stage IIIA – AJCC 8th) onstrating a benefit in RFS for patients with microscopic The majority of the panel (70%) recognized that nodal disease treated with pegylated interferon-α2b [6]. A patients with microscopically involved lymph nodes post-hoc analysis of that trial also suggested patients with (N1a disease) represents a different population from ulcerated primary tumors might derive more clinical those with macroscopic nodal disease (N1b and N2– benefit from pegylated interferon-α2b [33]. In this ana- N3 disease) and agreed that the AJCC 8th edition lysis, patients with ulceration of their primary melanoma takes this into account by redefining Stage IIIA as be- (n = 849) were compared to patients without ulceration of ing associated with a lower risk than in the AJCC 7th their primary melanoma (n = 1336), and patients with ul- edition. However, whereas the majority (52%) of the ceration demonstrated a significant improvement in RFS former panel in 2014 recommended a standard 1-year (P = 0.02), distant metastasis-free survival (P <0.001) and course of interferon-α2b for adjuvant therapy of pa- OS (P < 0.001). The analysis also found that the greatest tients with microscopic nodal disease, only a small reduction in risk was seen in patients with ulcerated pri- number recommended this therapy in this update. Ra- mary melanomas who were classified as stage IIb–IIIN1, ther, the majority of the panel (58%) recommended a demonstrating a HR of 0.58 for OS benefit (P < 0.0001) clinical trial, 10% recommended observation, 5% ipili- [34]. Thus, patients with ulcerated primary tumors and mumab (10 mg/kg), and 10% adjuvant interferon-α2b, those with microscopic nodal disease could consider pegy- if a clinical trial was not available. No panelists recom- lated interferon-α2b based on this Level B data, although mend pegylated interferon-α2b or ipilimumab given at further evaluation of this regimen is ongoing in an 3 mg/kg (see Fig. 2). EORTC trial. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 7 of 23 Table 1 Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma Clinical Issue Current Consensus Recommendations Biomarker Status � The panel recognized the importance of identifying predictive biomarkers to aid in clinical decision-making � At present there are no validated biomarkers that reliably predict response to individual therapeutic agents � There is considerable interest in PD-L1 expression, mutation burden, lymphocyte infiltration, interferon-γ and related cytokine gene signatures as potential biomarkers � There are data suggesting higher response rates to monotherapy, but not combination therapy, with T cell checkpoint inhibitors when PD-L1 expression is increased but the panel does not recommend PD-L1 status be used outside of clinical trials Laboratory Assessment � Immunotherapy is associated with significant irAEs that require laboratory monitoring before and during active treatment � Clinicians should be alert for irAEs during therapy and for several months after stopping treatment � All panelists agreed that baseline and routine labs should include complete blood count, liver enzymes, metabolic panel, serum LDH and thyroid function studies (free T4, TSH) � Additional hormone levels should be assessed in patient with suspected treatment-related hypophysitis (free T4, TSH, ACTH, morning cortisol, cosyntropin stimulation test, LH, FSH, testosterone, prolactin) and early endocrinology referral � The frequency of laboratory testing was more controversial with most panelists recommending testing prior to each infusion for most drugs and less frequent surveillance during follow-up Imaging Guidelines � Confirming disease response/progression may be challenging with immunotherapy due to the delayed kinetics of response and induction of local inflammation � The panel (100%) recommends whole body imaging for melanoma patients treated with immunotherapy prior to starting and at regular intervals no more than 12 weeks apart while disease persists � A majority of the panel recommends imaging with CT scans of the chest, abdomen and pelvis and MRI of the brain � A minority recommend initial imaging with PET scans � Imaging should continue after complete responses at regular intervals for five years to identify recurrence Treatment Cessation � Since the kinetics of response to immunotherapy may be delayed decisions to stop treatment can be challenging � The panel recommended stopping treatment for any unresolved or recurrent high grade adverse event or when disease progression is confirmed by two independent imaging scans or clinical deterioration � Pseudo-progression has been reported for checkpoint inhibitors and T-VEC but is rare for interferon and IL-2; most panelists suggested that treatment with interferon or IL-2 should be stopped with any sign of disease progression � Repeat imaging within 1–2 months was recommended to confirm response or progression when pseudo-progression is suspected � Minority opinions included considering surgical resection for incomplete responses and tumor biopsy for equivocal cases Abbreviations: ACTH adrenocorticotropic hormone, CT computed tomography, FSH follicle stimulating hormone, LH luteinizing hormone, MRI magnetic resonance imaging, PD-L1 programmed cell death 1 ligand, PET positron emission tomography, TSH thyroid stimulating hormone Ipilimumab has been studied in patients with stage III with stage IIIA disease, despite being required to have melanoma in a prospective clinical trial (EORTC 18071), one or more nodal metastases at least 1 mm in size, had which randomized 951 patients to either placebo or ipili- no evidence of benefit (HR 0.98, 95% CI: 0.46–2.09) mumab, given at 10 mg/kg induction (4 doses every [30]. Thus, there was hesitation in considering adjuvant 3 weeks) followed by maintenance (every 12 weeks for ipilimumab for patients with lower risk, stage III disease up to 3 years) [30]. With a median follow up of over in light of known toxicity, although adjuvant ipilimumab 5 years, ipilimumab was associated with improved RFS was recommended by a minority of the panel (10%). compared to patients treated with placebo (median 27.6 In an older trial, which included patients with com- vs. 17.1 months, HR 0.76, 95% CI: 0.64–0.89; P = 0.0008) pletely resected stage IV or high-risk stage III melanoma, and OS (5-year 65% vs. 54%, HR 0.72, 95% CI: 0.58– adjuvant granulocyte-macrophage colony stimulating fac- 0.88; P = 0.001). However, in subgroup analysis, patients tor (GM-CSF) did not demonstrate improvements in RFS Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 8 of 23 or OS in a randomized, placebo-controlled phase 3 study < 1 mm metastatic nodal deposit. With a median follow [35]. GM-CSF, an immunomodulatory agent with pleio- up of 2.8 years, D/T was associated with improved RFS tropic and sometimes opposing effects on antitumor im- (HR 0.47; 95% CI: 0.39–0.58, P < 0.001) and OS (HR munity, remains investigational for any stage of 0.57; 95% CI: 0.42–0.79, P < 0.001) compared to placebo. melanoma, although its incorporation into an oncolytic Moreover, there were no additional safety concerns that virotherapy for intratumoral administration is approved arose with D/T that had not previously been seen in pa- for advanced melanoma, and its role in combination im- tients with unresectable or stage IV melanoma [32]. munotherapy appears promising [12, 36]. While this combination is not considered immunother- Although immunomodulatory therapy is the only apy, inhibitors of BRAF and associated pathways in the intervention that had ever shown promise in the adju- tumor cell have been shown to have immunomodulatory vant therapy of melanoma, there is now evidence that properties that contribute to their activity. For these pa- molecularly-targeted therapies can benefit patients with tients, the choice between molecularly targeted and im- resected high-risk melanoma whose tumor cells carry an mune checkpoint-based adjuvant therapy remains activating BRAF mutation. A trial of dabrafenib and tra- unclear, as direct comparisons have not yet been made. metinib given at standard doses (CombiAD), random- However, benefit was seen across all AJCC 7th (and by ized 870 patients (1:1) to either the combination of extrapolation 8th) edition stage III subgroups, and this dabrafenib and trametinib (D/T) or placebo for 1 year. combination can be considered for any patient with V600E/K This trial excluded patients with stage IIIA (N1) with a stage III, BRAF -mutant melanoma. Fig. 3 Stage III N1b-3 (AJCC 7th)/Stage IIIB-D (AJCC 8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III subsets should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone. (2) After evaluation by multi-disciplinary team with surgical oncology, if complete resection is possible patients should undergo resection followed by adjuvant therapy listed. If the tumor is considered unresectable, a different treatment paradigm should be followed. (3) In patients with Stage IIIB-IV resected melanoma, there is Level A evidence supporting the use of nivolumab over ipilimumab and pembrolizumab over placebo for stage IIIB-C and IIA patients with micrometastases > 1 mm. Accordingly, nivolumab or pembrolizumab were supported by 46% of the panel. (4) Ipilimumab at 3 mg/kg was supported by a minority of panelists (8.3%). (5) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma. (6) While there are Level A data that 1 year interferon-α2b is associated with improvement in RFS, no panelists recommended considering this therapy for this patient population. (7) Overall, the majority of panelists recommended a clinical trial, if available. (8) The majority of the panelists have had experience with T-VEC, and half of respondents said they would recommend T-VEC for first-line treatment for limited disease burden, and a significant minority (39%) would consider T-VEC for patients with locoregional disease. (9) Unresectable disease could be managed by options available for stage IV patients (see Fig. 4). Abbreviations: CR, complete response; LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; PD, progressive disease; RFS, recurrence-free survival, TVEC, talimogene laherparepvec Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 9 of 23 Consensus management of macroscopic nodal disease recurrence-free survival compared to placebo in the (stage N1b/c, N2b/c, N3b/c in 7th edition or stage IIIB-IIID in intention-to-treat population (75.4% [95% CI: 71.3–78.9] vs. 8th edition) 61.0% [95% CI: 56.5–65.1]; HR for recurrence or death, Patients with macroscopic involvement of a single or 0.57 [98.4% CI: 0.43–0.74; p <0.001]). In a cohort of 853 multiple lymph nodes (stage N1b and N2b–N3 disease patients with PD-L1-positive tumors, the 1-year rate of per AJCC 7th Edition; or Stages IIIB-IIID in AJCC 8th recurrence-free survival was 77.1% in the pembrolizumab Edition) are at significant risk for melanoma recurrence. treated group compared to 62.6% in the placebo group (HR The panel recommendations for these melanoma pa- 0.54; 95% CI: 0.42–0.69). Grade 3 or greater adverse events tients are detailed in Fig. 3. Whereas the majority of the were observed in 14.7% of patients treated with pembroli- panel in 2014 recommended that these patients consider zumab - with one treatment-related death attributed to 1 year of interferon-α2b treatment (73%) [4], in the myositis - versus 3.4% in patients treated with placebo. current setting, the majority of panelists recommended In light of these newer data, patients with resected stage either a clinical trial (56%), or if a trial is not available IIIB, IIIC, and IV melanoma could consider several options, then adjuvant nivolumab based on the results of the andthe panelconsideredanti-PD-1 antibodytherapy with CheckMate 238 trial, or adjuvant pembrolizumab based either nivolumab or pembrolizumab (46%), ipilimumab at on the results of the recent phase III clinical trial (46% 3 mg/kg (8%), D/T in BRAF mutant patients (13%), or of panelists) [31, 32, 37]. A minority of panelists would high-dose interferon (4%) as acceptable recommendations. consider adjuvant ipilimumab (8%) based on the results Almost one third of the panel members (29%) were unable of the EORTC 18071 trial [33]. For patients whose to make a specific recommendation. These members sug- tumor harbors a BRAF V600E/K mutation, combination gested using either anti-PD-1 therapy or D/T, while others dabrafenib/trametinib may be preferred over immuno- preferred the use of D/T if the tumor was BRAF mutant or therapy since the impact of adjuvant checkpoint inhibi- enrollment onto a clinical trial incorporating ipilimumab at tors on the management of subsequent disease 3 mg/kg. The recommendation to use low dose ipilimumab progression is not known. Of note, no panelists recom- is supported by data from the phase III U.S. Intergroup mend pegylated interferon-α2b for patients with resected E1609 study in which patients with resected high-risk mel- macroscopic nodal disease, and only one panelist consid- anoma were treated with interferon-α, ipilimumab at ered high-dose interferon-α2b as an option if a clinical 10 mg/kg or ipilimumab at 3 mg/kg; while there was no ob- trial was not available. vious difference in recurrence-free survival between the CheckMate 238 is a phase 3 trial that randomized 906 two ipilimumab cohorts (although no formal statistical patients with resected stage IIIB-IV melanoma to either comparison was performed), there was a significant in- 1 year of nivolumab (3 mg/kg every 2 weeks) or ipilimu- crease in toxicity reported for the 10 mg/kg cohort com- mab (10 mg/kg every 3 weeks for 4 doses, followed by pared with 3 mg/kg [38]. No panelists endorsed every 12 weeks). With minimum follow-up of 18 months, observation as a clinical option. the trial met its primary endpoint showing that nivolu- mab was associated with an improved RFS compared Consensus management of unresectable stage III/IV with ipilimumab (RFS at 12 months 70.5% vs. 60.8% for melanoma with injectable lesions nivolumab and ipilimumab, respectively; HR 0.65; CI: In patients with unresectable stage III disease, the use of 0.51–0.83; P < 0.001). Furthermore, the rate of T-VEC, an oncolytic herpes virus engineered to express treatment-related grade 3–4 toxicity was 14.4% with GM-CSF, was felt to be appropriate by a significant mi- nivolumab vs. 42.6% in patients treated with ipilimumab nority of panelists (39%). This recommendation was [31]. OS data were immature and not reported. The data based on results from a prospective, randomized trial in from this trial led to the FDA-approval of nivolumab in which 436 patients with unresectable stage IIIB-IV mel- patients with resected Stage III melanoma. anoma were randomized in a 2:1 fashion to treatment More recently, a prospective, double-blind phase III clin- with T-VEC or recombinant GM-CSF [12]. The primary ical trial was conducted in patients with resected, high-risk endpoint of the study was durable response rate (DRR), stage III melanoma. In this study patients were eligble if which was significantly better for T-VEC treated patients they had stage IIIB or IIIC, while a subset of patients with compared to control subjects (16.3% vs. 2.1%, odds ratio stage IIIA were also included if they had at least one micro- [OR] 8.9; P < 0.001). T-VEC was also associated with im- metastasis measuring > 1 mm. The trial randomly assigned proved objective response rate (ORR 26.4% vs. 5.7%) and 514 patients to treatment with 200 mg of pembrolizumab OS (median OS 23.3 months for T-VEC vs. 18.9 months and 505 patients to placebo every 3 weeks for 1 year [37]. for control, HR 0.79, P = 0.051). On a pre-specified sub- In this study, patients were stratified by cancer stage and set analysis, however, a particularly strong effect was geographic location. At a median follow-up of 15 months, seen in patients with stage IIIB-IVM1a disease, where pembrolizumab was associated with significantly longer the DRR was 33% vs. 0% in stage III patients and 16% Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 10 of 23 vs. 2% for stage IVM1a patients. A similar effect on OS The panel considered the overall approach to the was seen in the stage III-IVM1a patients with a 43% im- patient with stage IV melanoma and, while previous provement in survival for patients treated with T-VEC recommendations suggested that BRAF mutation sta- [12]. Thus, there is Level A data supporting T-VEC in tusand performancestatusbe consideredascritical these patients, and T-VEC may be more appropriate for elements in the decision-making process, all Task patients with limited visceral disease. Other options for Force participants agreed that immunotherapy should this patient population would be enrollment onto a clin- be considered prior to targeted therapy in patients ical trial or treatment as stage IV melanoma (see Fig. 4). with good performance status, based on the potential Of particular interest are the multiple emerging trials of for durable responses with immunotherapy. There is neo-adjuvant/pre-operative therapy for patients with little data available to support optimal sequencing of melanoma of borderline resectability, who may be better targeted therapy and immunotherapy in this setting. served by initial cytoreduction and possibly a scenario, if However, two retrospective studies have suggested en- significant response is seen, where the patient may not hanced clinical benefit from immunotherapy adminis- require resection. tered prior to BRAF-targeted therapy in those patients who required both (those who did not Immunotherapy for stage IV melanoma achieve durable or curative responses to the first line Initial assessment of therapy) [40, 49]. A data series of 274 patients In patients with stage lV melanoma, a diagnostic workup with BRAF-mutated melanoma who sequentially re- that includes a multidisciplinary team review of clinical and ceived BRAF inhibitors and immunotherapy (high-- tumor data should be conducted. Staging should be con- dose IL-2, ipilimumab, or PD-1 inhibitors) illustrated firmed via pathological evaluation, whole body imaging, that ipilimumab therapy after BRAF inhibitors was as- and serum LDH analysis. Genetic mutation analysis of the sociated with no tumor response and poor survival tumor should also be performed with special emphasis on [50]. In another study of 93 patients with identifying mutations in BRAF. In addition, careful atten- BRAF-mutated melanoma who received BRAF inhibi- tion should be paid to central nervous system (CNS) assess- tors (vemurafenib or dabrafenib) before or after ipili- ment since melanoma patients are at high risk of CNS mumab, longer OS was found in the cohort of metastasis. Thus, in addition to computed tomography patients receiving ipilimumab prior to BRAF inhibitor (CT) imaging of the chest, abdomen and pelvis, an MRI of therapy (14.5 vs. 9.9 months, P = 0.04) [49]. In both the brain should be obtained to fully stage potential meta- studies, theresponserates to BRAF-targetedtherapy static melanoma patients. Surgical evaluation by a was similar regardless of prior immunotherapy. Thus, multi-disciplinary team that includes an experienced surgi- starting with immunotherapymay providepatients cal oncologist for possible metastectomy is important, espe- with an opportunity for long-term benefit without cially in patients with solitary pulmonary metastasis where negatively affecting the activity of BRAF inhibitor complete extirpation is possible. If complete resection of all therapy. In order to determine optimal sequencing, metastatic disease is likely, metastasectomy can be consid- theECOG-ACRIN-ledintergrouprandomizedproto- ered based on Level B retrospective outcome studies, but col EA6134 (NCT02224781) has been initiated to the panel agreed that this operative management is less compare the sequential administration of ipilimumab/ compelling as systemic therapy improves [39–41]. Patients nivolumab and dabrafenib/trametinib. OS at the who achieve partial response (PR) or stable disease (SD) fol- 2-year landmark, the primary endpoint of this ran- lowing immunotherapy should also be reassessed for pos- domizedphase 3trial, isexpectedtobereportedin sible resection [42, 43]. The panel recognizes several 2019 or 2020. systemic treatment options for patients with unresectable In this edition of the guidelines, the panel suggested stage IV melanoma, including immunotherapy with that key elements to consider for individual patients high-dose IL-2 (where available), ipilimumab, nivolumab, should include clinical performance status, tumor bur- pembrolizumab, T-VEC (if accessible lesions are present), den, and presence of visceral metastases (compared to combination ipilimumab and nivolumab, clinical trial par- M1a patients with cutaneous, soft tissue or nodal only ticipation, and cytotoxic chemotherapy [7–12]. Addition- metastatic disease), and the tempo of disease progres- ally, vemurafenib, dabrafenib, trametinib, and the sion. While there is limited evidence, where available, combinations of either dabrafenib and trametinib or most immunotherapy agents do appear to be effective vemurafenib and cobimetinib are options for patients with against CNS metastases from melanoma [51–53]. Data BRAF-mutated tumors [44–48]. An additional combination recently reported from two studies also show evidence regimen of potent BRAF and MEK inhibitors (encorafenib that combination nivolumab/ipilimumab has clinical ac- and binimetinib) is anticipated to receive regulatory ap- tivity in patients with asymptomatic brain metastases proval in the future. [53, 54]. In 75 patients with > 1 measurable brain Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 11 of 23 Fig. 4 (See legend on next page.) Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 12 of 23 (See figure on previous page.) Fig. 4 Stage IV melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. The panel recommended all patients be evaluated with full body imaging, histopathology review, serum LDH, and tumor mutation analysis with emphasis on BRAF mutations. Other factors to be considered in selecting appropriate treatment should include performance status, burden and tempo of disease and presence of CNS metastases. (1) All patients should be evaluated for resection by a multi-disciplinary team including surgical oncology before and after immunotherapy treatment, although the role of surgery is changing and may be appropriate for patients with solitary pulmonary lesions where complete extirpation is possible; each case must be individualized. (2) All patients should have an MRI of the brain prior to treatment to rule out or manage CNS metastasis. (3) There was level B data for a clinical benefit with surgical resection when complete excision of all disease is possible although first-line surgical resection was a minority opinion of the panel. (4) As determined by an experienced surgical oncologist, patient is eligible to receive surgical intervention as first-line treatment. (5) Immunotherapy was recommended for any patient with a good performance status regardless of BRAF mutation status and provided that any CNS disease was treated and controlled. Clinical trial was the favored first line approach by the panel. 6) In the absence of an appropriate clinical trial, the panel recommended combination ipilimumab and nivolumab based on the high response rates reported. This may also be preferred for patients with CNS disease with a minority of panelists (33.3%) recommending stereotactic radiation prior to systemic therapy for CNS lesions (7) Next, the panel recommended single agent anti-PD-1 therapy (pembrolizumab or nivolumab). The panel considered these agents to have the same therapeutic efficacy and treatment selection could be based on physician experience and patient preference. (8) The panel also recommended T-VEC in patients with accessible tumor for injection and limited visceral tumor burden. This option may be especially appropriate for elderly patients and those not eligible for checkpoint inhibitors. (9) Patients with poor performance status were not considered good candidates for combination immunotherapy and BRAF mutation was an important factor for determining therapeutic planning. Most panelists considered clinical trials to be the most important option in these patients, if available. In those patients without a BRAF mutation, the next option should be single agent anti-PD-1 therapy (pembrolizumab or nivolumab). (10) In patients with poor performance status and a BRAF mutation who are not eligible or whose tumors progress after a clinical trial, treatment with a BRAF and/or MEK inhibitor therapy is indicated. This option was also considered appropriate for patients with uncontrolled CNS disease. Single agent anti-PD-1 treatment could be considered if disease progression occurs after targeted therapy. (11) In patients with disease progression following the recommendations, management should be carefully considered. If patients can tolerate treatment, ipilimumab/ nivolumab should be considered. If patients have a BRAF mutation and have not been treated with BRAF/MEK inhibitors previously these can be considered. Ipilimimab monotherapy and high-dose IL-2 can also be considered in these patients. (12) Patients should have a good PS and otherwise qualify for IL-2 administration per local institutional guidelines. (13) Dacarbazine is the only approved chemotherapy agent but temozolomide and carboplatin/paclitaxel are often used as well depending on patient preference and physician experience. Abbreviations: BRAF+, positive for actionable BRAF mutations; BRAF–, negative for actionable BRAF mutations; CNS, central nervous system; IL, interleukin; LDH, lactate dehydrogenase; PS, performance status metastasis who received combination ipilimumab/nivo- PD-L1 expression status (15%) or tumor cell mutation lumab, the intracranial response rate (IRR) was 56% burden (10%) was important for treatment planning. For (95% CI: 44–68); in addition, 19% of patients had a a typical patient with a good performance status, regard- complete response (CR) [54]. Moreover, in 50 patients less of BRAF status, a majority of the panel members with untreated brain metastases, both nivolumab mono- recommended enrollment onto a clinical trial (75%) as a therapy (ICR 20% [95% CI: 7–41]) and combination ipili- first-line option, followed by treatment with combination mumab/nivolumab (ICR 44% [95% CI: 24–65]) were ipilimumab and nivolumab, which was favored over found to be active [55]. Based on the discussion, recom- single-agent PD-1 inhibitor therapy (pembrolizumab or mendations for the management of stage IV melanoma nivolumab) by three of the five members who did not were considered independently for patients with a good favor clinical trial. This ratio of support for combined performance status, generally low disease burden and ipilimumab and nivolumab versus single-agent slow tempo of disease progression versus patients with a anti-PD-1 therapy held up by the panel when a clinical declining performance status, widespread visceral metas- trial was not an option (12 of 20 respondents). Half of tases and/or rapid disease progression (Fig. 4). Extent of the panelists felt that the selection of the combination of CNS involvement, mass effect, cerebral edema and ster- ipilimumab and nivolumab should mandate transfer of oid requirements and symptoms will also factor into the patient to a physician or center with more immuno- treatment decisions. therapy experience due to the higher toxicity incidence and complexity associated with combination immuno- Consensus management of stage IV melanoma patients therapy. Panel members (83%) also suggested that with a good clinical performance status T-VEC be considered if accessible lesions for injection The treatment approach for patients with good perform- are present in patients whose disease has progressed ance status stage IV melanoma who are not surgical can- after combination or monotherapy checkpoint inhibitors didates should include an assessment of BRAF mutation and who still maintain a good performance status. status, history and physical examination, serum LDH, Participation in clinical trials is dependent on having ac- baseline laboratory evaluation and whole body imaging cess to appropriate studies and ensuring that patients meet (see Table 1), and assessment of tempo of disease, tumor protocol-specific eligibility requirements. In addition, pa- burden, and presence or absence of CNS disease before tients must be willing to participate in a clinical trial and treatment selection. Only a minority of panelists felt that provide written, informed consent. The high priority placed Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 13 of 23 on clinical trials is a reflection of the progress being made ipilimumab alone [HR 0.42, P < 0.001] and 6.9 months in clinical drug development in melanoma and interest in for nivolumab alone [HR 0.57, P < 0.001]). In this study, defining more effective regimens with acceptable toxicity. If patients whose tumors exhibited > 5% PD-L1 expression such clinical trials are not readily available or patients are had a median PFS of 14 months in both combination not willing or do not qualify for participation, combination and nivolumab alone arms; however, in patients with ipilimumab and nivolumab was considered the treatment PD-L1 negative tumors, the median PFS was 11.2 months of choice for patients with good performance status. This for combination treated subjects compared to 5.3 months recommendation was based on a series of prospective clin- in patients treated with nivolumab alone. TRAEs of ical trials demonstrating improved response rates with the grade 3 or greater were reported in 55% of the combin- combination, although increased incidence of ation treated patients, 16.3% in those receiving nivolu- immune-related adverse events (irAEs) was also re- mab alone and 27.3% in the ipilimumab alone cohort. At ported. In a phase 1 study, 53 melanoma patients were a minimum follow-up of 37 months, the median OS has treated with concurrent nivolumab (doses ranged from not been reached for patients on the combination arm 0.3–10 mg/kg) and ipilimumab (dose ranged from 1 to compared to 37.6 months and 19.9 months in patients 10 mg/kg) IV every 3 weeks for four doses followed by receiving nivolumab or ipilimumab alone, respectively nivolumab alone every 3 weeks for another four doses [58]. The three-year OS was 58% for combination ther- [56]. The ORR was 40% based on World Health apy patients compared to 52% in nivolumab alone (HR Organization (WHO) criteria with a disease control 0.85, 95% CI: 0.68–1.07; non-significant P-value) and rate of 65% [56]. Treatment-related adverse events 34% in patients treated with ipilimumab alone (HR for (TRAEs) were seen in 93% of patients with grade 3 or ipilimumab/nivolumab vs. ipilimumab 0.55, 95% CI: greater events from all causes observed in 72%; 53% 0.45–0.69; P < 0.0001; HR for nivolumab vs. ipilimumab were considered treatment-related. The authors con- 0.65, 95% CI: 0.53–0.80; P < 0.0001) [58]. cluded that the maximum doses with an acceptable The above described studies collectively provide Level A safety profile were nivolumab at 1 mg/kg and ipilimu- evidence supporting the role of combination ipilimumab mab at 3 mg/kg, with objective responses seen in 53% and nivolumab for first-line treatment in patients with mel- of patients treated with this dosing regimen [56]. anoma. However, the lack of a significant OS benefit for the Following the phase 1 data, a double-blind study was combination over nivolumab alone, particularly in patients conducted in 142 treatment-naïve, metastatic melanoma with BRAF WT or PD-L1-expressing tumors [58], suggests patients and enrolled in a 2:1 manner to treatment with it is reasonable to consider anti-PD-1 agents alone at this ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) or ipili- time. In CheckMate 067, a sub-group analysis showed sig- mumab (3 mg/kg) and placebo every 3 weeks for four nificant improvement in PFS and numerical improvement doses [57]. Patients in the combination group were able in OS with combination therapy only in patients with low to receive additional maintenance nivolumab and at a (< 5 and < 1%) PD-L1 staining; however, the panel did not median follow-up of 24.5 months, 2-year OS was 63.8% consider there to be sufficient data to support a role for for those in the combination treatment arm vs. 53.6% in PD-L1 expression in clinical decision-making at this time the ipilimumab arm [57]. Of note, patients in the ipili- [56–58]. While adverse events are significantly greater with mumab arm were permitted to cross over to nivolumab combination ipilimumab/nivolumab treatment compared monotherapy at time of disease progression, making this to monotherapy, there is some evidence that health-related trial a study of combination ipilimumab and nivolumab quality of life may not be significantly impacted by concur- vs. sequential ipilimumab followed by nivolumab. Inter- rent combination treatment [59] due to a greater time with- estingly, there was a 22% CR rate and improvement in out disease related symptoms or treatment toxicity (as progression-free survival (PFS) for the combination al- measure by QTWIST) [60]. though median OS was not reached in either treatment The panel went on to recommend monotherapy with group. Similar to other trials, the grade 3 or greater anti-PD-1 agents as another option for patients who are TRAE rate was 54% in the combination cohort com- not able to participate in a clinical trial or are not eli- pared to 20% in the ipilimumab alone cohort. gible for combination ipilimumab/nivolumab. There are These data led to a randomized phase 3 trial in which two agents available, pembrolizumab, which is adminis- 945 treatment-naïve patients with unresectable stage III tered at 200 mg IV every 3 weeks, and nivolumab ad- or IV melanoma were randomized in a 1:1:1 ratio to ministered at 240 mg IV every 2 weeks or 480 mg IV treatment with ipilimumab and nivolumab, nivolumab every 4 weeks (per a recent change to non-weight-based alone or ipilimumab alone [11]. The study was designed dosing). The panel considered these drugs equally effect- with two primary endpoints, PFS and OS, with a signifi- ive, with indistinguishable toxicities, and advised that se- cant improvement seen in PFS (11.5 months for the lection can be based on physician experience or patient combination treated patients vs. 2.9 months for preference. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 14 of 23 Pembrolizumab and nivolumab are monoclonal anti- study in which 655 melanoma patients were treated with bodies that block the PD-1 T cell checkpoint, and there pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every are considerable data supporting their use in the treat- 3 weeks, or 2 mg/kg every 3 weeks until disease progres- ment of metastatic melanoma. In a clinical dose-finding sion, intolerable toxicity, or investigator decision to stop study, patients with advanced melanoma were treated treatment [63]. In this study, investigators evaluated the with pembrolizumab (initially called lambrolizumab) at a impact of pembrolizumab based on prior exposure to dose of 10 mg/kg every two or three weeks or 2 mg/kg ipilimumab. To address this, 135 patients (48 with prior every 3 weeks [9]. Patients were allowed, but not re- ipilimumab and 87 without) were enrolled without quired, to have had prior ipilimumab therapy to be eli- randomization and 520 patients were prospectively ran- gible for study participation. The study enrolled 135 domized (294 with prior ipilimumab and 226 without). patients and the response rate assessed by standard Re- Response rates were reported at a median follow-up of sponse Evaluation Criteria in Solid Tumors (RECIST) 21 months; response rates were 33% in patients with 1.1 criteria was 38% without significant differences be- prior ipilimumab exposure and 45% in treatment-naïve tween doses or by prior ipilimumab exposure. The re- patients. The 12-month PFS was 35% overall and 52% in sponses were durable with 81% of patients still in treatment-naïve patients, and the median OS was response at a median follow-up of 11 months. The most 23 months overall and 31 months in treatment-naïve frequent adverse events were fatigue, rash, pruritus and subjects. Overall, 14% of patients reported at least one diarrhea, and these were generally grade 2 or less [9]. grade 3 or greater TRAE. These results confirmed re- Pembrolizumab was also evaluated in a separate sponse rates seen in the phase 1 trials and also sup- multi-institutional phase 1 study evaluating doses of ported the 2 mg/kg dosing schedule. 2 mg/kg and 10 mg/kg every 3 weeks in patients with These initial studies were followed by a randomized ipilimumab-refractory advanced melanoma [61]. In this phase 3 clinical trial in which 834 patients with ad- study, 173 patients received 2 mg/kg (n = 89) or 10 mg/ vanced melanoma were randomized 1:1:1 to pembrolizu- kg (n = 84) pembrolizumab and data were reported at a mab (10 mg/kg) every 2 weeks or every 3 weeks or four median follow-up of 8 months. The response rate by doses of ipilimumab (3 mg/kg) every 3 weeks [64]. The RECIST was 26% at both doses. Treatment was consid- study was powered for primary endpoints of PFS and ered tolerable with the most frequent TRAEs being fa- OS. In this study, the estimated 6-month PFS was 47.3% tigue, pruritus, and rash; all were grade 2 or less except for pembrolizumab every 2 weeks, 46.4% for pembroli- for five patients (3%) who reported grade 3 fatigue [61]. zumab every 3 weeks and 26.5% for ipilimumab (HR, These studies led to the regulatory approval of pembroli- 0.58; P < 0.001). The response rate was higher with pem- zumab, at a dose of 2 mg/kg every 3 weeks, for the treat- brolizumab administered every 2 weeks (33.7%) and ment of patients with metastatic melanoma. The every 3 weeks (32.9%), vs. ipilimumab (11.9%) (P < 0.001 approved dose and schedule was subsequently changed for both comparisons) and responses were durable in to 200 mg IV every 3 weeks. 89.4, 96.7, and 87.9% of patients, respectively, after a me- In a multi-institutional phase 2 study, 540 melanoma dian follow-up of 7.9 months. Grade 3 or greater TRAEs patients with disease that had progressed following ipili- were lower in the pembrolizumab cohorts (13.3 and mumab and BRAF/MEK inhibitor therapy, if their tu- 10.1%) compared to ipilimumab alone (19.9%). mors harbored a BRAF (V600) mutation, were The panel was queried about when single-agent randomized 1:1:1 to treatment with pembrolizumab at anti-PD-1, as opposed to combination immunother- 2 mg/kg every 3 weeks (N = 180), 10 mg/kg every apy, was most appropriate. In considering BRAF mu- 3weeks (N = 181) or investigator-choice chemotherapy tation, LDH, PD-L1 expression status and mucosal (N = 179) [62]. Patients were stratified for performance histology, 42% of panelists stated that PD-L1 expres- status, LDH level and BRAF mutation status. The PFS sion was the most important discriminating factor was significantly better for patients in both pembrolizu- supporting single agent anti-PD-1 treatment, despite mab treatment arms compared to chemotherapy (HR lack of level A evidence. One each said mucosal mel- 0.57, P < 0.0001 for 2 mg/kg and HR 0.50, P < 0.0001 for anoma or PD-L1 negative status should prompt com- 10 mg/kg). The 6-month PFS was 34% in patients bination therapy, two stated that single-agent PD-1 treated with pembrolizumab at 2 mg/kg, 38% at 10 mg/ therapy should always be favored, and 10 panelists kg and 16% for chemotherapy. The toxicity profile was felt that a number of other factors should be consid- similar to previous pembrolizumab trials with an inci- ered, including medical co-morbidities (e.g. auto- dence of grade 3–4 adverse events of 11 and 14% in the immune disease, history of organ transplantation, pembrolizumab 2 mg/kg and 10 mg/kg cohorts, com- etc.), disease volume/tumor burden, site of disease, pared to 26% for patients receiving chemotherapy. These performance status, functional status, and patient data were also similar to another global phase 1b clinical preference. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 15 of 23 Pembrolizumab has also been tested in a reported [4, 67]. Treatment generally requires referral to non-randomized phase 2 study in 52 patients with CNS centers with experience in management of high-dose metastases; eighteen patients with melanoma and 34 IL-2 and patients should have a good performance status with non-small cell lung cancer (NSCLC) presented with when starting treatment. untreated brain metastases and were treated with 10 mg/kg every 2 weeks until disease progression [65]. Consensus management of patients with stage IV Eligible patients had metastatic lesions measuring 5– melanoma and poor clinical performance status 20 mm, had no neurologic symptoms, did not require The panel considered that patients with a poor or de- corticosteroids, and for the NSCLC cohort were re- clining performance status, those with extensive disease quired to have positive tumor PD-L1 expression. A pre- burden, rapid tempo of progression, presence of active liminary analysis was reported with evidence of CNS CNS disease and those that have documented disease disease response in 4 of the 18 (22%) patients with mel- progression after T cell checkpoint inhibitors or T-VEC anoma and 6 of 18 (33%) patients with NSCLC. The re- should be treated differently than those with overall sponses appeared to be durable and TRAEs were typical good performance status, limited disease burden, slow of pembrolizumab toxicity in other studies and only 3 tempo of progression and without active CNS metasta- patients (17%) with melanoma had neurologic toxicities, sis. Patients with poor performance status should have including grade 3 cognitive dysfunction and grade 1–2 BRAF mutation analysis to determine if there is a V600 seizures. The authors concluded that pembrolizumab or other targetable mutation, for which targeted therapy was safe in patients with CNS metastasis and might be regimens are available [44–48]. Noting that clinical trial associated with therapeutic responses. participation in patients with poor performance status is Finally, a minority of panel members (46%) who were fa- challenging due to protocol restrictions, the panel miliar with T-VEC recommended T-VEC be considered in applauded efforts by the ASCO-Friends of Cancer Re- patients with good performance status stage IV melanoma search working group, which is taking steps to broaden based on the results of the previously mentioned random- clinical trial eligibility and recommended that, whenever ized phase 3 clinical trial [12]. This requires that tumors feasible, these patients be considered for clinical trial be clinically visible or palpable for injection or be access- participation whether or not their tumor harbors a ible by ultrasound guidance. This option may be especially BRAF mutation (see Fig. 4). In the absence of a BRAF appropriate for patients who are not candidates for T cell mutation, and if clinical trials are not an option, the checkpoint inhibitors, such as patients with significant panel recommended treatment with single agent co-morbid conditions, or older patients unable to tolerate anti-PD-1 therapy, such as pembrolizumab or nivolumab significant systemic toxicity (Fig. 4). based on the Level A data described above. In patients Patients with tumors that do not respond to ipilimumab whose tumor harbors a BRAF mutation and who are not and nivolumab, monotherapy with anti-PD-1 agents, or eligible for clinical trial participation, treatment with T-VEC should be treated according to the guidelines for BRAF/MEK targeted therapy should be considered, and poor performance status patients (see Fig. 4) and treat- readers are referred elsewhere for guidance on adminis- ment selection will depend on BRAF mutation status and tration of these agents [68]. If patients progress on tar- which drug(s) an individual patient has already received. geted therapy or are not eligible for such agents, In general, panel members recommended targeted therapy monotherapy with pembrolizumab or nivolumab is rec- (if BRAF mutation is present), combination immunother- ommended. There is evidence for activity with both apy (if not previously received and performance status is BRAF/MEK inhibitors and anti-PD-1 agents alone or good), ipilimumab monotherapy (if the patient has not with ipilimumab in the treatment of CNS metastasis been previously exposed to the agent), high-dose IL-2, [69]. Combination ipilimumab/nivolumab could also be clinical trial participation, or chemotherapy. considered in selected patients where they have not pre- There is considerable evidence supporting a role for viously received such treatment, the performance status high-dose IL-2 in the treatment of patients with stage IV decline is not related to significant medical melanoma, and the drug has been approved since 1998. co-morbidities and the patients is clinically able to toler- A fairly consistent ORR of 16–17%, including 6–7% ate therapy. While response rates are notably higher CRs, has been reported [7]. Further analysis of the ori- with combination ipilimumab/nivolumab, the incidence ginal 270 patients treated in the regulatory trials at a of serious adverse events is also higher, and the risk/ median follow-up at 7 years demonstrated a median dur- benefit ratio must be considered on an individual basis. ation of response that was unchanged in patients achiev- The majority of the panel (67%) recommended combin- ing an initial CR or PR at 8.9 and 5.9 months, ation ipilimumab/nivolumab for treatment of CNS mel- respectively [66]. The benefits of IL-2 and contemporary anoma, while a minority of the panel (33%) would treat management of IL-2-related toxicity has been previously individual CNS lesions with stereotactic radiation prior Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 16 of 23 to systemic immunotherapy, and this may require con- retrospective trials was performed [73]. Across all stud- sultation/coordination with neurosurgery and/or radi- ies included in the analysis, median OS was 11.4 months ation oncology specialists [65, 70]. As always, disease (range 10.7–12.1 months) and the investigators saw a symptomatology and corticosteroid requirements will in- similar plateau in the survival curve at approximately fluence treatment decisions. 3 years. A 3-year survival rate of 22% was seen in all pa- In patients who have failed the above treatments, re- tients with 26% in treatment-naïve subjects and 20% in gardless of performance status, other therapeutic options previously treated patients. Ipilimumab has also been should include renewed consideration of targeted ther- shown to have activity against CNS metastases in a sin- apy in patients with BRAF mutated tumors if this has gle arm phase 2 clinical trial [74]. A randomized clinical not been previously used. Other options include clinical study in 245 unresectable stage III-IV melanoma pa- trial participation, single agent ipilimumab, high-dose tients evaluated ipilimumab at 10 mg/kg intravenously IL-2, T-VEC, and cytotoxic chemotherapy (Fig. 4). on day 1 and GM-CSF at 250 μg subcutaneously on days Ipilimumab was initially approved for the treatment of 1–14 of each 21-day cycle [36]. In this study, an im- metastatic melanoma based on several clinical trials that provement in overall survival for the combination treat- demonstrated durable responses and improvement in ment was observed (17.5 vs. 12.7 months) and, OS [8, 71]. Further follow-up studies have confirmed the unexpectedly, the incidence of serious grade 3 or greater potential for durable responses and long-term survival adverse events was lower in the combination group providing Level A data supporting a role for ipilimumab compared to ipilimumab alone (44.9% vs. 58.3%). Al- in melanoma [72, 73]. Here we summarize key data from though promising, further validation of this combination ipilimumab trials that support the rationale for its use in in a larger sample size and at ipilimumab doses of 3 mg/ the second-line setting in patients with advanced melan- kg are needed. oma. The first important study was a multi-institutional, Some panel members also recommended T-VEC in double-blind, randomized phase 3 trial in which 676 pa- this setting. There is limited evidence supporting this tients with advanced melanoma expressing human recommendation. In the randomized phase 3 study, a leukocyte antigen (HLA)-A2 were randomized to treat- subset analysis found that durable response was higher ment with ipilimumab (3 mg/kg every 3 weeks for four than control therapy in treatment-naïve patients (24% doses), ipilimumab (same dose and schedule) given with vs. 0%) when compared to those receiving T-VEC as an HLA-A2-restricted modified gp100 peptide vaccine, second-line or later therapy (10 vs. 4%), and a similar or vaccine alone [8]. Overall, patients treated with ipili- trend toward better OS was seen when T-VEC was used mumab demonstrated improved OS compared to pa- in the first-line setting [12]. As mentioned, T-VEC treat- tients receiving vaccine alone (10 months vs. 6 months; ment requires accessible lesions for direct injection. P = 0.0026). This study led to FDA approval for ipilimu- Thus, while IL-2 and T-VEC are good options to con- mab as single agent therapy for melanoma in 2011. An- sider, careful patient selection is required to optimize other prospective, randomized clinical trial was therapeutic benefit. subsequently reported in which 502 patients with treatment-naive melanoma were randomized to ipilimu- Special issues in tumor immunotherapy for melanoma mab at 10 mg/kg every 3 weeks for four doses and The panel recognized that there are several unique is- 2 2 dacarbazine (850 mg/m ) or dacarbazine (850 mg/m ) sues related to clinical management of patients with and placebo [71]. This trial reported improved OS in pa- melanoma opting for immunotherapy. These include is- tients treated with ipilimumab and dacarbazine sues related to the clinical integration of biomarkers, la- (11.2 months vs. 9.1 months; P < 0.001). The study also boratory assessment, and imaging in the management of reported improved 3-year survival of 20.8% for patients before and during treatment. There are also ipilimumab-dacarbazine-treated patients compared to concerns over management of irAEs that are unique to 12.2% for dacarbazine alone (HR 0.72; P < 0.001). An up- immunotherapy treatment and guidelines for when to date of this study population demonstrated 5-year sur- stop therapy given the potential for delayed regression. vival rate of 18.2% in patients in the ipilimumab and While the panel largely acknowledged that there is only dacarbazine cohort compared to 8.8% in the dacarbazine Level C data to inform decision-making with respect to alone arm (P = 0.002) [72]. A plateau in the survival these issues, consensus recommendations were made curve was observed around 3 years and persisted out to and are summarized in Table 1. 5 years. The authors also reported safety and found the only persistent grade 3 or greater irAEs involved the Consensus management of immune-related adverse events skin. In order to better estimate the survival benefit in Immunotherapy is associated with irAEs that manifest as patients treated with ipilimumab, a retrospective, pooled autoimmune-like phenomenon involving lymphocytic analysis of 1861 patients treated in 10 prospective and 2 infiltration and inflammation of various tissues and Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 17 of 23 organ systems. These events may range from vitiligo not assay sensitivity or reliability, the dynamic regulation of requiring intervention to more serious episodes of PD-L1 expression and sampling error [85]. At this time, immune-related colitis, pneumonitis, hepatitis and hypo- PD-L1 expression is not considered valuable in clinical physitis [75]. More recently, there have been rare case management of patients with melanoma by the majority reports of immune-related myocarditis associated with (58%) of the consensus panel. However, some panelists did mortality [76–78]. These events are problematic and consider PD-L1 expression as important in clinical may occur early in the treatment course or weeks to decision-making in special situations, such as in patients even months after stopping therapy, and a high level of with co-morbid medical conditions that might preclude clinical suspicion must be maintained in patients treated combination immunotherapy (25% of panelists), patients with immunotherapy. The panel did not specifically ad- older than 65 years of age (8%), patients less than 65 years dress toxicity management in detail but endorsed of age (4%) or in the presence of BRAF mutation (4%). In current clinical recommendations to educate patients these settings, high PD-L1 expression would support using and caregivers about toxicities, monitor patients care- single agent PD-1 blockade and reserve combination ther- fully for emergence of potential irAEs, rapidly rule out apy for those without PD-L1 expression since these patients other causes and initiate corticosteroid management are less likely to respond to monotherapy [58]. once a high-grade immune-mediated event is identified. Mutation burden in the tumor has also recently been rec- There is currently some controversy as to whether there ognized as a potential predictor of response to immuno- is an association between irAEs and improved thera- therapy with T cell checkpoint inhibitors [86, 87]. Thus, it is peutic responses [79]. The panel, however, felt the data interesting to note that melanoma, NSCLC and other tu- were strong enough to demonstrate prolonged responses mors where these agents have shown clinical activity appear even after treatment was stopped due to toxicity, and to be associated with higher levels of mutations within the with the use of steroids; thus, the panel did not recom- tumor genome [86, 88, 89]. The biologic basis of this find- mend continued treatment through significant toxicity ing may be due to the emergence of neoantigens derived for the purpose of enhancing clinical response. from the mutations resulting in abnormal proteins and In patients who experience grade 2 or greater adverse peptide fragments within the tumor cells allowing recogni- events, treatment may be withheld during acute manage- tion by T cells that might not recognize the native peptide ment and resumed upon resolution, but treatment will [81]. Thus, mutation burden could be an important pre- likely need to be permanently discontinued in the face of a dictor of benefit for treatment with immunotherapy. In its high grade or recurrent immune-mediate adverse event first tissue-agnostic approval based on a biomarker, the [14]. Additional management guidelines are widely antici- FDA recently granted accelerated approval to pembrolizu- pated in the near future and clinicians should monitor the mab for the treatment of patients with unresectable or literature for new guidance in this area. Several groups, in- metastatic mismatch repair deficient (dMMR) or microsat- cluding the SITC Toxicity Management Working Group, ellite instability-high (MSI-H) solid tumors that have pro- have recently published guidelines to address the manage- gressed after prior treatment and have no alternative ment of adverse events from immune checkpoint inhibition treatment options. This approval was based on data from [80–82]. We have previously reported on the management 149 patients across 5 single-arm clinical trials in which of acute IL-2 and interferon-related side effects, including pembrolizumab illustrated an ORR of 39.6%, including 11 interferon-associated depression in the first consensus CRs and 48 PRs [90]. Similar results led to approval of statement on melanoma [4]. nivolumab in this population based on results from the CheckMate 142 clinical trial [91]. Another area of intense Consensus statement on predictive biomarkers for investigation is the association between therapeutic effect- melanoma immunotherapy iveness of immunotherapy regimens and the presence of The panel acknowledged the importance of identifying pre- IFN-γ-related gene signatures within the tumor microenvir- dictive biomarkers to help inform clinical decision-making onment [92]. While the Task Force agreed with the import- in melanoma immunotherapy. Preliminary reports of higher ance of emerging data in this area, there are not sufficient response rates in patients treated with T cell checkpoint in- prospective validation studies to recommend use of these hibitors who have high tumor-infiltrating lymphocytes and parameters for clinical decision-making for patients with PD-L1 expression in the tumor microenvironment sug- melanoma at this time (see Table 1). gested these factors might serve as biomarkers [83]. In fact, PD-L1 expression has been used for patient selection and is Consensus statement on laboratory assessment for associated with improved outcomes with anti-PD-1 therapy melanoma patients on immunotherapy in NSCLC [84]. Nonetheless, PD-L1 expression has not The panel strongly recommended routine baseline and been validated for melanoma patient selection or thera- surveillance laboratory assessments be performed on pa- peutic monitoring, and this may relate to differences in the tients undergoing treatment with tumor immunotherapy. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 18 of 23 While panelists acknowledged a lack of evidence-based brain imaging depending on tumor stage and location, data in this area, serum LDH is considered an important the disease-free period from initial diagnosis and as clin- prognostic marker as it is part of the current AJCC (v7 ically indicated (see Table 1). A minority opinion sug- and v8) staging for melanoma, and toxicity management gested that imaging could be individualized for each is supported by careful laboratory analysis with baseline patient. values for comparison. Clinicians should be alert for signs and symptoms of irAEs, which can present with isolated Consensus statement on clinical endpoints and treatment laboratory abnormalities, such as elevated hepatic en- cessation zymes, serum creatinine, amylase, lipase, glucose and The panel considered the issue of when to stop treat- others. A baseline complete blood count, serum chemistry ment, which is complicated in patients receiving im- panel to evaluate hepatic, renal and electrolyte parameters, munotherapy since “pseudo-progression” has been and a thyroid function panel that includes at least free T4 reported and is thought to be related to delayed re- and thyroid stimulating hormone (TSH) should be ob- sponse kinetics and/or tumor immune infiltration. This tained on all patients. With increasing awareness of the possibility has suggested that additional criteria may be risk of myocarditis, monitoring of creatine kinase and needed to assess response optimally and avoid discon- troponin I or T should also be considered. The panel also tinuing treatment in patients who might experience de- unanimously agreed that these same laboratory assays layed regression; these criteria have been termed should be repeated during therapy but there was no agree- immune-related response criteria (irRC) or iRECIST [93, ment on the frequency of assessment. Some panel mem- 94]. While pseudo-progression has been reported with bers suggested obtaining lab work prior to each infusion, ipilimumab [8] and T-VEC [12], there is some evidence whereas others suggested early monitoring and then limit- that this phenomenon may also occur with anti-PD-1 ing collection to periodic assessment or as clinically indi- agents [95]. In a review of 655 patients treated with cated. Patients who present with signs or symptoms of pembrolizumab, 24 (7%) had atypical responses defined possible hypophysitis should have additional hormone as “early pseudo-progression” in 15 (5%) and “delayed levels monitored prior to starting corticosteroid interven- pseudo-progression” in 9 (3%) by the investigators [95]. tion (see Table 1 for recommended panel). This study also found 14% of patients had progression by RECIST criteria but did not meet the definition for Consensus statement on imaging for melanoma patients on disease progression by the irRC and suggested that clin- immunotherapy ical benefit may be underestimated if standard RECIST The type and frequency of imaging for patients with criteria are used in monitoring clinical endpoints for im- melanoma treated with immunotherapy continues to be munotherapy studies. There are also case reports of controversial and there are no prospective, randomized pseudoprogression of melanoma brain metastases in pa- clinical trials to guide clinical decision-making. Since tients treated with pembrolizumab [96]. tumor regression may be delayed with immunotherapy, The panel generally agreed that new lesions or an in- appropriate imaging becomes increasingly important to crease in tumor burden in patients treated with inter- ensure patients achieve optimal therapeutic benefit. feron or IL-2 is cause for treatment cessation. The Thus, all panel members recommended that whole body assessment of response in patients receiving T cell imaging be performed prior to and at regular intervals checkpoint inhibitors or T-VEC is more challenging. during immunotherapy. The majority of the panel use The majority of the panel recommends that patients computed tomography (CT) scans of the chest, abdo- with disease progression by imaging and who are clinic- men and pelvis and magnetic resonance imaging (MRI) ally asymptomatic without a decline in performance sta- of the brain. Additional imaging may also be necessary tus can be safely continued on treatment and re-imaged in some patients with suspected disease in locations not in 1–2 months to evaluate response. There is limited imaged with these scans, such as the neck or extremities. Level B evidence to support this position. In a retro- A minority of panel members recommended whole body spective study using pooled data of 526 randomized pa- positron emission tomography (PET) or PET–CT scans tients from two phase 3 trials of nivolumab in as the preferred imaging modality. The false-positive rate treatment-naïve melanoma patients, those who received for PET imaging and difficulty providing definitive lesion continued treatment beyond first disease progression (N measurements were reasons cited for preferring CT and = 85) were compared to those patients who immediately MRI imaging by the majority of panel participants. Al- discontinued nivolumab at first signs of disease progres- though the panel recognized the absence of Level A data sion (N = 221). The authors reported that 24 of the 85 to support post-treatment imaging, the consensus rec- (28%) patients treated beyond progression went on to ommendation was that patients should be followed every experience greater than 30% regression after further 3–12 months with whole body CT imaging and selective therapy [97]. The authors concluded that selected Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 19 of 23 patients might derive further clinical benefit from con- CR, which was allowable per protocol [98]. In presented tinued treatment beyond progression. The panel also data at ASCO 2017, Robert and colleagues presented recommended that patients with unacceptable toxicity data from the Keynote 006 (described above) showing or clinical deterioration should be promptly removed that in the 104 patients with SD, PR, or CR who com- from treatment and only if disease progression is docu- pleted 2 years of therapy with a median follow up off mented should they move on to another therapeutic pembrolizumab of 9.7 months, 23 of 24 CRs and 60 of regimen. 