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Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a... � � VOLUME 36 NUMBER 32 NOVEMBER 10, 2018 ORIGIN AL REPORT JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037) Tara C. Mitchell, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, and Thomas F. Gajewski Author affiliations and support information ABSTRACT (if applicable) appear at the end of this article. Purpose Published at jco.org on September 28, Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label Clinical trial information: NCT02178722. phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed Correspondence to: Tara C. Mitchell, MD, death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum Abramson Cancer Center, University of tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: tara. Patients and Methods mitchell@uphs.upenn.edu. Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus © 2018 by American Society of Clinical intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, Oncology. Creative Commons Attribution patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every Non-Commercial No Derivatives 4.0 3 weeks. License. $ = Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum 0732-183X/18/3632w-3223w/$20.00 tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in $ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial ad- enocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors. J Clin Oncol 36:3223-3230. © 2018 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/ that target various immune evasion pathways INTRODUCTION to improve patient response rates and survival. Nivolumab (a PD-1 inhibitor) plus ipilimumab Immunotherapies, such as immune checkpoint (a CTLA-4 inhibitor) provides improved re- inhibitors (ICIs) that target programmed death sponse rates compared with monotherapy but protein 1 (PD-1)/programmed death-ligand 1 is associated with high grade 3/4 treatment- (PD-L1) and cytotoxic T-lymphocyte–associated related adverse events (TRAEs; 33% to 55%) protein 4 (CTLA-4), have resulted in meaningful and immune-related adverse events (AEs; 40% 1 2-5 advances in cancer treatment. However, interest to 45%). Other combination immunother- DOI: https://doi.org/10.1200/JCO.2018. 78.9602 exists in developing combination immunotherapies apies, including epacadostat—apotentand © 2018 by American Society of Clinical Oncology 3223 Mitchell et al highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 Additional eligibility criteria were presence of measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) ; (IDO1) enzyme—plus ICIs, also have been under clinical life expectancy . 12 weeks; Eastern Cooperative Oncology Group per- investigation. formance status# 1; ALT, AST, and alkaline phosphatase levels, 2.5 times The intracellular IDO1 enzyme catalyzes the first and rate- the upper limit of normal; and conjugated bilirubin , 2.0 times the upper 6,7 limiting step in the degradation of tryptophan to kynurenine. limit of normal. Exclusion criteria included prior treatment with ICIs Induced by interferon-g, prostaglandin E2, tumor necrosis factor-a, (except prior adjuvant CTLA-4 inhibitors for melanoma) or IDO in- transforming growth factor-b, and other proinflammatory signals, hibitors at any time, investigational device or treatment within 28 days or five half-lives (whichever was longer) before the first dose of study drug, IDO1 primarily is expressed by tumor, endothelial, and dendritic active autoimmune disease, known history of immunodeficiency, and use cells and macrophages within the tumor microenvironment 8,9 of systemic corticosteroids within 7 days before the first dose of study drug. (TME). IDO1-mediated depletion of cellular tryptophan and production of downstream metabolites may result in cell cycle arrest, anergy, and apoptosis of effector T cells and activation Study Design and Treatment In this multicenter, nonrandomized, open-label phase I/II study, of immunosuppressive cells (eg, regulatory T cells, myeloid- 10 11 phase I included a 3 + 3 + 3 epacadostat dose escalation in combination derived suppressor cells, tumor-associated macrophages ), with pembrolizumab, followed by three safety expansion cohorts of up to thereby contributing to immunosuppression within the TME. nine patients each. During dose escalation, patients received oral epaca- Furthermore, IDO1 upregulation may be associated with poor dostat (25, 50, or 100 mg) twice per day in combination with intravenous 12,13 prognosis in patients with advanced cancers. Therefore, pembrolizumab 2 mg/kg every 3 weeks or epacadostat 300 mg twice per IDO1 may represent a potential