64 PRs remained in response, while 8 of 10 patients with In addition, it is critical that clinicians monitoring mel- SD remained with stable disease. anoma patients on immunotherapy be able to confirm Further, a recent pooled retrospective analysis of 2624 clinical responses and stop therapy at an appropriate melanoma patients treated with PD-1 blockade from timepoint. The panel recognized that there is consider- eight multi-center clinical trials submitted to the FDA, able controversy on how best to define when to stop identified 692 of 1361 patients (51%) who had continued therapy and agreed that there may be limited evidence PD-1-directed treatment after documentation of to support continued treatment beyond disease progres- RECIST-defined progressive disease [99]. The authors sion. Because of this uncertainty, the panel considered pooled data from all patients and found 19% of patients confirmation of objective responses to be important for treated beyond progression had a 30% or greater de- optimal clinical decision making, and suggested that pa- crease in tumor burden and this represented 4% of the tients achieving CR, PR or SD, should be re-imaged entire 2624 patient population. The median overall sur- within 2–3 months to confirm response. A minority of vival was also greater in patients treated beyond progres- the panel suggested that patients with incomplete re- sion compared to patients who did not receive sponses, and where all remaining sites of disease can be treatment beyond progression (24.2 vs. 11.2 months). In completely excised, could be considered for surgical this study, the rate of serious adverse events was slightly management or biopsy to confirm existence of viable lower in the patients treated beyond progression com- tumor in these areas and/or identify other potential pared to patients who stopped treatment at progression treatment options (e.g., through mutational burden ana- (43% vs. 54%), and immune-related adverse events were lysis). Finally, the panel was asked about scenarios in similar in incidence in both groups. The authors con- which it would be appropriate to stop therapy in a pa- cluded that treatment beyond progression with tient with SD or better response. Of the panelists anti-PD-1 therapy in might be appropriate in selected responding, 4% would be comfortable stopping therapy melanoma patients but clinical benefit remains to be once a patient achieves a radiographic complete re- proven. sponse, 8% would stop after achieving PET-CT-based complete response, and 29% would stop after completing Conclusions 2 years of therapy. A further 38% would consider any of The approval of six new immunotherapy agents since these endpoints appropriate to prompt treatment dis- 2011 has led to the emergence of cancer immunotherapy continuation. Five panelists had alternative suggestions as the standard of care for patients with high-risk and as to when to stop treatment: after 1–2 years of therapy advanced melanoma. However, limited data are available if disease remains stable, 1 year after documentation of a to guide optimal patient selection, treatment sequencing CR, or after a radiographic CR or 2 years of therapy. and clinical monitoring during therapy. Immunotherapy None of the panelists felt that pathologic CR was neces- differs from standard chemotherapy in its mode of ac- sary to halt treatment. tion, in being associated with a higher likelihood of dur- The data to support these recommendations are, to be able response when response occurs, and in the fair, premature. With that said, the above recommenda- potential for delayed response and appearance of irAEs tions are made based on the anecdotal experience of that require clinical diligence to detect and treat. Further each panel member who have seen the maintenance of progress in the field is anticipated to focus on combin- prolonged clinical benefit off therapy, appreciating that ation immunotherapy strategies between two or more the risks of continuing therapy indefinitely are legitim- immunotherapy agents and with targeted therapies, ate, and the available data from melanoma clinical trials metabolic (e.g., indoleamine 2,3-dioxygenase [IDO], vas- are premature. The existing published data come from cular endothelial growth factor [VEGF]) inhibitors and the Keynote 001 study, which enrolled 655 patients with adoptively transferred T cells. This updated SITC con- melanoma, 105 of whom developed a CR. With a me- sensus statement provides recommendations by an ex- dian follow up of 30 months from first identification of pert panel of melanoma specialists to assist in the CR, the chance of maintaining a CR was 91% in the 105 clinical management of melanoma patients treated with patients treated beyond response and 90% in the 67 pa- immunotherapy, the use of which provides a beneficial tients who discontinued therapy for observation after therapeutic option for patients with melanoma. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 20 of 23 Endnotes Providence Cancer Center, Portland, OR 97213, USA. Carolinas Medical Center, Charlotte, NC 28204, USA. Carol G. Simon Cancer Center, There are no available data from adjuvant Morristown, NJ 07046, USA. Dana-Farber Cancer Institute, Boston, MA BRAF-targeted therapy in resected Stage IV melanoma. 02215, USA. Received: 12 January 2018 Accepted: 17 May 2018 Additional files Additional file 1: Cancer Immunotherapy Guidelines- Cutaneous melanoma version 2.0 Task Force Roster. (DOCX 13 kb) References Additional file 2: Comments from Open Review. (DOCX 14 kb) 1. Cancer Stat Facts: Melanoma of the Skin. https://seer.cancer.gov/statfacts/ html/melan.html. Accessed 8 March 2018. Additional file 3: Cancer Immunotherapy Guidelines (Melanoma). 2. Hayes AJ, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, (DOCX 145 kb) Theaker J, Bliss JM, Thomas JM. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol. 2016;17(2):184–92. Abbreviations CI: Confidence interval; CR: Complete response; CT: Computed tomography; 3. Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and CTLA-4: Cytotoxic T lymphocyte antigen-4; FDA: U.S. Food and Drug immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. Administration; GM-CSF: Granulocyte macrophage colony-stimulating factor; 2017;14(8):463–82. HR: Hazard ratio; ICR: Intracranial response; IDO: Indoleamine 2,3- 4. Kaufman HL, Kirkwood JM, Hodi FS, Agarwala S, Amatruda T, Bines SD, Clark dioxygenase; IL-2: Interleukin-2; irAE: Immune-related adverse event; JI, Curti B, Ernstoff MS, Gajewski T, et al. The Society for Immunotherapy of IV: Intravenous; LDH: Lactate dehydrogenase; MRI: Magnetic resonance Cancer consensus statement on tumour immunotherapy for the treatment imaging; NSCLC: Non-small cell lung cancer; OR: Odds ratio; OS: Overall of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10(10):588–98. survival; PD-1: Programmed cell death 1; PET: Positron emission tomography; 5. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. PFS: Progression-free survival; PR: Partial response; SITC: Society for Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous immunotherapy of cancer; TSH: Thyroid stimulating hormone; T- melanoma: the eastern cooperative oncology group trial EST 1684. J Clin VEC: Talimogene laherparepvec; VEGF: Vascular endothelial growth factor Oncol. 1996;14(1):7–17. 6. Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, Mackie R, et al. Adjuvant therapy with pegylated Acknowledgments interferon alfa-2b versus observation alone in resected stage III melanoma: We would like to thank SITC staff for logistical and medical writing support. final results of EORTC 18991, a randomised phase III trial. Lancet. 2008; 372(9633):117–26. Authors’ contributions 7. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, HLK and RJS drafted the manuscript with input from the Task Force Sznol M, Parkinson D, Hawkins M, et al. High-dose recombinant interleukin (discussion during the in-person Task Force meeting and follow-up surveys 2 therapy for patients with metastatic melanoma: analysis of 270 patients that were sent after the meeting). All members of the Task Force participated treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16. in the conceptualization, review, and editing of this manuscript. In addition, 8. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, all authors read and approved the final version of this manuscript. Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; Ethics approval and consent to participate 363(8):711–23. Not applicable. 9. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with Competing interests lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. RJS, MBA, JMK, SA, JIC, MSE, LF, TFG, BG, DHL, JL, DFM, KAM, JMM, JMR, KMR, 10. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski WS, SS, VKS, AAT, WJU, RLW, EDW, FSH, HLK. The authors declare that they P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated have no competing interests. melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. 11. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al. Combined Publisher’sNote Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Springer Nature remains neutral with regard to jurisdictional claims in Engl J Med. 2015;373(1):23–34. published maps and institutional affiliations. 12. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, et al. 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Patients with melanoma treated with an anti- PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2018;19(2):229–39. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

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Copyright © 2018 by The Author(s).
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Medicine & Public Health; Oncology; Immunology
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Abstract

Background: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. Methods: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. Results: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. Conclusion: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy. Keywords: Guidelines, Immunotherapy, Melanoma, Treatment * Correspondence: howardkaufman6@gmail.com; HLK12@mgh.harvard.edu Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 2 of 23 Background melanoma. SITC is a non-profit professional Cutaneous melanoma continues to be a serious public organization dedicated to improving cancer patient out- health threat with a slow, but steady increase in annual comes through the use of cancer immunotherapy. The incidence over the past four decades [1]. In 2017, there Task Force consisted of melanoma experts, including were an estimated 87,110 new cases and 9730 deaths physicians, nurses and patient advocates who met in per- due to melanoma in the United States. While melano- son and communicated through email to consider major mas detected early can often be treated by complete sur- issues and provide recommendations related to patient gical excision with good outcomes, the development of selection, toxicity management, treatment cessation and metastatic disease, which is associated with reduced sur- treatment sequencing. The panel published the first con- vival, is correlated with increasing stage and other sensus statement in 2013 [4], and this publication repre- high-risk features of the primary tumor [2]. Contempor- sents an update based on more recent assessment of the ary systemic therapeutic options for patients with meta- peer-reviewed literature and clinical experience of the static melanoma include cytotoxic chemotherapy, expert Task Force participants. These recommendations molecularly targeted therapy, and immunotherapy. Since are not intended to supplant sound clinical judgment 2011, the treatment landscape for patients with melan- but to provide clinicians who care for melanoma pa- oma has changed considerably with regulatory approval tients the most current thinking on how experts inte- of 11 new drugs and/or combination regimens [3]. Im- grate immunotherapy into the treatment munotherapy agents in particular have been associated armamentarium for patients with advanced cutaneous with durable long-term survival in responding patients melanoma. and have emerged as first-line treatment in most melan- oma populations [4]. Methods The immunotherapy agents approved for melanoma Consensus statement policy include cytokines, such as interferon α2b/pegylated SITC utilized the National Academy of Medicine interferon α2b for high-risk adjuvant therapy and (formerly Institute of Medicine) March 2011 Standards high-dose interleukin-2 (IL-2) for metastatic disease; ipi- for Developing Trustworthy Clinical Guidelines as a limumab and nivolumab, immune checkpoint inhibitors model for organizing and preparing this consensus state- targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) ment [13]. These standards include a transparent process and programmed cell death 1 (PD-1), respectively for for guideline development and funding, managing and high-risk adjuvant melanoma, and four T cell checkpoint reporting conflicts of interest, maintaining a multidiscip- inhibitors for metastatic melanoma, including ipilimu- linary and balanced group composition, establishing an mab (anti-CTLA-4), pembrolizumab (anti-PD-1), nivolu- evidence-based foundation for recommendations and rat- mab (anti-PD-1) and the combination of ipilimumab/ ing system to assess the strength of the evidence, report- nivolumab; finally, one gene-modified oncolytic virus, ing the results through a peer-reviewed publication and talimogene laherparepvec (T-VEC), has been approved publicly available website, and updating the statement as for intralesional therapy [5–12]. While the clinical trials changes in the field warrant revisions. supporting regulatory approvals have dramatically chan- The Melanoma Task Force was established through ged the melanoma treatment landscape and provided pa- SITC in 2011, with additional panel members added as tients and providers with several new options, there is necessary (Additional file 1). A Steering Committee led a relatively little data for evidence-based decisions in re- panel discussion to develop clinical treatment guidelines gard to optimal sequencing of these agents, methods or considering four basic issues for each immunotherapy biomarkers to select the right treatment for individual agent in current clinical practice: patient selection, toxicity patients, or rigorous information on how best to manage management, assessment of response, and therapy se- potential adverse events or indicators for optimal dur- quencing and combinations. The in-person meeting was ation of therapy. The availability of other therapeutic op- supplemented by email voting on several issues due to the tions, in particular targeted therapy for patients whose rapid development of new findings and drug approvals for melanoma harbors a mutation in BRAF, highlight the melanoma over the last 2 years. Full consensus recom- importance of having data or consensus agreement from mendations can be found on the SITC website [14]. experts in the field on how best to manage patients Owing to disparities in drug approval and availability in while waiting for new clinical and clinical trial data to some countries, this panel focused solely on drugs ap- help inform decision-making. proved by the U.S. Food and Drug Administration (FDA). To address the gap in evidence-based data, the Society An advance copy of this manuscript was submitted to the for Immunotherapy of Cancer (SITC) established a Mel- FDA for comment before submission for publication. The anoma Task Force to provide consensus recommenda- panel also recognized that the AJCC Cancer Staging Man- tions for clinical decision making for patients with ual, 8th Edition has been released but the clinical trial data Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 3 of 23 reviewed utilized earlier versions of AJCC staging; as such, independent searches, resulting in a final bibliography of the recommendations presented in this manuscript were 1643 manuscripts (see Additional file 3) catalogued using largely based on 7th edition staging criteria. However, rec- EndNote X5.0.1. The bibliography was supplemented with ommendations that extrapolate clinical trial data using additional literature identified by the panel, as appropriate. 7th edition staging criteria in the setting of completion Literature was graded into three levels of evidence, as pre- lymph node dissection (CLND), are made to the current viously described [4]. Level A evidence is based on strong era using the 8th edition staging system in the non-CLND supporting evidence, such as data derived from appropri- era where appropriate. ately powered prospective, randomized clinical trials or meta-analyses; Level B is based on moderate supporting Consensus panel and conflicts of interest data, such as uncontrolled, prospective clinical trials; and Potential panel members were solicited from the SITC Level C is based on weaker supporting data, such as retro- membership and supplemented with non-member mel- spective reviews and case reports. anoma multidisciplinary experts, clinicians and groups in the U.S. expected to be affected by the development Consensus recommendations of any recommendations, including patients, patient ad- The Task Force considered individual melanoma stages vocates and nurses. Panel members were screened for independently and provided the following consensus rec- conflicts of interest using the SITC disclosure form, ommendations described by stage of disease. These rec- which mandates full financial and other disclosures in- ommendations were based on data available for AJCC cluding relationships with commercial entities that version 7 staging guidelines; where appropriate, modifi- might reasonably be expected to have direct regulatory cations relevant for AJCC version 8, which became ac- or commercial impact resulting from the publication of tive in January 2018, are noted. The majority of the this statement. Disclosures of potential conflicts of inter- immunotherapy trials on which the following recom- est are noted in this manuscript. No commercial funding mendations are based included patients with ECOG Per- was used to support the consensus panel, literature re- formance Status 0 or 1. These guidelines are intended to view or preparation of the manuscript. assist clinicians in critical decision-making for patients The consensus panel convened in June 2016 in accord- with melanoma and should not supplant clinical judg- ance with the National Academy of Medicine and SITC ment for individual patient management. guidelines to review results from a previously distributed questionnaire collecting information on the participants’ Immunotherapy for stage II melanoma role in the care of patients with melanoma, primary clin- Initial assessment ical focus, experience with FDA-approved agents used Patients with stage II melanoma have an excellent over- for immunotherapy treatments, and current practices in all survival (OS) of 80% or better provided the primary the use or recommendation for use of such agents. Add- tumor is completely excised [2]. A subset of tumors, itional questionnaires were distributed electronically characterized as deep (Breslow thickness > 4 mm), and/ after the meeting to collect further information, includ- or with ulceration, and possibly those with a high tumor ing a final questionnaire in the late summer of 2017. mitotic rate (≥1 per mm ), are considered at higher risk The final consensus statement was made available to the for recurrence [15]. Practically speaking, using both entire SITC membership for open comment and these AJCC 7th and 8th additions, Stage IIB and IIC are con- comments were considered for the final manuscript and sidered higher risk. The panel discussed at length the are available in supplementary materials (see Add- changing landscape with respect to how to define high itional file 2) and online at the SITC website [14]. risk and when to consider further intervention with the goal of preventing tumor relapse. There was unanimous Literature review and rating system agreement that all stage II patients should have a com- A search of the scientific literature (using the MEDLINE prehensive diagnostic workup and be reviewed by a database) was conducted focusing on current therapeutic multidisciplinary team, including physicians with expert- approaches in humans. The search terms included “mel- ise in surgical oncology, medical oncology, dermatology anoma” and “interferon”, “interleukin-2”, “ipilimumab”, and dermatopathology to accurately determine tumor “vemurafenib,”“BRAF,”“dabrafenib, dacarbazine, temozo- stage and estimate the risk