therapeutic target in various cancers, day with pembrolizumab 200 mg every 3 weeks. The first safety expansion especially in combination with other immunotherapies, including (epacadostat 50 mg twice per day plus pembrolizumab 200 mg every 3 weeks) enrolled patients with melanoma; the second and third ex- ICIs. pansions (epacadostat 100 mg twice per day and 300 mg twice per day, Epacadostat decreases tryptophan metabolism by inhibiting respectively, plus pembrolizumab 200 mg every 3 weeks) included patients IDO1, which results in enhanced proliferation of effector T cells with other eligible tumors. All patients could continue combination and natural killer cells, decreased apoptosis and increased acti- treatment with epacadostat and pembrolizumab for up to 24 months high vation of CD86 dendritic cells, and reduced expansion of followed by optional epacadostat monotherapy until confirmed radio- regulatory T cells. These changes shift the TME away from an graphic disease progression, intolerable toxicity, or withdrawal of consent. immunosuppressive state toward one that supports productive The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization guidelines for immune responses. In preclinical models, epacadostat plus an Good Clinical Practice and was approved by an independent ethics ICI suppressed tumor growth more effectively than single-agent committee or institutional review board at each study site. All patients treatment, primarily through reactivation of antitumor immu- provided written informed consent before initiation of any study pro- nity. Phase I and II clinical studies have shown that single-agent cedures or for any biomarker sample collections. 16,17 epacadostat is well tolerated in patients with advanced cancers, and doses $ 100 mg twice per day provide optimal inhibition of Assessments IDO1 activity and normalization of kynurenine levels. Favorable Safety and tolerability assessments were conducted at all scheduled objective response rate, disease control rate, and progression-free study visits (day 1 of every cycle), at end of treatment, and during follow- survival were observed in immunotherapy-naive patients with up. Laboratory assessments, including liver function tests, were performed melanoma treated with epacadostat plus ipilimumab. In addition weekly for the first 6 weeks. AEs were graded per Common Terminology to these encouraging safety and efficacy findings, interferon-g– Criteria for Adverse Events (version 4.0). AEs of special interest were those induced expression of IDO1 and PD-L1 in the TME supports the with an immune-related cause regardless of attribution to study treatment by the investigator. investigation of epacadostat plus PD-1/PD-L1 inhibitors, such as DLTs were protocol-specified AEs that occurred within the first pembrolizumab. 6 weeks of treatment, regardless of attribution to study drug. Such AEs The primary objectives of the phase I portion of the ECHO- could include grade 4 thrombocytopenia or neutropenia lasting . 7 days; 202/KEYNOTE-037 study were to evaluate the dose-limiting nonhematologic grade 4 toxicities; any grade 3/4 AST, ALT, or total bil- toxicities (DLTs), maximum tolerated dose (MTD), safety, and irubin elevation; any other grade 3 nonhematologic toxicity (except tolerability of epacadostat plus pembrolizumab in patients with protocol-defined controllable nausea, vomiting, and rash); or grade $ 2 advanced solid tumors. Exploratory end points were preliminary episcleritis, uveitis, or iritis. The recommended phase II dose (RP2D) was selected on the basis of tolerability during the safety expansion. Per study antitumor activity of this combination, epacadostat pharmacoki- protocol, dose escalation was permitted if there were no more than zero, netics, and pharmacokinetic-based projected pharmacodynamics. one, or three DLTs in three, six, or nine patients, respectively. If four or more of the first six or nine evaluable patients in a dose cohort experienced a DLT, the next-lower dose of epacadostat was deemed the RP2D. PATIENTS AND METHODS Tumor response was assessed at baseline, every 9 weeks for the first 18 months of treatment, and every 12 weeks thereafter. Objective response Patients rate (complete response [CR] or partial response [PR]) and duration of Eligible patients were $ 18 years old with histologically or cyto- response (time from response to disease progression) were determined on logically confirmed stage IIIB, stage IV, or recurrent non–small-cell lung the basis of investigator assessment per RECIST v1.1. Immune-related cancer (NSCLC), melanoma, renal cell cancer (RCC), endometrial ade- RECIST v1.1 was used to guide treatment; if imaging showed progressive nocarcinoma (EA), urothelial carcinoma (UC), triple-negative breast disease, patients could continue study treatment at the investigator’s cancer (TNBC), or squamous cell carcinoma of the head and neck discretion until confirmatory assessment $ 4 weeks later. (SCCHN). All patients progressed on one or more prior lines of therapy or Tumor PD-L1 status was determined at baseline by immunohisto- had no available curative treatment, except for patients with melanoma. chemistry using an investigational version of the PD-L1 IHC 22C3 3224 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors pharmDx assay (Agilent, Carpinteria, CA). PD-L1 positivity was defined as Table 1. Patient Demographics and Baseline Characteristics membranous PD-L1 expression in $ 1% of tumor cells or inflammatory cells in nests of tumor cells (melanoma score) for patients with melanoma; Variable Total, No. (%) $ 1% of viable tumor cells showing partial or complete membrane No. of patients 62 staining at any intensity (tumor proportion score) for patients with Median age, years (range) 59 (30-88) NSCLC; and $ 1% of stained tumor and immune cells relative to total Sex tumor cells (combined positive score) for patients with RCC, EA, UC, Male 35 (56) TNBC, or SCCHN. IDO1 expression in tumor-infiltrating immune cells Female 27 (44) was determined by in situ hybridization using RNAscope technology Race (Advanced Cell Diagnostics, Newark, CA); a histoscore $ 5 was used as an White 56 (90) Black 3 (5) arbitrary cutoff for IDO1-positive status. Asian 2 (3) Blood samples were collected predose and postdose at protocol- Hawaiian/Pacific Islander 1 (2) defined time points for pharmacokinetic assessments of epacadostat and ECOG PS pembrolizumab. Pharmacokinetic-based projected IDO1 inhibition was 0 35 (56) determined from the plasma concentration of epacadostat using a three- 1 27 (44) parameter maximum effect model in which the minimum effect and Tumor type* maximum effect were constrained to be 0% and 100%, respectively, and Melanoma 22 (35) the IC was 0.070 mM. The immunogenicity of pembrolizumab also was 50 Non–small-cell lung cancer 12 (19) evaluated. Renal cell cancer 11 (18) Endometrial adenocarcinoma 7 (11) Urothelial carcinoma 5 (8) Triple-negative breast cancer 3 (5) Statistical Analyses Squamous cell carcinoma of the head and neck 2 (3) To determine epacadostat MTD and RP2D when administered in PD-L1 expression combination with pembrolizumab, planned enrollment was approximately Positive 32 (52) 54 patients (three to nine patients per each of four dose levels, plus nine Negative 11 (18) patients per each safety expansion cohort). Safety and efficacy were Unknown† 19 (31) evaluated in all patients who received one or more doses of study treat- IDO1 expression‡ ment. Pharmacokinetic analyses included patients who provided predose Positive 13 (21) (on cycle 1, day 1) and one or more postdose blood samples. Descriptive Negative 9 (15) statistics were used to summarize findings where appropriate. Unknown§ 40 (65) Pharmacokinetic and pharmacokinetic-based projected pharmaco- Abbreviations: ECOG PS, Eastern Cooperative Oncology Group perfor- dynamic data were analyzed using a model-independent approach (ie, mance status; IDO1, indoleamine 2,3-dioxygenase 1; PD-L1, programmed death- noncompartmental analysis) with commercial software (Phoenix Win- ligand 1. Nonlin 7.0; Certara, Princeton, NJ). Predose (trough) samples were an- *Mismatch repair deficiency status was not collected. †PD-L1 expression was not evaluable at the time of analysis in 14 patients alyzed with an assigned time point of 0. Actual times after dosing for (23%); tumor samples were not submitted or missing in an additional five pa- postdose samples were used for pharmacokinetic analysis where available. tients (8%). Because of limited pharmacokinetic sampling up to 6 to 8 hours postdose, ‡IDO1 positivity in tumor-infiltrating immune cells was determined by RNAscope 12-hour postdose concentrations for the visit at steady state (cycle 1, day 8, assay (Advanced Cell Diagnostics, Newark, CA) using an arbitrary histoscore threshold of $ 5%. or cycle 2, day 1) were imputed from the predose concentration on the §IDO1 expression was not available at the time of analysis in 27 patients (44%); same day. tumor samples were missing in an additional 13 patients (21%). RESULTS therapy), and 46 (74%) had discontinued combination treatment (Fig 1). Median epacadostat exposure was 193 days, with a median Patient Disposition and Baseline Characteristics daily dose of 197 mg. Patients received a median of nine pem- Between July 15, 2014, and October 