of melanoma recurrence for lomide”, “pembrolizumab”, “nivolumab”, “PD-1/PD-L1”, individual patients. This workup should include sentinel “combination”, “talimogene laherparepvec”, “adverse lymph node biopsy information, as appropriate [16]. event”,and “toxicity”. The search resulted in retrieval of nearly 2400 manuscripts, which were screened by Task Consensus management of stage II melanoma Force members to include only papers with clinically rele- The panel considered the therapeutic approach to stage vant information and removing duplicates from II melanoma should be based on an assessment of risk Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 4 of 23 for tumor recurrence or metastatic spread but recog- that high-risk patients be treated with standard 1-year nized that there is considerable controversy in how to high dose interferon-α2b, now a small majority (55%) determine risk stratification. Further, changes in the recommend enrollment onto a clinical trial - either un- AJCC staging system and emerging data using a variety selected or selected by a biomarker known to be associ- of histologic and molecular assays for risk assessment ated with either risk (prognostic) or responsiveness to have made firm recommendations challenging. For the the therapy (predictive) - as a preferred option for these purposes of our discussions, we defined high risk stage patients. Among panel members who did not recom- II as patients with tumors > 4 mm in depth (with or mend a clinical trial, twice as many recommended ob- without ulceration) or tumors > 2–4 mm with ulcer- servation (20%) as did the pursuit of standard of care ation. While this definition may change with further adjuvant interferon α-2b (10%). This is a reflection of a prospective data, the general approach to patient man- number of factors including: 1) improved systemic ther- agement can be considered based on clinical assessment apy for recurrent, metastatic disease [4]; 2) acknowledg- of higher versus lower risk. ment of the limitations of the AJCC staging system to There was general agreement that patients with lower identify those at high and low risk of recurrence (e.g., a risk stage I and IIA melanoma can be observed and that significant number of patients with low risk [by cur- there is no evidence that currently warrants treatment of rently available methods] melanoma will still die of dis- these patients (Fig. 1). The panel, however, was divided ease [15]); and 3) emerging, as yet non-validated on the role of immunotherapy for patients with biomarkers, which may better identify patients at great- higher-risk stage IIB-C melanoma (see Fig. 1) and recog- est risk of recurrence (e.g., ulceration, gene expression nized the limited Level A data available to inform clin- profile, circulating tumor DNA) [15, 17, 18]. None of the ical decision-making. The panel did consider emerging panel members recommended treatment with pegylated Level B data suggesting new recommendations are interferon-α2b for patients with stage II disease. needed for high-risk stage II melanoma patients. Patients with stage IIB or IIC melanoma who are Whereas before the majority of the panel recommended treated with interferon-α2b should have a good Fig. 1 Stage II melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate, and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) High-risk disease is defined as tumors > 4 mm in depth (with or without ulceration) or > 2–4 mm with ulceration. There is limited consensus on adjuvant therapy for this group with 10% of the panel recommending interferon-α2b, 20% recommending observation, 45 and 15% recommending therapeutic and/or biomarker-based clinical trial participation, respectively, and no panelists recommending pegylated-interferon-α2. (2) There is no evidence that immunotherapy is useful in patients with lower risk stage II melanoma, although the panel did recommend clinical trial participation, if available. Protocol-specific eligibility would need to be followed to select appropriate study candidates. (3) Patients should have a good performance status without evidence of significant depression, psychiatric history or underlying autoimmune disease to be considered for interferon-α2b. There are limited data available on interferon-α2b as treatment for stage II disease. (4) Clinical trials were the preferred treatment recommendation for patients with stage II disease associated with higher risk of tumor recurrence Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 5 of 23 performance status without evidence of significant de- believed that, in patients with microscopic metastasis to a pression or psychiatric history or underlying auto- single lymph node (stage N1a), especially when the node immune disease [4]. The data to support the use of has been excised by sentinel lymphadenectomy, cancer be- adjuvant, high-dose interferon-α2b are controversial and haves differently than in patients with more extensive many studies did not incorporate required sentinel lymph node involvement (stages N1b-3). In the updated lymph node biopsy into the study eligibility complicating recommendations, patients with N1a disease, in accord- the interpretation. In a prospective study, 499 patients ance with the AJCC 7th edition were considered as a dis- with melanoma Breslow thickness > 1.5 mm, and without tinct subset; management recommendations by nodal clinically detectable lymph node metastases, were ran- staging are shown in Fig. 2. With the recent publication domly assigned to 18 months of subcutaneous and adoption of the 8th edition of AJCC, which strived to interferon-α2b or observation [19]. Patients treated with identify a group of Stage III patients with significantly interferon-α2b demonstrated a significant improvement lower risk, the Task Force considered Stage IIIA (per AJJC in relapse-free survival (RFS) (P = 0.038) and a trend to- 8th Ed.) to have lower risk of tumor recurrence compared ward improved OS (P = 0.059). In another trial, 855 pa- to Stage IIIB-D. The management of stage III disease has tients were randomly assigned to observation or 4 weeks also been complicated by recent data showing that, while induction interferon-α2b followed by 1 or 2 years of immediate completion lymph node dissection was associ- interferon-α2b maintenance therapy [20]. The study in- ated with a decreased rate of lymph node basin recurrence vestigators reported an improvement in RFS for patients and increased disease-free survival in sentinel who received 1 year of maintenance interferon-α2b (haz- node-positive patients, there was no improvement in ard ratio [HR] 0.77, 95% Confidence interval [CI]: 0.63– melanoma-specific survival [27]. These findings along 0.96; P = 0.034), but no benefit in OS (HR 0.91, 95% CI: with the availability of more effective systemic treatment 0.74–1.10; P = 0.642). Several other prospective random- will change the management for sentinel node-positive pa- ized trials examined interferon-α2b at a variety of doses tients, although all of the reported clinical trials of adju- and treatment schedules in patients with stage II melan- vant therapy mandated completion lymph node dissection oma, but none has demonstrated a survival benefit [5, as a key eligibility criterion for study participation. Thus, 21–25]. A recently reported phase 3 randomized study the recommendations for stage III management should be in 1150 patients with resectable melanoma (T2bN0, considered carefully in light of these recent developments. T3a-bN0, T4a-bN0, and T1-4N1a-2a) who were ran- domly assigned to receive intravenous (IV) high-dose Initial assessment interferon-α2b for 5 days every week for 4 weeks or ob- In all patients with stage lll melanoma, a diagnostic workup servation, produced equivalent 5-year RFS rates between should be performed and reviewed by a multidisciplinary groups. Moreover, 4 weeks of IV interferon-α2b resulted team for patient and tumor characteristics. Complete in higher rates of treatment-related grade 3 and higher tumor staging information should be assessed, including toxicities (57.9% vs. 4.6%; P < .001) and worsened quality pathological features of the primary tumor and any in- of life [26]. These studies are complicated by a lack of a volved lymph nodes, as well as BRAF mutation testing. In standardized definition of ‘high risk for relapse’, 23 dif- addition, whole-body imaging (see Table 1)and perform- ferent interferon-α2b dosages/formulations/schedules ance status assessment should be completed prior to mak- were evaluated, and in some cases, the inclusion of other ing treatment decisions. Nodal status should be determined drugs in combination. Thus, the efficacy of interferon in based on physical examination and sentinel lymph node bi- sentinel node negative stage II melanoma patients re- opsy (SNB) with or without subsequent completion lymph- mains unresolved. To date, there are no data with ipili- adenectomy if SNB is positive. The consensus panel mumab, nivolumab, pembrolizumab, or BRAF-targeted identified five potential immunotherapy agents with poten- therapy (either single-agent BRAF inhibitors or com- tial clinical benefit in the adjuvant therapy of patients with bined BRAF/MEK inhibitor therapy) to justify the use of stage III melanoma: interferon-α2b, pegylated these agents/regimens in patients with stage II melan- interferon-α2b, ipilimumab, pembrolizumab, and nivolu- oma. However, data from planned clinical trials may pro- mab [6, 28–31]. Furthermore, the consensus panel noted vide additional information to guide the use of the that the combination of the BRAF and MEK inhibitors, anti-PD1 agent pembrolizumab in this setting. dabrafenib and trametinib, respectively, was recently shown to be superior to placebo in patients with stage III melan- Immunotherapy for stage III melanoma oma with BRAF V600E/K mutations; these data provide Stage III comprises a heterogeneous group of patients the first evidence for significant RFS and OS benefit of a with 5-year survival rates ranging from 30 to 80% [15]. targeted antitumor therapy that does not fit the putative While the previous consensus statement considered stage immunotherapy approach and can be considered for pa- III patients as a single group, the Task Force strongly tients with tumors harboring BRAF mutations [32]. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 6 of 23 Fig. 2 Stage III N1a (7th)/Stage IIIA (8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III patients should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone, which is anticipated to become more common. (2) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma independent of the volume of lymph node involvement or the number of lymph nodes involved. (3) Level A data supporting the use of nivolumab over ipilimumab was demonstrated in patients with Stage IIIB to IV resected melanoma and did not include patients with Stage IIIA (based on 7th) disease. Ipilimumab 10 mg/kg dosing was supported by a minority of panelists (10%), however, subset analysis suggests that the risk: benefit ratio for patients with Stage IIIA melanoma does not support its use in Stage IIIA patients at this time. (4) There are level A data that 1 year interferon-α2b is associated with improvement in RFS and, while this therapy was generally recommended by the consensus panel previously, only two panelists recommended considering this therapy. There are level B data to support a benefit in RFS for pegylated-interferon-α2b in patients with N1a disease and in patients with ulceration of the primary tumor site; however, no panelists considered this a reasonable option for these patients. Abbreviations: LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; RFS, recurrence-free survival Consensus management of microscopic single node disease There is one prospective randomized clinical trial dem- (stage N1a – AJCC 7th; stage IIIA – AJCC 8th) onstrating a benefit in RFS for patients with microscopic The majority of the panel (70%) recognized that nodal disease treated with pegylated interferon-α2b [6]. A patients with microscopically involved lymph nodes post-hoc analysis of that trial also suggested patients with (N1a disease) represents a different population from ulcerated primary tumors might derive more clinical those with macroscopic nodal disease (N1b and N2– benefit from pegylated interferon-α2b [33]. In this ana- N3 disease) and agreed that the AJCC 8th edition lysis, patients with ulceration of their primary melanoma takes this into account by redefining Stage IIIA as be- (n = 849) were compared to patients without ulceration of ing associated with a lower risk than in the AJCC 7th their primary melanoma (n = 1336), and patients with ul- edition. However, whereas the majority (52%) of the ceration demonstrated a significant improvement in RFS former panel in 2014 recommended a standard 1-year (P = 0.02), distant metastasis-free survival (P <0.001) and course of interferon-α2b for adjuvant therapy of pa- OS (P < 0.001). The analysis also found that the greatest tients with microscopic nodal disease, only a small reduction in risk was seen in patients with ulcerated pri- number recommended this therapy in this update. Ra- mary melanomas who were classified as stage IIb–IIIN1, ther, the majority of the panel (58%) recommended a demonstrating a HR of 0.58 for OS benefit (P < 0.0001) clinical trial, 10% recommended observation, 5% ipili- [34]. Thus, patients with ulcerated primary tumors and mumab (10 mg/kg), and 10% adjuvant interferon-α2b, those with microscopic nodal disease could consider pegy- if a clinical trial was not available. No panelists recom- lated interferon-α2b based on this Level B data, although mend pegylated interferon-α2b or ipilimumab given at further evaluation of this regimen is ongoing in an 3 mg/kg (see Fig. 2). EORTC trial. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 7 of 23 Table 1 Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma Clinical Issue Current Consensus Recommendations Biomarker Status � The panel recognized the importance of identifying predictive biomarkers to aid in clinical decision-making � At present there are no validated biomarkers that reliably predict response to individual therapeutic agents � There is considerable interest in PD-L1 expression, mutation burden, lymphocyte infiltration, interferon-γ and related cytokine gene signatures as potential biomarkers � There are data suggesting higher response rates to monotherapy, but not combination therapy, with T cell checkpoint inhibitors when PD-L1 expression is increased but the panel does not recommend PD-L1 status be used outside of clinical trials Laboratory Assessment � Immunotherapy is associated with significant irAEs that require laboratory monitoring before and during active treatment � Clinicians should be alert for irAEs during therapy and for several months after stopping treatment � All panelists agreed that baseline and routine labs should include complete blood count, liver enzymes, metabolic panel, serum LDH and thyroid function studies (free T4, TSH) � Additional hormone levels should be assessed in patient with suspected treatment-related hypophysitis (free T4, TSH, ACTH, morning cortisol, cosyntropin stimulation test, LH, FSH, testosterone, prolactin) and early endocrinology referral � The frequency of laboratory testing was more controversial with most panelists recommending testing prior to each infusion for most drugs and less frequent surveillance during follow-up Imaging Guidelines � Confirming disease response/progression may be challenging with immunotherapy due to the delayed kinetics of response and induction of local inflammation � The panel (100%) recommends whole body imaging for melanoma patients treated with immunotherapy prior to starting and at regular intervals no more than 12 weeks apart while disease persists � A majority of the panel recommends imaging with CT scans of the chest, abdomen and pelvis and MRI of the brain � A minority recommend initial imaging with PET scans � Imaging should continue after complete responses at regular intervals for five years to identify recurrence Treatment Cessation � Since the kinetics of response to immunotherapy may be delayed decisions to stop treatment can be challenging � The panel recommended stopping treatment for any unresolved or recurrent high grade adverse event or when disease progression is confirmed by two independent imaging scans or clinical deterioration � Pseudo-progression has been reported for checkpoint inhibitors and T-VEC but is rare for interferon and IL-2; most panelists suggested that treatment with interferon or IL-2 should be stopped with any sign of disease progression � Repeat imaging within 1–2 months was recommended to confirm response or progression when pseudo-progression is suspected � Minority opinions included considering surgical resection for incomplete responses and tumor biopsy for equivocal cases Abbreviations: ACTH adrenocorticotropic hormone, CT computed tomography, FSH follicle stimulating hormone, LH luteinizing hormone, MRI magnetic resonance imaging, PD-L1 programmed cell death 1 ligand, PET positron emission tomography, TSH thyroid stimulating hormone Ipilimumab has been studied in patients with stage III with stage IIIA disease, despite being required to have melanoma in a prospective clinical trial (EORTC 18071), one or more nodal metastases at least 1 mm in size, had which randomized 951 patients to either placebo or ipili- no evidence of benefit (HR 0.98, 95% CI: 0.46–2.09) mumab, given at 10 mg/kg induction (4 doses every [30]. Thus, there was hesitation in considering adjuvant 3 weeks) followed by maintenance (every 12 weeks for ipilimumab for patients with lower risk, stage III disease up to 3 years) [30]. With a median follow up of over in light of known toxicity, although adjuvant ipilimumab 5 years, ipilimumab was associated with improved RFS was recommended by a minority of the panel (10%). compared to patients treated with placebo (median 27.6 In an older trial, which included patients with com- vs. 17.1 months, HR 0.76, 95% CI: 0.64–0.89; P = 0.0008) pletely resected stage IV or high-risk stage III melanoma, and OS (5-year 65% vs. 54%, HR 0.72, 95% CI: 0.58– adjuvant granulocyte-macrophage colony stimulating fac- 0.88; P = 0.001). However, in subgroup analysis, patients tor (GM-CSF) did not demonstrate improvements in RFS Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 8 of 23 or OS in a randomized, placebo-controlled phase 3 study < 1 mm metastatic nodal deposit. With a median follow [35]. GM-CSF, an immunomodulatory agent with pleio- up of 2.8 years, D/T was associated with improved RFS tropic and sometimes opposing effects on antitumor im- (HR 0.47; 95% CI: 0.39–0.58, P < 0.001) and OS (HR munity, remains investigational for any stage of 0.57; 95% CI: 0.42–0.79, P < 0.001) compared to placebo. melanoma, although its incorporation into an oncolytic Moreover, there were no additional safety concerns that virotherapy for intratumoral administration is approved arose with D/T that had not previously been seen in pa- for advanced melanoma, and its role in combination im- tients with unresectable or stage IV melanoma [32]. munotherapy appears promising [12, 36]. While this combination is not considered immunother- Although immunomodulatory therapy is the only apy, inhibitors of BRAF and associated pathways in the intervention that had ever shown promise in the adju- tumor cell have been shown to have immunomodulatory vant therapy of melanoma, there is now evidence that properties that contribute to their activity. For these pa- molecularly-targeted therapies can benefit patients with tients, the choice between molecularly targeted and im- resected high-risk melanoma whose tumor cells carry an mune checkpoint-based adjuvant therapy remains activating BRAF mutation. A trial of dabrafenib and tra- unclear, as direct comparisons have not yet been made. metinib given at standard doses (CombiAD), random- However, benefit was seen across all AJCC 7th (and by ized 870 patients (1:1) to either the combination of extrapolation 8th) edition stage III subgroups, and this dabrafenib and trametinib (D/T) or placebo for 1 year. combination can be considered for any patient with V600E/K This trial excluded patients with stage IIIA (N1) with a stage III, BRAF -mutant melanoma. Fig. 3 Stage III N1b-3 (AJCC 7th)/Stage IIIB-D (AJCC 8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III subsets should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone. (2) After evaluation by multi-disciplinary team with surgical oncology, if complete resection is possible patients should undergo resection followed by adjuvant therapy listed. If the tumor is considered unresectable, a different treatment paradigm should be followed. (3) In patients with Stage IIIB-IV resected melanoma, there is Level A evidence supporting the use of nivolumab over ipilimumab and pembrolizumab over placebo for stage IIIB-C and IIA patients with micrometastases > 1 mm. Accordingly, nivolumab or pembrolizumab were supported by 46% of the panel. (4) Ipilimumab at 3 mg/kg was supported by a minority of panelists (8.3%). (5) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma. (6) While there are Level A data that 1 year interferon-α2b is associated with improvement in RFS, no panelists recommended considering this therapy for this patient population. (7) Overall, the majority of panelists recommended a clinical trial, if available. (8) The majority of the panelists have had experience with T-VEC, and half of respondents said they would recommend T-VEC for first-line treatment for limited disease burden, and a significant minority (39%) would consider T-VEC for patients with locoregional disease. (9) Unresectable disease could be managed by options available for stage IV patients (see Fig. 4). Abbreviations: CR, complete response; LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; PD, progressive disease; RFS, recurrence-free survival, TVEC, talimogene laherparepvec Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 9 of 23 Consensus management of macroscopic nodal disease recurrence-free survival compared to placebo in the (stage N1b/c, N2b/c, N3b/c in 7th edition or stage IIIB-IIID in intention-to-treat population (75.4% [95% CI: 71.3–78.9] vs. 8th edition) 61.0% [95% CI: 56.5–65.1]; HR for recurrence or death, Patients with macroscopic involvement of a single or 0.57 [98.4% CI: 0.43–0.74; p <0.001]). In a cohort of 853 multiple lymph nodes (stage N1b and N2b–N3 disease patients with PD-L1-positive tumors, the 1-year rate of per AJCC 7th Edition; or Stages IIIB-IIID in AJCC 8th recurrence-free survival was 77.1% in the pembrolizumab Edition) are at significant risk for melanoma recurrence. treated group compared to 62.6% in the placebo group (HR The panel recommendations for these melanoma pa- 0.54; 95% CI: 0.42–0.69). Grade 3 or greater adverse events tients are detailed in Fig. 3. Whereas the majority of the were observed in 14.7% of patients treated with pembroli- panel in 2014 recommended that these patients consider zumab - with one treatment-related death attributed to 1 year of interferon-α2b treatment (73%) [4], in the myositis - versus 3.4% in patients treated with placebo. current setting, the majority of panelists recommended In light of these newer data, patients with resected stage either a clinical trial (56%), or if a trial is not available IIIB, IIIC, and IV melanoma could consider several options, then adjuvant nivolumab based on the results of the andthe panelconsideredanti-PD-1 antibodytherapy with CheckMate 238 trial, or adjuvant pembrolizumab based either nivolumab or pembrolizumab (46%), ipilimumab at on the results of the recent phase III clinical trial (46% 3 mg/kg (8%), D/T in BRAF mutant patients (13%), or of panelists) [31, 32, 37]. A minority of panelists would high-dose interferon (4%) as acceptable recommendations. consider adjuvant ipilimumab (8%) based on the results Almost one third of the panel members (29%) were unable of the EORTC 18071 trial [33]. For patients whose to make a specific recommendation. These members sug- tumor harbors a BRAF V600E/K mutation, combination gested using either anti-PD-1 therapy or D/T, while others dabrafenib/trametinib may be preferred over immuno- preferred the use of D/T if the tumor was BRAF mutant or therapy since the impact of adjuvant checkpoint inhibi- enrollment onto a clinical trial incorporating ipilimumab at tors on the management of subsequent disease 3 mg/kg. The recommendation to use low dose ipilimumab progression is not known. Of note, no panelists recom- is supported by data from the phase III U.S. Intergroup mend pegylated interferon-α2b for patients with resected E1609 study in which patients with resected high-risk mel- macroscopic nodal disease, and only one panelist consid- anoma were treated with interferon-α, ipilimumab at ered high-dose interferon-α2b as an option if a clinical 10 mg/kg or ipilimumab at 3 mg/kg; while there was no ob- trial was not available. vious difference in recurrence-free survival between the CheckMate 238 is a phase 3 trial that randomized 906 two ipilimumab cohorts (although no formal statistical patients with resected stage IIIB-IV melanoma to either comparison was performed), there was a significant in- 1 year of nivolumab (3 mg/kg every 2 weeks) or ipilimu- crease in toxicity reported for the 10 mg/kg cohort com- mab (10 mg/kg every 3 weeks for 4 doses, followed by pared with 3 mg/kg [38]. No panelists endorsed every 12 weeks). With minimum follow-up of 18 months, observation as a clinical option. the trial met its primary endpoint showing that nivolu- mab was associated with an improved RFS compared Consensus management of unresectable stage III/IV with ipilimumab (RFS at 12 months 70.5% vs. 60.8% for melanoma with injectable lesions nivolumab and ipilimumab, respectively; HR 0.65; CI: In patients with unresectable stage III disease, the use of 0.51–0.83; P < 0.001). Furthermore, the rate of T-VEC, an oncolytic herpes virus engineered to express treatment-related grade 3–4 toxicity was 14.4% with GM-CSF, was felt to be appropriate by a significant mi- nivolumab vs. 42.6% in patients treated with ipilimumab nority of panelists (39%). This recommendation was [31]. OS data were immature and not reported. The data based on results from a prospective, randomized trial in from this trial led to the FDA-approval of nivolumab in which 436 patients with unresectable stage IIIB-IV mel- patients with resected Stage III melanoma. anoma were randomized in a 2:1 fashion to treatment More recently, a prospective, double-blind phase III clin- with T-VEC or recombinant GM-CSF [12]. The primary ical trial was conducted in patients with resected, high-risk endpoint of the study was durable response rate (DRR), stage III melanoma. In this study patients were eligble if which was significantly better for T-VEC treated patients they had stage IIIB or IIIC, while a subset of patients with compared to control subjects (16.3% vs. 2.1%, odds ratio stage IIIA were also included if they had at least one micro- [OR] 8.9; P < 0.001). T-VEC was also associated with im- metastasis measuring > 1 mm. The trial randomly assigned proved objective response rate (ORR 26.4% vs. 5.7%) and 514 patients to treatment with 200 mg of pembrolizumab OS (median OS 23.3 months for T-VEC vs. 18.9 months and 505 patients to placebo every 3 weeks for 1 year [37]. for control, HR 0.79, P = 0.051). On a pre-specified sub- In this study, patients were stratified by cancer stage and set analysis, however, a particularly strong effect was geographic location. At a median follow-up of 15 months, seen in patients with stage IIIB-IVM1a disease, where pembrolizumab was associated with significantly longer the DRR was 33% vs. 0% in stage III patients and 16% Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 10 of 23 vs. 2% for stage IVM1a patients. A similar effect on OS The panel considered the overall approach to the was seen in the stage III-IVM1a patients with a 43% im- patient with stage IV melanoma and, while previous provement in survival for patients treated with T-VEC recommendations suggested that BRAF mutation sta- [12]. Thus, there is Level A data supporting T-VEC in tusand performancestatusbe consideredascritical these patients, and T-VEC may be more appropriate for elements in the decision-making process, all Task patients with limited visceral disease. Other options for Force participants agreed that immunotherapy should this patient population would be enrollment onto a clin- be considered prior to targeted therapy in patients ical trial or treatment as stage IV melanoma (see Fig. 4). with good performance status, based on the potential Of particular interest are the multiple emerging trials of for durable responses with immunotherapy. There is neo-adjuvant/pre-operative therapy for patients with little data available to support optimal sequencing of melanoma of borderline resectability, who may be better targeted therapy and immunotherapy in this setting. served by initial cytoreduction and possibly a scenario, if However, two retrospective studies have suggested en- significant response is seen, where the patient may not hanced clinical benefit from immunotherapy adminis- require resection. tered prior to BRAF-targeted therapy in those patients who required both (those who did not Immunotherapy for stage IV melanoma achieve durable or curative responses to the first line Initial assessment of therapy) [40, 49]. A data series of 274 patients In patients with stage lV melanoma, a diagnostic workup with BRAF-mutated melanoma who sequentially re- that includes a multidisciplinary team review of clinical and ceived BRAF inhibitors and immunotherapy (high-- tumor data should be conducted. Staging should be con- dose IL-2, ipilimumab, or PD-1 inhibitors) illustrated firmed via pathological evaluation, whole body imaging, that ipilimumab therapy after BRAF inhibitors was as- and serum LDH analysis. Genetic mutation analysis of the sociated with no tumor response and poor survival tumor should also be performed with special emphasis on [50]. In another study of 93 patients with identifying mutations in BRAF. In addition, careful atten- BRAF-mutated melanoma who received BRAF inhibi- tion should be paid to central nervous system (CNS) assess- tors (vemurafenib or dabrafenib) before or after ipili- ment since melanoma patients are at high risk of CNS mumab, longer OS was found in the cohort of metastasis. Thus, in addition to computed tomography patients receiving ipilimumab prior to BRAF inhibitor (CT) imaging of the chest, abdomen and pelvis, an MRI of therapy (14.5 vs. 9.9 months, P = 0.04) [49]. In both the brain should be obtained to fully stage potential meta- studies, theresponserates to BRAF-targetedtherapy static melanoma patients. Surgical evaluation by a was similar regardless of prior immunotherapy. Thus, multi-disciplinary team that includes an experienced surgi- starting with immunotherapymay providepatients cal oncologist for possible metastectomy is important, espe- with an opportunity for long-term benefit without cially in patients with solitary pulmonary metastasis where negatively affecting the activity of BRAF inhibitor complete extirpation is possible. If complete resection of all therapy. In order to determine optimal sequencing, metastatic disease is likely, metastasectomy can be consid- theECOG-ACRIN-ledintergrouprandomizedproto- ered based on Level B retrospective outcome studies, but col EA6134 (NCT02224781) has been initiated to the panel agreed that this operative management is less compare the sequential administration of ipilimumab/ compelling as systemic therapy improves [39–41]. Patients nivolumab and dabrafenib/trametinib. OS at the who achieve partial response (PR) or stable disease (SD) fol- 2-year landmark, the primary endpoint of this ran- lowing immunotherapy should also be reassessed for pos- domizedphase 3trial, isexpectedtobereportedin sible resection [42, 43]. The panel recognizes several 2019 or 2020. systemic treatment options for patients with unresectable In this edition of the guidelines, the panel suggested stage IV melanoma, including immunotherapy with that key elements to consider for individual patients high-dose IL-2 (where available), ipilimumab, nivolumab, should include clinical performance status, tumor bur- pembrolizumab, T-VEC (if accessible lesions are present), den, and presence of visceral metastases (compared to combination ipilimumab and nivolumab, clinical trial par- M1a patients with cutaneous, soft tissue or nodal only ticipation, and cytotoxic chemotherapy [7–12]. Addition- metastatic disease), and the tempo of disease progres- ally, vemurafenib, dabrafenib, trametinib, and the sion. While there is limited evidence, where available, combinations of either dabrafenib and trametinib or most immunotherapy agents do appear to be effective vemurafenib and cobimetinib are options for patients with against CNS metastases from melanoma [51–53]. Data BRAF-mutated tumors [44–48]. An additional combination recently reported from two studies also show evidence regimen of potent BRAF and MEK inhibitors (encorafenib that combination nivolumab/ipilimumab has clinical ac- and binimetinib) is anticipated to receive regulatory ap- tivity in patients with asymptomatic brain metastases proval in the future. [53, 54]. In 75 patients with > 1 measurable brain Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 11 of 23 Fig. 4 (See legend on next page.) Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 12 of 23 (See figure on previous page.) Fig. 4 Stage IV melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. The panel recommended all patients be evaluated with full body imaging, histopathology review, serum LDH, and tumor mutation analysis with emphasis on BRAF mutations. Other factors to be considered in selecting appropriate treatment should include performance status, burden and tempo of disease and presence of CNS metastases. (1) All patients should be evaluated for resection by a multi-disciplinary team including surgical oncology before and after immunotherapy treatment, although the role of surgery is changing and may be appropriate for patients with solitary pulmonary lesions where complete extirpation is possible; each case must be individualized. (2) All patients should have an MRI of the brain prior to treatment to rule out or manage CNS metastasis. (3) There was level B data for a clinical benefit with surgical resection when complete excision of all disease is possible although first-line surgical resection was a minority opinion of the panel. (4) As determined by an experienced surgical oncologist, patient is eligible to receive surgical intervention as first-line treatment. (5) Immunotherapy was recommended for any patient with a good performance status regardless of BRAF mutation status and provided that any CNS disease was treated and controlled. Clinical trial was the favored first line approach by the panel. 6) In the absence of an appropriate clinical trial, the panel recommended combination ipilimumab and nivolumab based on the high response rates reported. This may also be preferred for patients with CNS disease with a minority of panelists (33.3%) recommending stereotactic radiation prior to systemic therapy for CNS lesions (7) Next, the panel recommended single agent anti-PD-1 therapy (pembrolizumab or nivolumab). The panel considered these agents to have the same therapeutic efficacy and treatment selection could be based on physician experience and patient preference. (8) The panel also recommended T-VEC in patients with accessible tumor for injection and limited visceral tumor burden. This option may be especially appropriate for elderly patients and those not eligible for checkpoint inhibitors. (9) Patients with poor performance status were not considered good candidates for combination immunotherapy and BRAF mutation was an important factor for determining therapeutic planning. Most panelists considered clinical trials to be the most important option in these patients, if available. In those patients without a BRAF mutation, the next option should be single agent anti-PD-1 therapy (pembrolizumab or nivolumab). (10) In patients with poor performance status and a BRAF mutation who are not eligible or whose tumors progress after a clinical trial, treatment with a BRAF and/or MEK inhibitor therapy is indicated. This option was also considered appropriate for patients with uncontrolled CNS disease. Single agent anti-PD-1 treatment could be considered if disease progression occurs after targeted therapy. (11) In patients with disease progression following the recommendations, management should be carefully considered. If patients can tolerate treatment, ipilimumab/ nivolumab should be considered. If patients have a BRAF mutation and have not been treated with BRAF/MEK inhibitors previously these can be considered. Ipilimimab monotherapy and high-dose IL-2 can also be considered in these patients. (12) Patients should have a good PS and otherwise qualify for IL-2 administration per local institutional guidelines. (13) Dacarbazine is the only approved chemotherapy agent but temozolomide and carboplatin/paclitaxel are often used as well depending on patient preference and physician experience. Abbreviations: BRAF+, positive for actionable BRAF mutations; BRAF–, negative for actionable BRAF mutations; CNS, central nervous system; IL, interleukin; LDH, lactate dehydrogenase; PS, performance status metastasis who received combination ipilimumab/nivo- PD-L1 expression status (15%) or tumor cell mutation lumab, the intracranial response rate (IRR) was 56% burden (10%) was important for treatment planning. For (95% CI: 44–68); in addition, 19% of patients had a a typical patient with a good performance status, regard- complete response (CR) [54]. Moreover, in 50 patients less of BRAF status, a majority of the panel members with untreated brain metastases, both nivolumab mono- recommended enrollment onto a clinical trial (75%) as a therapy (ICR 20% [95% CI: 7–41]) and combination ipili- first-line option, followed by treatment with combination mumab/nivolumab (ICR 44% [95% CI: 24–65]) were ipilimumab and nivolumab, which was favored over found to be active [55]. Based on the discussion, recom- single-agent PD-1 inhibitor therapy (pembrolizumab or mendations for the management of stage IV melanoma nivolumab) by three of the five members who did not were considered independently for patients with a good favor clinical trial. This ratio of support for combined performance status, generally low disease burden and ipilimumab and nivolumab versus single-agent slow tempo of disease progression versus patients with a anti-PD-1 therapy held up by the panel when a clinical declining performance status, widespread visceral metas- trial was not an option (12 of 20 respondents). Half of tases and/or rapid disease progression (Fig. 4). Extent of the panelists felt that the selection of the combination of CNS involvement, mass effect, cerebral edema and ster- ipilimumab and nivolumab should mandate transfer of oid requirements and symptoms will also factor into the patient to a physician or center with more immuno- treatment decisions. therapy experience due to the higher toxicity incidence and complexity associated with combination immuno- Consensus management of stage IV melanoma patients therapy. Panel members (83%) also suggested that with a good clinical performance status T-VEC be considered if accessible lesions for injection The treatment approach for patients with good perform- are present in patients whose disease has progressed ance status stage IV melanoma who are not surgical can- after combination or monotherapy checkpoint inhibitors didates should include an assessment of BRAF mutation and who still maintain a good performance status. status, history and physical examination, serum LDH, Participation in clinical trials is dependent on having ac- baseline laboratory evaluation and whole body imaging cess to appropriate studies and ensuring that patients meet (see Table 1), and assessment of tempo of disease, tumor protocol-specific eligibility requirements. In addition, pa- burden, and presence or absence of CNS disease before tients must be willing to participate in a clinical trial and treatment selection. Only a minority of panelists felt that provide written, informed consent. The high priority placed Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 13 of 23 on clinical trials is a reflection of the progress being made ipilimumab alone [HR 0.42, P < 0.001] and 6.9 months in clinical drug development in melanoma and interest in for nivolumab alone [HR 0.57, P < 0.001]). In this study, defining more effective regimens with acceptable toxicity. If patients whose tumors exhibited > 5% PD-L1 expression such clinical trials are not readily available or patients are had a median PFS of 14 months in both combination not willing or do not qualify for participation, combination and nivolumab alone arms; however, in patients with ipilimumab and nivolumab was considered the treatment PD-L1 negative tumors, the median PFS was 11.2 months of choice for patients with good performance status. This for combination treated subjects compared to 5.3 months recommendation was based on a series of prospective clin- in patients treated with nivolumab alone. TRAEs of ical trials demonstrating improved response rates with the grade 3 or greater were reported in 55% of the combin- combination, although increased incidence of ation treated patients, 16.3% in those receiving nivolu- immune-related adverse events (irAEs) was also re- mab alone and 27.3% in the ipilimumab alone cohort. At ported. In a phase 1 study, 53 melanoma patients were a minimum follow-up of 37 months, the median OS has treated with concurrent nivolumab (doses ranged from not been reached for patients on the combination arm 0.3–10 mg/kg) and ipilimumab (dose ranged from 1 to compared to 37.6 months and 19.9 months in patients 10 mg/kg) IV every 3 weeks for four doses followed by receiving nivolumab or ipilimumab alone, respectively nivolumab alone every 3 weeks for another four