13, 2015, 62 patients were brolizumab doses. Median follow-up was 19 months (range, 11 to enrolled in the phase I portion of the study. Median age was 59 25 months). years (range, 30 to 88 years). Most patients were male (56%) and white (90%) with an Eastern Cooperative Oncology Group per- formance status of 0 (56%; Table 1). Melanoma (22 patients, Safety including 19 who were treatment-naive for advanced or metastatic During dose escalation, eight of 53 patients experienced DLTs. disease), NSCLC (12 patients), and RCC (11 patients) were the At 50 mg twice per day (18 patients), grade 3 arthralgia and grade 3 most frequent tumor types. Thirty-two patients were PD-L1 rash occurred in one patient each. At 100 mg twice per day (15 positive and 11 were PD-L1 negative; 19 had unknown PD-L1 patients), a grade 3 AST increased/grade 2 ALT increased and grade status. Thirteen patients were IDO1 positive and nine were IDO1 2 nervous system disorder occurred in one patient each. At 300 mg negative; 40 had unknown IDO1 status. Among 17 patients twice per day (16 patients), a grade 3 rash occurred in two patients; evaluable for both PD-L1 and IDO1 expression, eight were IDO1 grade 2 brain edema and grade 1 skin erythema (recurrent grade 2 positive and PD-L1 positive. Four patients were treated with rash that required a dose reduction) occurred in one patient each. epacadostat 25 mg twice per day, 20 with 50 mg twice per day, 18 All DLTs resolved with dose modification, drug discontinuation, with 100 mg twice per day, and 20 with 300 mg twice per day (Fig and/or concomitant medications, except in the one patient with 1). As of October 29, 2017, 15 (24%) of 62 patients had completed brain edema who died as a result of disease progression before combination treatment (12 patients completed 2 years of therapy resolution of this event. MTD of epacadostat in combination with and three achieved CR and discontinued after $ 6 months of pembrolizumab was not reached. jco.org © 2018 by American Society of Clinical Oncology 3225 Treatment ongoing Mitchell et al Enrolled (N = 62) 25 mg twice per day 50 mg twice per day 100 mg twice per day 300 mg twice per day (n = 4) (n = 20) (n = 18) (n = 20) Completed* (n = 2; 50%) Completed* (n = 6; 30%) Completed* (n = 4; 22%) Completed* (n = 3; 15%) Discontinued (n = 2; 50%) Discontinued (n = 14; 70%) Discontinued (n = 14; 78%) Discontinued (n = 16; 80%) Disease (n = 2; 50%) Disease (n = 8; 40%) Disease (n = 7; 39%) Disease (n = 9; 45%) progression progression progression progression (n = 0) Adverse (n = 2; 10%) Adverse (n = 4; 22%) Adverse (n = 5; 25%) event event event Patient (n = 1; 5%) Death (n = 2; 11%) Patient (n = 1; 5%) decision decision Patient (n = 1; 6%) Physician (n = 1; 5%) decision Physician (n = 1; 5%) decision decision Treatment (n = 0) Death (n = 1; 5%) ongoing Treatment (n = 1; 5%) Other (n = 1; 5%) ongoing Treatment (n = 0) ongoing Fig 1. CONSORT diagram of the study design and patient disposition. (*) Patients who completed treatment either received 2 years of combination therapy or received $ 6 months of combination treatment and achieved a complete response with two or more doses of pembrolizumab administered beyond the date of initial complete response. Three patients with melanoma met the latter criteria for early stopping of treatment (50 mg twice per day, two patients; 100 mg twice per day, one patient). TRAEs of any grade and grade 3/4 occurred in 84% and 24% patients), and amylase increased (two patients). TRAEs led to dose of patients, respectively (Table 2). TRAEs reported in $ 20% of interruption and reduction in 32% and 19% of patients, re- patients were fatigue (36%), rash (36%), arthralgia (24%), pruritus spectively. Seven patients (11%) discontinued treatment because of (23%), and nausea (21%). Grade 3/4 TRAEs that occurred in more TRAEs (grade 3 arthralgia, grade 3 AST increased, grade 3 lipase than one patient were rash (five patients), lipase increased (five increased, grade 3 aseptic meningitis, grade 2 brain edema, grade 2 Table 2. Summary of Treatment-Related AEs Epacadostat Treatment Group, No. (%) 25 mg Twice Per Day* 50 mg Twice Per Day* 100 mg Twice Per Day* 300 mg Twice Per Day* (n = 4) (n = 20) (n = 18) (n = 20) Total (N = 62) Event All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Treatment-related AEs 4 (100) 1 (25) 14 (70) 2 (10) 16 (89) 5 (28) 18 (90) 7 (35) 52 (84) 15 (24) Fatigue 3 (75) 0 7 (35) 0 6 (33) 0 6 (30) 1 (5) 22 (36) 1 (2) Rash† 2 (50) 0 9 (45) 1 (5) 0 0 11 (55) 4 (20) 22 (36) 5 (8) Arthralgia 2 (50) 0 4 (20) 1 (5) 4 (22) 0 5 (25) 0 15 (24) 1 (2) Pruritus‡ 2 (50) 0 5 (25) 0 0 0 7 (35) 0 14 (23) 0 Nausea 3 (75) 0 3 (15) 0 3 (17) 0 4 (20) 0 13 (21) 0 Diarrhea 2 (50) 0 3 (15) 0 3 (17) 0 3 (15) 0 11 (18) 0 Pyrexia 0 0 1 (5) 0 1 (6) 0 5 (25) 0 7 (11) 0 AST increased 0 0 2 (10) 0 4 (22) 1 (6) 0 0 6 (10) 1 (2) Dizziness 0 0 4 (20) 0 1 (6) 0 1 (5) 0 6 (10) 0 Vomiting 0 0 1 (5) 0 3 (17) 0 2 (10) 0 6 (10) 0 Chills 0 0 2 (10) 0 2 (11) 0 1 (5) 0 5 (8) 0 Cough 0 0 2 (10) 0 1 (6) 0 2 (10) 0 5 (8) 0 Lipase increased 0 0 0 0 3 (17) 3 (17) 2 (10) 2 (10) 5 (8) 5 (8) Myalgia 0 0 1 (5) 0 2 (11) 0 2 (10) 0 5 (8) 0 ALT increased 0 0 1 (5) 0 3 (17) 0 0 0 4 (7) 0 Back pain 0 0 0 0 1 (6) 0 3 (15) 0 4 (7) 0 Constipation 2 (50) 0 1 (5) 0 0 0 1 (5) 0 4 (7) 0 Decreased appetite 0 0 0 0 0 0 4 (20) 0 4 (7) 0 Musculoskeletal pain 0 0 2 (10) 1 (5) 1 (6) 0 0 0 3 (5) 1 (2) NOTE. Treatment-related AEs are listed by preferred term for events that occurred in $ 5% of the total study population. Grade 3/4 treatment-related AEs not listed in the table were amylase increased (n = 2), stomatitis (n = 1), and aseptic meningitis (n = 1). Abbreviation: AE, adverse event. *Combined with pembrolizumab 2 mg/kg every 3 weeks or 200 mg every 3 weeks. †Rash includes the following Medical Dictionary for Regulatory Activities–preferred terms: rash, rash maculopapular, rash generalized, rash pruritic, erythema, erythema multiforme, rash erythematous, palmar-plantar erythrodysesthesia syndrome, rash follicular, rash pustular, and skin exfoliation. ‡Pruritus includes the following Medical Dictionary for Regulatory Activities–preferred terms: pruritus and pruritus generalized. 3226 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors Table 3. Pharmacokinetic Assessments of Epacadostat Epacadostat*, Mean 6 SD (geometric mean) 25 mg 50 mg 100 mg 300 mg Parameter Twice Per Day Twice Per Day Twice Per Day Twice Per Day Cycle 1, day 1, No. of patients 3 20 18 19 C , mM 0.23 6 0.15 (0.20) 0.54 6 0.22 (0.50) 0.80 6 0.38 (0.72) 2.3 6 1.2 (2.0) max t , hours† 2.0 (1.0-3.2) 2.0 (0.45-4.0) 2.0 (0.83-4.4) 2.0 (0.53-6.0) max AUC , hours $ mM 0.71 6 0.35 (0.65) 1.4 6 0.62 (1.3) 2.4 6 0.82 (2.3) 7.2 6 2.9 (6.7) last Cycle 1, day 8, No. of patients 3 19 16 19 C , mM 0.27 6 0.16 (0.24) 0.50 6 0.24 (0.45) 0.92 6 0.42 (0.81) 2.7 6 1.2 (2.5) max t , hours† 1.0 (1.0-2.0) 2.0 (0.85-4.0) 2.0 (1.0-4.0) 2.0 (0.50-4.1) max t , hours 5.2, 5.5‡ 3.5 6 1.4 (3.3) 3.9 6 1.6 (3.6) 4.0 6 1.4 (3.8) 1/2 AUC , hours $ mM1.2 6 0.17 (1.2) 2.1 6 1.1 (1.8) 3.7 6 1.4 (3.4) 12 6 5.8 (11) 0-t Abbreviations: AUC , area under the steady-state concentration versus time curve over one dosing interval; AUC , area under the concentration versus time 0-t last curve from time zero to the time of the last measurable concentration; C , maximum observed plasma concentration; SD, standard deviation; t , terminal elimination max 1/2 half-life; t , time of observed maximum observed plasma concentration. max *Combined with pembrolizumab 2 mg/kg every 3 weeks or 200 mg every 3 weeks. †Median (range). ‡One of the three patients was excluded because of pathologic plasma epacadostat concentration-time profile at cycle 1, day 8; individual values for the remaining two patients are listed. colitis, and grade 3 fatigue [one patient each]). The grade 3 aseptic each other and consistent with simulated concentration-time meningitis subsequently resolved after hospitalization and treat- profiles for similar doses from a population pharmacokinetic ment (including empirical antibiotic treatment and oral dexa- model of pembrolizumab monotherapy using data from ap- methasone). No TRAEs led to death. AEs of special interest proximately 3,000 patients. occurred in 10 patients (16%): severe skin reactions (five patients Pharmacokinetic-based projected IDO1 inhibition at steady state [all grade $ 3 rash]), hypothyroidism (three patients), colitis (one is plotted in Figure 2 for individual patients grouped by epacadostat patient), and pneumonitis (one patient). dose. Most patients (. 90%) were projected to have achieved $ 50% time-averaged IDO1 inhibition (level of pharmacodynamic activity Pharmacokinetics, Pharmacodynamics, and associated with inhibition of tumor growth seen in nonclinical Immunogenicity models). PD-L1 expression did not seem to have any clear effects on Pharmacokinetic parameters of epacadostat at days 1 and 8 pharmacokinetic-predicted pharmacodynamics. The treatment-emergent antipembrolizumab antibody rate in of cycle 1 are listed in Table 3. Epacadostat plasma exposures (area under the concentration v time curve and maximum the 54 evaluable patients treated with pembrolizumab plus epa- observed plasma concentration) increased in an approximately cadostat was 3.7%. This rate seemed to be similar to that observed dose-proportional manner, with time of observed a maximum in a pembrolizumab monotherapy reference data set (2.1%), observed plasma concentration at approximately 2 hours. Se- although the small number of patients evaluated in this study rum concentrations of pembrolizumab 2 mg/kg and 200 mg makes it difficult to draw conclusions about the effects of epa- every 3 weeks during cycle 1 and at steady state were similar to cadostat on pembrolizumab immunogenicity. 