doses [58]. The three-year OS was 58% for combination ther- [56]. The ORR was 40% based on World Health apy patients compared to 52% in nivolumab alone (HR Organization (WHO) criteria with a disease control 0.85, 95% CI: 0.68–1.07; non-significant P-value) and rate of 65% [56]. Treatment-related adverse events 34% in patients treated with ipilimumab alone (HR for (TRAEs) were seen in 93% of patients with grade 3 or ipilimumab/nivolumab vs. ipilimumab 0.55, 95% CI: greater events from all causes observed in 72%; 53% 0.45–0.69; P < 0.0001; HR for nivolumab vs. ipilimumab were considered treatment-related. The authors con- 0.65, 95% CI: 0.53–0.80; P < 0.0001) [58]. cluded that the maximum doses with an acceptable The above described studies collectively provide Level A safety profile were nivolumab at 1 mg/kg and ipilimu- evidence supporting the role of combination ipilimumab mab at 3 mg/kg, with objective responses seen in 53% and nivolumab for first-line treatment in patients with mel- of patients treated with this dosing regimen [56]. anoma. However, the lack of a significant OS benefit for the Following the phase 1 data, a double-blind study was combination over nivolumab alone, particularly in patients conducted in 142 treatment-naïve, metastatic melanoma with BRAF WT or PD-L1-expressing tumors [58], suggests patients and enrolled in a 2:1 manner to treatment with it is reasonable to consider anti-PD-1 agents alone at this ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) or ipili- time. In CheckMate 067, a sub-group analysis showed sig- mumab (3 mg/kg) and placebo every 3 weeks for four nificant improvement in PFS and numerical improvement doses [57]. Patients in the combination group were able in OS with combination therapy only in patients with low to receive additional maintenance nivolumab and at a (< 5 and < 1%) PD-L1 staining; however, the panel did not median follow-up of 24.5 months, 2-year OS was 63.8% consider there to be sufficient data to support a role for for those in the combination treatment arm vs. 53.6% in PD-L1 expression in clinical decision-making at this time the ipilimumab arm [57]. Of note, patients in the ipili- [56–58]. While adverse events are significantly greater with mumab arm were permitted to cross over to nivolumab combination ipilimumab/nivolumab treatment compared monotherapy at time of disease progression, making this to monotherapy, there is some evidence that health-related trial a study of combination ipilimumab and nivolumab quality of life may not be significantly impacted by concur- vs. sequential ipilimumab followed by nivolumab. Inter- rent combination treatment [59] due to a greater time with- estingly, there was a 22% CR rate and improvement in out disease related symptoms or treatment toxicity (as progression-free survival (PFS) for the combination al- measure by QTWIST) [60]. though median OS was not reached in either treatment The panel went on to recommend monotherapy with group. Similar to other trials, the grade 3 or greater anti-PD-1 agents as another option for patients who are TRAE rate was 54% in the combination cohort com- not able to participate in a clinical trial or are not eli- pared to 20% in the ipilimumab alone cohort. gible for combination ipilimumab/nivolumab. There are These data led to a randomized phase 3 trial in which two agents available, pembrolizumab, which is adminis- 945 treatment-naïve patients with unresectable stage III tered at 200 mg IV every 3 weeks, and nivolumab ad- or IV melanoma were randomized in a 1:1:1 ratio to ministered at 240 mg IV every 2 weeks or 480 mg IV treatment with ipilimumab and nivolumab, nivolumab every 4 weeks (per a recent change to non-weight-based alone or ipilimumab alone [11]. The study was designed dosing). The panel considered these drugs equally effect- with two primary endpoints, PFS and OS, with a signifi- ive, with indistinguishable toxicities, and advised that se- cant improvement seen in PFS (11.5 months for the lection can be based on physician experience or patient combination treated patients vs. 2.9 months for preference. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 14 of 23 Pembrolizumab and nivolumab are monoclonal anti- study in which 655 melanoma patients were treated with bodies that block the PD-1 T cell checkpoint, and there pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every are considerable data supporting their use in the treat- 3 weeks, or 2 mg/kg every 3 weeks until disease progres- ment of metastatic melanoma. In a clinical dose-finding sion, intolerable toxicity, or investigator decision to stop study, patients with advanced melanoma were treated treatment [63]. In this study, investigators evaluated the with pembrolizumab (initially called lambrolizumab) at a impact of pembrolizumab based on prior exposure to dose of 10 mg/kg every two or three weeks or 2 mg/kg ipilimumab. To address this, 135 patients (48 with prior every 3 weeks [9]. Patients were allowed, but not re- ipilimumab and 87 without) were enrolled without quired, to have had prior ipilimumab therapy to be eli- randomization and 520 patients were prospectively ran- gible for study participation. The study enrolled 135 domized (294 with prior ipilimumab and 226 without). patients and the response rate assessed by standard Re- Response rates were reported at a median follow-up of sponse Evaluation Criteria in Solid Tumors (RECIST) 21 months; response rates were 33% in patients with 1.1 criteria was 38% without significant differences be- prior ipilimumab exposure and 45% in treatment-naïve tween doses or by prior ipilimumab exposure. The re- patients. The 12-month PFS was 35% overall and 52% in sponses were durable with 81% of patients still in treatment-naïve patients, and the median OS was response at a median follow-up of 11 months. The most 23 months overall and 31 months in treatment-naïve frequent adverse events were fatigue, rash, pruritus and subjects. Overall, 14% of patients reported at least one diarrhea, and these were generally grade 2 or less [9]. grade 3 or greater TRAE. These results confirmed re- Pembrolizumab was also evaluated in a separate sponse rates seen in the phase 1 trials and also sup- multi-institutional phase 1 study evaluating doses of ported the 2 mg/kg dosing schedule. 2 mg/kg and 10 mg/kg every 3 weeks in patients with These initial studies were followed by a randomized ipilimumab-refractory advanced melanoma [61]. In this phase 3 clinical trial in which 834 patients with ad- study, 173 patients received 2 mg/kg (n = 89) or 10 mg/ vanced melanoma were randomized 1:1:1 to pembrolizu- kg (n = 84) pembrolizumab and data were reported at a mab (10 mg/kg) every 2 weeks or every 3 weeks or four median follow-up of 8 months. The response rate by doses of ipilimumab (3 mg/kg) every 3 weeks [64]. The RECIST was 26% at both doses. Treatment was consid- study was powered for primary endpoints of PFS and ered tolerable with the most frequent TRAEs being fa- OS. In this study, the estimated 6-month PFS was 47.3% tigue, pruritus, and rash; all were grade 2 or less except for pembrolizumab every 2 weeks, 46.4% for pembroli- for five patients (3%) who reported grade 3 fatigue [61]. zumab every 3 weeks and 26.5% for ipilimumab (HR, These studies led to the regulatory approval of pembroli- 0.58; P < 0.001). The response rate was higher with pem- zumab, at a dose of 2 mg/kg every 3 weeks, for the treat- brolizumab administered every 2 weeks (33.7%) and ment of patients with metastatic melanoma. The every 3 weeks (32.9%), vs. ipilimumab (11.9%) (P < 0.001 approved dose and schedule was subsequently changed for both comparisons) and responses were durable in to 200 mg IV every 3 weeks. 89.4, 96.7, and 87.9% of patients, respectively, after a me- In a multi-institutional phase 2 study, 540 melanoma dian follow-up of 7.9 months. Grade 3 or greater TRAEs patients with disease that had progressed following ipili- were lower in the pembrolizumab cohorts (13.3 and mumab and BRAF/MEK inhibitor therapy, if their tu- 10.1%) compared to ipilimumab alone (19.9%). mors harbored a BRAF (V600) mutation, were The panel was queried about when single-agent randomized 1:1:1 to treatment with pembrolizumab at anti-PD-1, as opposed to combination immunother- 2 mg/kg every 3 weeks (N = 180), 10 mg/kg every apy, was most appropriate. In considering BRAF mu- 3weeks (N = 181) or investigator-choice chemotherapy tation, LDH, PD-L1 expression status and mucosal (N = 179) [62]. Patients were stratified for performance histology, 42% of panelists stated that PD-L1 expres- status, LDH level and BRAF mutation status. The PFS sion was the most important discriminating factor was significantly better for patients in both pembrolizu- supporting single agent anti-PD-1 treatment, despite mab treatment arms compared to chemotherapy (HR lack of level A evidence. One each said mucosal mel- 0.57, P < 0.0001 for 2 mg/kg and HR 0.50, P < 0.0001 for anoma or PD-L1 negative status should prompt com- 10 mg/kg). The 6-month PFS was 34% in patients bination therapy, two stated that single-agent PD-1 treated with pembrolizumab at 2 mg/kg, 38% at 10 mg/ therapy should always be favored, and 10 panelists kg and 16% for chemotherapy. The toxicity profile was felt that a number of other factors should be consid- similar to previous pembrolizumab trials with an inci- ered, including medical co-morbidities (e.g. auto- dence of grade 3–4 adverse events of 11 and 14% in the immune disease, history of organ transplantation, pembrolizumab 2 mg/kg and 10 mg/kg cohorts, com- etc.), disease volume/tumor burden, site of disease, pared to 26% for patients receiving chemotherapy. These performance status, functional status, and patient data were also similar to another global phase 1b clinical preference. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 15 of 23 Pembrolizumab has also been tested in a reported [4, 67]. Treatment generally requires referral to non-randomized phase 2 study in 52 patients with CNS centers with experience in management of high-dose metastases; eighteen patients with melanoma and 34 IL-2 and patients should have a good performance status with non-small cell lung cancer (NSCLC) presented with when starting treatment. untreated brain metastases and were treated with 10 mg/kg every 2 weeks until disease progression [65]. Consensus management of patients with stage IV Eligible patients had metastatic lesions measuring 5– melanoma and poor clinical performance status 20 mm, had no neurologic symptoms, did not require The panel considered that patients with a poor or de- corticosteroids, and for the NSCLC cohort were re- clining performance status, those with extensive disease quired to have positive tumor PD-L1 expression. A pre- burden, rapid tempo of progression, presence of active liminary analysis was reported with evidence of CNS CNS disease and those that have documented disease disease response in 4 of the 18 (22%) patients with mel- progression after T cell checkpoint inhibitors or T-VEC anoma and 6 of 18 (33%) patients with NSCLC. The re- should be treated differently than those with overall sponses appeared to be durable and TRAEs were typical good performance status, limited disease burden, slow of pembrolizumab toxicity in other studies and only 3 tempo of progression and without active CNS metasta- patients (17%) with melanoma had neurologic toxicities, sis. Patients with poor performance status should have including grade 3 cognitive dysfunction and grade 1–2 BRAF mutation analysis to determine if there is a V600 seizures. The authors concluded that pembrolizumab or other targetable mutation, for which targeted therapy was safe in patients with CNS metastasis and might be regimens are available [44–48]. Noting that clinical trial associated with therapeutic responses. participation in patients with poor performance status is Finally, a minority of panel members (46%) who were fa- challenging due to protocol restrictions, the panel miliar with T-VEC recommended T-VEC be considered in applauded efforts by the ASCO-Friends of Cancer Re- patients with good performance status stage IV melanoma search working group, which is taking steps to broaden based on the results of the previously mentioned random- clinical trial eligibility and recommended that, whenever ized phase 3 clinical trial [12]. This requires that tumors feasible, these patients be considered for clinical trial be clinically visible or palpable for injection or be access- participation whether or not their tumor harbors a ible by ultrasound guidance. This option may be especially BRAF mutation (see Fig. 4). In the absence of a BRAF appropriate for patients who are not candidates for T cell mutation, and if clinical trials are not an option, the checkpoint inhibitors, such as patients with significant panel recommended treatment with single agent co-morbid conditions, or older patients unable to tolerate anti-PD-1 therapy, such as pembrolizumab or nivolumab significant systemic toxicity (Fig. 4). based on the Level A data described above. In patients Patients with tumors that do not respond to ipilimumab whose tumor harbors a BRAF mutation and who are not and nivolumab, monotherapy with anti-PD-1 agents, or eligible for clinical trial participation, treatment with T-VEC should be treated according to the guidelines for BRAF/MEK targeted therapy should be considered, and poor performance status patients (see Fig. 4) and treat- readers are referred elsewhere for guidance on adminis- ment selection will depend on BRAF mutation status and tration of these agents [68]. If patients progress on tar- which drug(s) an individual patient has already received. geted therapy or are not eligible for such agents, In general, panel members recommended targeted therapy monotherapy with pembrolizumab or nivolumab is rec- (if BRAF mutation is present), combination immunother- ommended. There is evidence for activity with both apy (if not previously received and performance status is BRAF/MEK inhibitors and anti-PD-1 agents alone or good), ipilimumab monotherapy (if the patient has not with ipilimumab in the treatment of CNS metastasis been previously exposed to the agent), high-dose IL-2, [69]. Combination ipilimumab/nivolumab could also be clinical trial participation, or chemotherapy. considered in selected patients where they have not pre- There is considerable evidence supporting a role for viously received such treatment, the performance status high-dose IL-2 in the treatment of patients with stage IV decline is not related to significant medical melanoma, and the drug has been approved since 1998. co-morbidities and the patients is clinically able to toler- A fairly consistent ORR of 16–17%, including 6–7% ate therapy. While response rates are notably higher CRs, has been reported [7]. Further analysis of the ori- with combination ipilimumab/nivolumab, the incidence ginal 270 patients treated in the regulatory trials at a of serious adverse events is also higher, and the risk/ median follow-up at 7 years demonstrated a median dur- benefit ratio must be considered on an individual basis. ation of response that was unchanged in patients achiev- The majority of the panel (67%) recommended combin- ing an initial CR or PR at 8.9 and 5.9 months, ation ipilimumab/nivolumab for treatment of CNS mel- respectively [66]. The benefits of IL-2 and contemporary anoma, while a minority of the panel (33%) would treat management of IL-2-related toxicity has been previously individual CNS lesions with stereotactic radiation prior Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 16 of 23 to systemic immunotherapy, and this may require con- retrospective trials was performed [73]. Across all stud- sultation/coordination with neurosurgery and/or radi- ies included in the analysis, median OS was 11.4 months ation oncology specialists [65, 70]. As always, disease (range 10.7–12.1 months) and the investigators saw a symptomatology and corticosteroid requirements will in- similar plateau in the survival curve at approximately fluence treatment decisions. 3 years. A 3-year survival rate of 22% was seen in all pa- In patients who have failed the above treatments, re- tients with 26% in treatment-naïve subjects and 20% in gardless of performance status, other therapeutic options previously treated patients. Ipilimumab has also been should include renewed consideration of targeted ther- shown to have activity against CNS metastases in a sin- apy in patients with BRAF mutated tumors if this has gle arm phase 2 clinical trial [74]. A randomized clinical not been previously used. Other options include clinical study in 245 unresectable stage III-IV melanoma pa- trial participation, single agent ipilimumab, high-dose tients evaluated ipilimumab at 10 mg/kg intravenously IL-2, T-VEC, and cytotoxic chemotherapy (Fig. 4). on day 1 and GM-CSF at 250 μg subcutaneously on days Ipilimumab was initially approved for the treatment of 1–14 of each 21-day cycle [36]. In this study, an im- metastatic melanoma based on several clinical trials that provement in overall survival for the combination treat- demonstrated durable responses and improvement in ment was observed (17.5 vs. 12.7 months) and, OS [8, 71]. Further follow-up studies have confirmed the unexpectedly, the incidence of serious grade 3 or greater potential for durable responses and long-term survival adverse events was lower in the combination group providing Level A data supporting a role for ipilimumab compared to ipilimumab alone (44.9% vs. 58.3%). Al- in melanoma [72, 73]. Here we summarize key data from though promising, further validation of this combination ipilimumab trials that support the rationale for its use in in a larger sample size and at ipilimumab doses of 3 mg/ the second-line setting in patients with advanced melan- kg are needed. oma. The first important study was a multi-institutional, Some panel members also recommended T-VEC in double-blind, randomized phase 3 trial in which 676 pa- this setting. There is limited evidence supporting this tients with advanced melanoma expressing human recommendation. In the randomized phase 3 study, a leukocyte antigen (HLA)-A2 were randomized to treat- subset analysis found that durable response was higher ment with ipilimumab (3 mg/kg every 3 weeks for four than control therapy in treatment-naïve patients (24% doses), ipilimumab (same dose and schedule) given with vs. 0%) when compared to those receiving T-VEC as an HLA-A2-restricted modified gp100 peptide vaccine, second-line or later therapy (10 vs. 4%), and a similar or vaccine alone [8]. Overall, patients treated with ipili- trend toward better OS was seen when T-VEC was used mumab demonstrated improved OS compared to pa- in the first-line setting [12]. As mentioned, T-VEC treat- tients receiving vaccine alone (10 months vs. 6 months; ment requires accessible lesions for direct injection. P = 0.0026). This study led to FDA approval for ipilimu- Thus, while IL-2 and T-VEC are good options to con- mab as single agent therapy for melanoma in 2011. An- sider, careful patient selection is required to optimize other prospective, randomized clinical trial was therapeutic benefit. subsequently reported in which 502 patients with treatment-naive melanoma were randomized to ipilimu- Special issues in tumor immunotherapy for melanoma mab at 10 mg/kg every 3 weeks for four doses and The panel recognized that there are several unique is- 2 2 dacarbazine (850 mg/m ) or dacarbazine (850 mg/m ) sues related to clinical management of patients with and placebo [71]. This trial reported improved OS in pa- melanoma opting for immunotherapy. These include is- tients treated with ipilimumab and dacarbazine sues related to the clinical integration of biomarkers, la- (11.2 months vs. 9.1 months; P < 0.001). The study also boratory assessment, and imaging in the management of reported improved 3-year survival of 20.8% for patients before and during treatment. There are also ipilimumab-dacarbazine-treated patients compared to concerns over management of irAEs that are unique to 12.2% for dacarbazine alone (HR 0.72; P < 0.001). An up- immunotherapy treatment and guidelines for when to date of this study population demonstrated 5-year sur- stop therapy given the potential for delayed regression. vival rate of 18.2% in patients in the ipilimumab and While the panel largely acknowledged that there is only dacarbazine cohort compared to 8.8% in the dacarbazine Level C data to inform decision-making with respect to alone arm (P = 0.002) [72]. A plateau in the survival these issues, consensus recommendations were made curve was observed around 3 years and persisted out to and are summarized in Table 1. 5 years. The authors also reported safety and found the only persistent grade 3 or greater irAEs involved the Consensus management of immune-related adverse events skin. In order to better estimate the survival benefit in Immunotherapy is associated with irAEs that manifest as patients treated with ipilimumab, a retrospective, pooled autoimmune-like phenomenon involving lymphocytic analysis of 1861 patients treated in 10 prospective and 2 infiltration and inflammation of various tissues and Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 17 of 23 organ systems. These events may range from vitiligo not assay sensitivity or reliability, the dynamic regulation of requiring intervention to more serious episodes of PD-L1 expression and sampling error [85]. At this time, immune-related colitis, pneumonitis, hepatitis and hypo- PD-L1 expression is not considered valuable in clinical physitis [75]. More recently, there have been rare case management of patients with melanoma by the majority reports of immune-related myocarditis associated with (58%) of the consensus panel. However, some panelists did mortality [76–78]. These events are problematic and consider PD-L1 expression as important in clinical may occur early in the treatment course or weeks to decision-making in special situations, such as in patients even months after stopping therapy, and a high level of with co-morbid medical conditions that might preclude clinical suspicion must be maintained in patients treated combination immunotherapy (25% of panelists), patients with immunotherapy. The panel did not specifically ad- older than 65 years of age (8%), patients less than 65 years dress toxicity management in detail but endorsed of age (4%) or in the presence of BRAF mutation (4%). In current clinical recommendations to educate patients these settings, high PD-L1 expression would support using and caregivers about toxicities, monitor patients care- single agent PD-1 blockade and reserve combination ther- fully for emergence of potential irAEs, rapidly rule out apy for those without PD-L1 expression since these patients other causes and initiate corticosteroid management are less likely to respond to monotherapy [58]. once a high-grade immune-mediated event is identified. Mutation burden in the tumor has also recently been rec- There is currently some controversy as to whether there ognized as a potential predictor of response to immuno- is an association between irAEs and improved thera- therapy with T cell checkpoint inhibitors [86, 87]. Thus, it is peutic responses [79]. The panel, however, felt the data interesting to note that melanoma, NSCLC and other tu- were strong enough to demonstrate prolonged responses mors where these agents have shown clinical activity appear even after treatment was stopped due to toxicity, and to be associated with higher levels of mutations within the with the use of steroids; thus, the panel did not recom- tumor genome [86, 88, 89]. The biologic basis of this find- mend continued treatment through significant toxicity ing may be due to the emergence of neoantigens derived for the purpose of enhancing clinical response. from the mutations resulting in abnormal proteins and In patients who experience grade 2 or greater adverse peptide fragments within the tumor cells allowing recogni- events, treatment may be withheld during acute manage- tion by T cells that might not recognize the native peptide ment and resumed upon resolution, but treatment will [81]. Thus, mutation burden could be an important pre- likely need to be permanently discontinued in the face of a dictor of benefit for treatment with immunotherapy. In its high grade or recurrent immune-mediate adverse event first tissue-agnostic approval based on a biomarker, the [14]. Additional management guidelines are widely antici- FDA recently granted accelerated approval to pembrolizu- pated in the near future and clinicians should monitor the mab for the treatment of patients with unresectable or literature for new guidance in this area. Several groups, in- metastatic mismatch repair deficient (dMMR) or microsat- cluding the SITC Toxicity Management Working Group, ellite instability-high (MSI-H) solid tumors that have pro- have recently published guidelines to address the manage- gressed after prior treatment and have no alternative ment of adverse events from immune checkpoint inhibition treatment options. This approval was based on data from [80–82]. We have previously reported on the management 149 patients across 5 single-arm clinical trials in which of acute IL-2 and interferon-related side effects, including pembrolizumab illustrated an ORR of 39.6%, including 11 interferon-associated depression in the first consensus CRs and 48 PRs [90]. Similar results led to approval of statement on melanoma [4]. nivolumab in this population based on results from the CheckMate 142 clinical trial [91]. Another area of intense Consensus statement on predictive biomarkers for investigation is the association between therapeutic effect- melanoma immunotherapy iveness of immunotherapy regimens and the presence of The panel acknowledged the importance of identifying pre- IFN-γ-related gene signatures within the tumor microenvir- dictive biomarkers to help inform clinical decision-making onment [92]. While the Task Force agreed with the import- in melanoma immunotherapy. Preliminary reports of higher ance of emerging data in this area, there are not sufficient response rates in patients treated with T cell checkpoint in- prospective validation studies to recommend use of these hibitors who have high tumor-infiltrating lymphocytes and parameters for clinical decision-making for patients with PD-L1 expression in the tumor microenvironment sug- melanoma at this time (see Table 1). gested these factors might serve as biomarkers [83]. In fact, PD-L1 expression has been used for patient selection and is Consensus statement on laboratory assessment for associated with improved outcomes with anti-PD-1 therapy melanoma patients on immunotherapy in NSCLC [84]. Nonetheless, PD-L1 expression has not The panel strongly recommended routine baseline and been validated for melanoma patient selection or thera- surveillance laboratory assessments be performed on pa- peutic monitoring, and this may relate to differences in the tients undergoing treatment with tumor immunotherapy. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 18 of 23 While panelists acknowledged a lack of evidence-based brain imaging depending on tumor stage and location, data in this area, serum LDH is considered an important the disease-free period from initial diagnosis and as clin- prognostic marker as it is part of the current AJCC (v7 ically indicated (see Table 1). A minority opinion sug- and v8) staging for melanoma, and toxicity management gested that imaging could be individualized for each is supported by careful laboratory analysis with baseline patient. values for comparison. Clinicians should be alert for signs and symptoms of irAEs, which can present with isolated Consensus statement on clinical endpoints and treatment laboratory abnormalities, such as elevated hepatic en- cessation zymes, serum creatinine, amylase, lipase, glucose and The panel considered the issue of when to stop treat- others. A baseline complete blood count, serum chemistry ment, which is complicated in patients receiving im- panel to evaluate hepatic, renal and electrolyte parameters, munotherapy since “pseudo-progression” has been and a thyroid function panel that includes at least free T4 reported and is thought to be related to delayed re- and thyroid stimulating hormone (TSH) should be ob- sponse kinetics and/or tumor immune infiltration. This tained on all patients. With increasing awareness of the possibility has suggested that additional criteria may be risk of myocarditis, monitoring of creatine kinase and needed to assess response optimally and avoid discon- troponin I or T should also be considered. The panel also tinuing treatment in patients who might experience de- unanimously agreed that these same laboratory assays layed regression; these criteria have been termed should be repeated during therapy but there was no agree- immune-related response criteria (irRC) or iRECIST [93, ment on the frequency of assessment. Some panel mem- 94]. While pseudo-progression has been reported with bers suggested obtaining lab work prior to each infusion, ipilimumab [8] and T-VEC [12], there is some evidence whereas others suggested early monitoring and then limit- that this phenomenon may also occur with anti-PD-1 ing collection to periodic assessment or as clinically indi- agents [95]. In a review of 655 patients treated with cated. Patients who present with signs or symptoms of pembrolizumab, 24 (7%) had atypical responses defined possible hypophysitis should have additional hormone as “early pseudo-progression” in 15 (5%) and “delayed levels monitored prior to starting corticosteroid interven- pseudo-progression” in 9 (3%) by the investigators [95]. tion (see Table 1 for recommended panel). This study also found 14% of patients had progression by RECIST criteria but did not meet the definition for Consensus statement on imaging for melanoma patients on disease progression by the irRC and suggested that clin- immunotherapy ical benefit may be underestimated if standard RECIST The type and frequency of imaging for patients with criteria are used in monitoring clinical endpoints for im- melanoma treated with immunotherapy continues to be munotherapy studies. There are also case reports of controversial and there are no prospective, randomized pseudoprogression of melanoma brain metastases in pa- clinical trials to guide clinical decision-making. Since tients treated with pembrolizumab [96]. tumor regression may be delayed with immunotherapy, The panel generally agreed that new lesions or an in- appropriate imaging becomes increasingly important to crease in tumor burden in patients treated with inter- ensure patients achieve optimal therapeutic benefit. feron or IL-2 is cause for treatment cessation. The Thus, all panel members recommended that whole body assessment of response in patients receiving T cell imaging be performed prior to and at regular intervals checkpoint inhibitors or T-VEC is more challenging. during immunotherapy. The majority of the panel use The majority of the panel recommends that patients computed tomography (CT) scans of the chest, abdo- with disease progression by imaging and who are clinic- men and pelvis and magnetic resonance imaging (MRI) ally asymptomatic without a decline in performance sta- of the brain. Additional imaging may also be necessary tus can be safely continued on treatment and re-imaged in some patients with suspected disease in locations not in 1–2 months to evaluate response. There is limited imaged with these scans, such as the neck or extremities. Level B evidence to support this position. In a retro- A minority of panel members recommended whole body spective study using pooled data of 526 randomized pa- positron emission tomography (PET) or PET–CT scans tients from two phase 3 trials of nivolumab in as the preferred imaging modality. The false-positive rate treatment-naïve melanoma patients, those who received for PET imaging and difficulty providing definitive lesion continued treatment beyond first disease progression (N measurements were reasons cited for preferring CT and = 85) were compared to those patients who immediately MRI imaging by the majority of panel participants. Al- discontinued nivolumab at first signs of disease progres- though the panel recognized the absence of Level A data sion (N = 221). The authors reported that 24 of the 85 to support post-treatment imaging, the consensus rec- (28%) patients treated beyond progression went on to ommendation was that patients should be followed every experience greater than 30% regression after further 3–12 months with whole body CT imaging and selective therapy [97]. The authors concluded that selected Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 19 of 23 patients might derive further clinical benefit from con- CR, which was allowable per protocol [98]. In presented tinued treatment beyond progression. The panel also data at ASCO 2017, Robert and colleagues presented recommended that patients with unacceptable toxicity data from the Keynote 006 (described above) showing or clinical deterioration should be promptly removed that in the 104 patients with SD, PR, or CR who com- from treatment and only if disease progression is docu- pleted 2 years of therapy with a median follow up off mented should they move on to another therapeutic pembrolizumab of 9.7 months, 23 of 24 CRs and 60 of regimen. 64 PRs remained in response, while 8 of 10 patients with In addition, it is critical that clinicians monitoring mel- SD remained with stable disease. anoma patients on immunotherapy be able to confirm Further, a recent pooled retrospective analysis of 2624 clinical responses and stop therapy at an appropriate melanoma patients treated with PD-1 blockade from timepoint. The panel recognized that there is consider- eight multi-center clinical trials submitted to the FDA, able controversy on how best to define when to stop identified 692 of 1361 patients (51%) who had continued therapy and agreed that there may be limited evidence PD-1-directed treatment after documentation of to support continued treatment beyond disease progres- RECIST-defined progressive disease [99]. The authors sion. Because of this uncertainty, the panel considered pooled data from all patients and found 19% of patients confirmation of objective responses to be important for treated beyond progression had a 30% or greater de- optimal clinical decision making, and suggested that pa- crease in tumor burden and this represented 4% of the tients achieving CR, PR or SD, should be re-imaged entire 2624 patient population. The median overall sur- within 2–3 months to confirm response. A minority of vival was also greater in patients treated beyond progres- the panel suggested that patients with incomplete re- sion compared to patients who did not receive sponses, and where all remaining sites of disease can be treatment beyond progression (24.2 vs. 11.2 months). In completely excised, could be considered for surgical this study, the rate of serious adverse events was slightly management or biopsy to confirm existence of viable lower in the patients treated beyond progression com- tumor in these areas and/or identify other potential pared to patients who stopped treatment at progression treatment options (e.g., through mutational burden ana- (43% vs. 54%), and immune-related adverse events were lysis). Finally, the panel was asked about scenarios in similar in incidence in both groups. The authors con- which it would be appropriate to stop therapy in a pa- cluded that treatment beyond progression with tient with SD or better response. Of the panelists anti-PD-1 therapy in might be appropriate in selected responding, 4% would be comfortable stopping therapy melanoma patients but clinical benefit remains to be once a patient achieves a radiographic complete re- proven. sponse, 8% would stop after achieving PET-CT-based complete response, and 29% would stop after completing Conclusions 2 years of therapy. A further 38% would consider any of The approval of six new immunotherapy agents since these endpoints appropriate to prompt treatment dis- 2011 has led to the emergence of cancer immunotherapy continuation. Five panelists had alternative suggestions as the standard of care for patients with high-risk and as to when to stop treatment: after 1–2 years of therapy advanced melanoma. However, limited data are available if disease remains stable, 1 year after documentation of a to guide optimal patient selection, treatment sequencing CR, or after a radiographic CR or 2 years of therapy. and clinical monitoring during therapy. Immunotherapy None of the panelists felt that pathologic CR was neces- differs from standard chemotherapy in its mode of ac- sary to halt treatment. tion, in being associated with a higher likelihood of dur- The data to support these recommendations are, to be able response when response occurs, and in the fair, premature. With that said, the above recommenda- potential for delayed response and appearance of irAEs tions are made based on the anecdotal experience of that require clinical diligence to detect and treat. Further each panel member who have seen the maintenance of progress in the field is anticipated to focus on combin- prolonged clinical benefit off therapy, appreciating that ation immunotherapy strategies between two or more the risks of continuing therapy indefinitely are legitim- immunotherapy agents and with targeted therapies, ate, and the available data from melanoma clinical trials metabolic (e.g., indoleamine 2,3-dioxygenase [IDO], vas- are premature. The existing published data come from cular endothelial growth factor [VEGF]) inhibitors and the Keynote 001 study, which enrolled 655 patients with adoptively transferred T cells. This updated SITC con- melanoma, 105 of whom developed a CR. With a me- sensus statement provides recommendations by an ex- dian follow up of 30 months from first identification of pert panel of melanoma specialists to assist in the CR, the chance of maintaining a CR was 91% in the 105 clinical management of melanoma patients treated with patients treated beyond response and 90% in the 67 pa- immunotherapy, the use of which provides a beneficial tients who discontinued therapy for observation after therapeutic option for patients with melanoma. Sullivan et al. Journal for ImmunoTherapy of Cancer (2018) 6:44 Page 20 of 23 Endnotes Providence Cancer Center, Portland, OR 97213, USA. Carolinas Medical Center, Charlotte, NC 28204, USA. Carol G. Simon Cancer Center, There are no available data from adjuvant Morristown, NJ 07046, USA. Dana-Farber Cancer Institute, Boston, MA BRAF-targeted therapy in resected Stage IV melanoma. 02215, USA. Received: 12 January 2018 Accepted: 17 May 2018 Additional files Additional file 1: Cancer Immunotherapy Guidelines- Cutaneous melanoma version 2.0 Task Force Roster. (DOCX 13 kb) References Additional file 2: Comments from Open Review. (DOCX 14 kb) 1. Cancer Stat Facts: Melanoma of the Skin. https://seer.cancer.gov/statfacts/ html/melan.html. Accessed 8 March 2018. Additional file 3: Cancer Immunotherapy Guidelines (Melanoma). 2. Hayes AJ, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, (DOCX 145 kb) Theaker J, Bliss JM, Thomas JM. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol. 2016;17(2):184–92. Abbreviations CI: Confidence interval; CR: Complete response; CT: Computed tomography; 3. Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and CTLA-4: Cytotoxic T lymphocyte antigen-4; FDA: U.S. Food and Drug immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. Administration; GM-CSF: Granulocyte macrophage colony-stimulating factor; 2017;14(8):463–82. HR: Hazard ratio; ICR: Intracranial response; IDO: Indoleamine 2,3- 4. Kaufman HL, Kirkwood JM, Hodi FS, Agarwala S, Amatruda T, Bines SD, Clark dioxygenase; IL-2: Interleukin-2; irAE: Immune-related adverse event; JI, Curti B, Ernstoff MS, Gajewski T, et al. The Society for Immunotherapy of IV: Intravenous; LDH: Lactate dehydrogenase; MRI: Magnetic resonance Cancer consensus statement on tumour immunotherapy for the treatment imaging; NSCLC: Non-small cell lung cancer; OR: Odds ratio; OS: Overall of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10(10):588–98. survival; PD-1: Programmed cell death 1; PET: Positron emission tomography; 5. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. PFS: Progression-free survival; PR: Partial response; SITC: Society for Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous immunotherapy of cancer; TSH: Thyroid stimulating hormone; T- melanoma: the eastern cooperative oncology group trial EST 1684. J Clin VEC: Talimogene laherparepvec; VEGF: Vascular endothelial growth factor Oncol. 1996;14(1):7–17. 6. Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, Mackie R, et al. Adjuvant therapy with pegylated Acknowledgments interferon alfa-2b versus observation alone in resected stage III melanoma: We would like to thank SITC staff for logistical and medical writing support. final results of EORTC 18991, a randomised phase III trial. Lancet. 2008; 372(9633):117–26. Authors’ contributions 7. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, HLK and RJS drafted the manuscript with input from the Task Force Sznol M, Parkinson D, Hawkins M, et al. High-dose recombinant interleukin (discussion during the in-person Task Force meeting and follow-up surveys 2 therapy for patients with metastatic melanoma: analysis of 270 patients that were sent after the meeting). All members of the Task Force participated treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16. in the conceptualization, review, and editing of this manuscript. In addition, 8. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, all authors read and approved the final version of this manuscript. Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; Ethics approval and consent to participate 363(8):711–23. Not applicable. 9. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with Competing interests lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. 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Journal for ImmunoTherapy of CancerSpringer Journals

Published: May 30, 2018

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