25 mg twice 50 mg 100 mg 300 mg per twice per day twice per day twice per day 100 day 90% IDO1 inhibition 70% IDO1 inhibition Fig 2. Pharmacokinetic-predicted time-- averaged inhibition of indoleamine 2,3-dioxygenase 50% IDO1 inhibition 1 (IDO1) inhibition for individual patients by epacadostat dose. Patients jco.org © 2018 by American Society of Clinical Oncology 3227 Time-Averaged IDO1 Inhibition (%) Mitchell et al KRAS mutation positive, three were PD-L1 positive (tumor pro- Antitumor Activity portion score $ 1%), one was PD-L1 negative, and one was IDO1 Antitumor activity was observed at all epacadostat doses and in negative. Responses were ongoing in four of five patients. several tumor types (Fig 3). Per investigator assessment by RECIST Among the two responders with RCC, each had intermediate v1.1, eight of 62 patients achieved CR as best response (treatment- and favorable Memorial Sloan Kettering Cancer Center risk, and naive melanoma [5 patients] and previously treated for advanced/ one was PD-L1 positive. Both responses were maintained for metastatic melanoma, EA, or UC [one patient each]), and 17 pa- approximately 15 months. tients achieved PR (treatment-naive melanoma [six patients], Thirteen patients across all doses experienced stable disease as NSCLC [five patients], RCC and UC [two patients each], and EA and best response. These included four with melanoma, two with SCCHN [one patient each]). Of 25 patients who achieved an ob- jective response, 14 received epacadostat doses$ 100 mg twice a day. NSCLC, five with RCC, one with TNBC, and one with SCCHN. For the purpose of RP2D evaluation, antitumor activities were Seventeen of 25 responses were ongoing at data cutoff. Among the 12 responders with melanoma, eight had stage observed at all dose levels, and no dose exceeded the MTD. Epacadostat 100 mg twice per day seemed to be better tolerated M1c disease at baseline, three were BRAF mutation positive, six were PD-L1 positive (melanoma score $ 1%), one was PD-L1 than 300 mg twice per day, with lower rates of grade 3/4 TRAEs negative, four were IDO1 positive, and one was IDO1 negative. (28% v 35%), treatment-related dose interruptions (22% v 45%) Responses were ongoing in 10 of 12 patients. By immune-related and reductions (11% v 35%), and AEs of special interest (6% v RECIST criteria, one additional patient achieved PR. 30%). Furthermore, all patients treated with epacadostat 100 mg Among the five responders with NSCLC, three had adeno- twice per day or 300 mg twice per day were projected to have carcinoma histology, one was EGFR mutation positive, two were achieved $ 50% time-averaged IDO1 inhibition; the majority of 25 mg twice per day 50 mg twice per day 100 mg twice per day 300 mg twice per day Melanoma NSCLC RCC EA TNBC UC SCCHN * * † † † * * ** * –25 –50 –75 –100 Patients Fig 3. Change from baseline in target le- B C sions. (A) Best percentage change from baseline in target lesions by tumor type in all 25 mg twice per day 100 25 mg twice per day patients. (B) to (D) Percentage change from 50 mg twice per day 100 mg twice per day baseline in target lesions over time in pa- 100 mg twice per day 300 mg twice per day tients with (B) melanoma, (C) non–small-cell 300 mg twice per day lung cancer (NSCLC), and (D) renal cell cancer 0 0 (RCC). EA, endometrial adenocarcinoma; RECIST, Response Evaluation Criteria in Solid –50 –50 Tumors; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative breast cancer; UC, urothelial carcinoma. (*) –100 { –100 Progressive disease per RECIST version 1.1. 18 36 54 72 90 108 126 144 162 18 36 54 72 90 108 126 144 162 (†) Partial response per RECIST version 1.1. Time (weeks) Time (weeks) 50 mg twice per day 100 mg twice per day 300 mg twice per day –50 –100 18 36 54 72 90 108 126 144 162 Time (weeks) 3228 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Change From Baseline (%) Change From Baseline (%) Best Change From Baseline (%) Change From Baseline (%) Epacadostat Plus Pembrolizumab in Advanced Solid Tumors patients treated with 100 mg twice per day achieved a minimum biomarkers, including PD-L1 and IDO1, with treatment response IDO1 inhibition of $ 50%. On the basis of these considerations, were not feasible in this study because of insufficient patient epacadostat 100 mg twice per day plus pembrolizumab 200 mg numbers. Across various tumor types, patients achieved durable every 3 weeks was selected for additional investigation in phase II. response, with the majority of responses (17 [68%] of 25) ongoing at data cutoff. The preliminary favorable toxicity profile, phar- macokinetics, and pharmacokinetic-predicted pharmacodynamics DISCUSSION along with encouraging clinical activity of epacadostat plus pembrolizumab reported here support additional phase II in- Phase I results of this trial show that epacadostat plus pem- vestigation of the combination, with epacadostat 100 mg twice per brolizumab generally is well tolerated in patients with various day selected as the RP2D. advanced solid tumors; the safety profile is similar to previous At the time of this publication, it has been announced that the experience with pembrolizumab monotherapy. No new safety pivotal phase III ECHO-301/KEYNOTE-252 study (ClinicalTrials. signals were detected for either epacadostat or pembrolizumab. gov identifier: NCT02752074) that was evaluating epacadostat plus TRAEs were primarily grade 1/2 and manageable with dose pembrolizumab in patients with unresectable or metastatic mel- modifications or concomitant medications. Seven patients (11%) anoma did not meet the primary end point of improving discontinued because of TRAEs. No epacadostat MTD was de- progression-free survival in the overall population compared with termined, and no patients died as a result of TRAEs. The safety pembrolizumab monotherapy. Future results from ECHO-301/ profile observed with epacadostat plus pembrolizumab compares KEYNOTE-252, including analyses of an extensive biomarker favorably with studies of other combination immunotherapies, panel and other pharmacodynamic analyses, will contribute to the such as nivolumab plus ipilimumab or pembrolizumab plus low- understanding of the role of IDO1 inhibition, and epacadostat in dose ipilimumab in advanced cancers. Nivolumab plus ipilimumab combination with PD-1 inhibitors, in cancer therapy. has been associated with higher rates of toxicities in patients with advanced melanoma, including grade 3/4 TRAEs in $ 45% and 3,4,25 drug discontinuations in approximately one third. The pre- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS liminary findings reported here suggest that dual inhibition of the OF INTEREST IDO1 enzyme and PD-1 is feasible with minimal additive 26-28 Disclosures provided by the authors are available with this article at toxicity. jco.org. Analyses of the pharmacokinetic parameters were comparable to previous reports of epacadostat and pembrolizumab mono- therapies, which suggests that the combination does not affect AUTHOR CONTRIBUTIONS the pharmacokinetics of either individual agent in patients with solid tumors. Kynurenine inhibition over time was not directly Conception and design: Tara C. Mitchell, Anthony J. Olszanski, Emmett measured in this study, so the pharmacodynamics were projected V. Schmidt, Janet Maleski, Lance Leopold, Thomas F. Gajewski on the basis of the phase I patient pharmacokinetic data to yield Provision of study materials or patient: David C. Smith, Todd M. Bauer, time-averaged IDO1 inhibition. All patients who received Jason J. Luke epacadostat $ 100 mg twice per day achieved average concen- Collection and assembly of data: Tara C. Mitchell, Omid Hamid, David C. trations at steady state that exceeded the IC associated with Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason optimal target inhibition on the basis of preclinical models. J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Janet Maleski, Lance Leopold, Thomas F. Gajewski Although not powered to evaluate efficacy, the phase I portion Data analysis and interpretation: Tara C. Mitchell, Omid Hamid, David of this study showed that epacadostat plus pembrolizumab had C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason encouraging and durable antitumor activity. Objective responses J. Luke, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, were observed in patients with treatment-naive and previously Lance Leopold, Thomas F. Gajewski treated (cytokine or interferon therapy) melanoma, NSCLC, RCC, Manuscript writing: All authors UC, EA, and SCCHN. Responses were observed in both PD- Final approval of manuscript: All authors L1–positive and –negative patients; however, correlative analyses of Accountable for all aspects of the work: All authors 4. Hodi FS, Chesney J, Pavlick AC, et al: Combined 7. Prendergast GC, Mondal A, Dey S, et al: In- REFERENCES nivolumab and ipilimumab versus ipilimumab alone in flammatory reprogramming with IDO1 inhibitors: patients with advanced melanoma: 2-year overall survival Turning immunologically unresponsive ‘cold’ tumors 1. Abril-Rodriguez G, Ribas A: SnapShot: Im- outcomes in a multicentre, randomised, controlled, phase ‘hot’. Trends Cancer 4:38-58, 2018 mune checkpoint inhibitors. Cancer Cell 31:848-848. 2 trial. Lancet Oncol 17:1558-1568, 2016 8. Theate I, van Baren N, Pilotte L, et al: Exten- e1, 2017 5. 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Li H, Yu J, Liu C, et al: Time dependent dostat plus pembrolizumab versus pembrolizumab in-human phase I study of the oral inhibitor of indo- pharmacokinetics of pembrolizumab in patients with alone in patients with unresectable or metastatic leamine 2,3-dioxygenase-1 epacadostat (INCB024360) solid tumor and its correlation with best overall re- melanoma: Results of the phase 3 ECHO-301/ in patients with advanced solid malignancies. Clin sponse. J Pharmacokinet Pharmacodyn 44:403-414, KEYNOTE-252 study. J Clin Oncol 36, (suppl; abstr Cancer Res 23:3269-3276, 2017 2017 108), 2018 Affiliations Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE. Support Supported by Incyte and Merck & Co. Prior Presentation Presented at the European Society for Medical Oncology Annual Meeting, Copenhagen, Denmark, October 7-11, 2016. nn n 3230 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO- 202/KEYNOTE-037) The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Tara C. Mitchell Jason J. Luke Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Incyte, Aduro Honoraria: Intellisphere Biotech, Regeneron Consulting or Advisory Role: Amgen, Array BioPharma, Bristol-Myers Research Funding: Merck (Inst), Incyte (Inst), Bristol-Myers Squibb Squibb, Merck, EMD Serono, Benevir Biopharm, Checkmate (Inst), Roche (Inst) Pharmaceuticals, Novartis, AstraZeneca, MedImmune, 7 Hills Pharma, Castle Biosciences, Actym Therapeutics, Gilead Sciences, Janssen Omid Hamid Pharmaceuticals, NewLink Genetics, RefleXion Medical, Syndax, Tempest Consulting or Advisory Role: Amgen, Novartis, Roche, Bristol-Myers Therapeutics Squibb, Merck Research Funding: Merck, Bristol-Myers Squibb, Boston Biomedical, Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Novartis, Amgen, MedImmune, Incyte, Celldex, Genentech, Roche, Pharmacyclics, Five Array BioPharma Prime Therapeutics, Corvus Pharmaceuticals, Delcath Systems, AbbVie, Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Immunocore, Palleon Pharmaceuticals, Checkmate Pharmaceuticals, Celldex (Inst), Genentech (Inst), Immunocore (Inst), Incyte (Inst), Merck Macrogenics, Novartis, Tesaro (Inst), Merck Serono (Inst), MedImmune (Inst), Novartis (Inst), Pfizer Travel, Accommodations, Expenses: Amgen, Bristol-Myers Squibb, Array (Inst), Rinat Neuroscience (Inst), Roche (Inst) BioPharma, AstraZeneca, MedImmune, Benevir Biopharm, Castle Biosciences, Checkmate Pharmaceuticals, EMD Serono, Gilead Sciences, David C. Smith Janssen Pharmaceuticals, Merck, Novartis, RefleXion Medical Research Funding: Agensys (Inst), Atterocor (Inst), Bayer AG (Inst), Boston Biomedical (Inst), Exelixis (Inst), Incyte (Inst), Eli Lilly (Inst), Ani S. Balmanoukian MedImmune (Inst), Novartis (Inst), OncoMed Pharmaceuticals (Inst), Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Merck, AstraZeneca Seattle Genetics (Inst), Bristol-Myers Squibb (Inst), Medarex (Inst), ESSA Pharma (Inst), Genentech (Inst), Medivation (Inst), Astellas Pharma Emmett V. Schmidt (Inst), Merck (Inst) Employment: Merck Stock or Other Ownership: Merck, Merck (I) Todd M. Bauer Employment: Tennessee Oncology, Sarah Cannon Research Institute Yufan Zhao Consulting or Advisory Role: Ignyta (Inst), Guardant Health, Loxo Employment: Incyte, Amgen Oncology, Pfizer Stock or Other Ownership: Incyte, Amgen Research Funding: Daiichi Sankyo (Inst), MedPacto (Inst), Incyte (Inst), Xiaohua Gong Mirati Therapeutics (Inst), MedImmune (Inst), AbbVie (Inst), Employment: Incyte AstraZeneca (Inst), Leap Therapeutics (Inst), MabVax Therapeutics (Inst), Stock or Other Ownership: Incyte Stemline Therapeutics (Inst), Merck (Inst), Eli Lilly (Inst), Travel, Accommodations, Expenses: Incyte GlaxoSmithKline (Inst), Novartis (Inst), Pfizer (Inst), Principia Biopharma (Inst), Genentech (Inst), Roche (Inst), Deciphera Pharmaceuticals (Inst), Janet Maleski Merrimack (Inst), Immunogen (Inst), Millennium Pharmaceuticals (Inst), Employment: Incyte Ignyta (Inst), Calithera Bioscience (Inst), Kolltan Pharmaceuticals (Inst), Stock or Other Ownership: Incyte Peloton Therapeutics (Inst), Immunocore (Inst), Roche (Inst), Aileron Travel, Accommodations, Expenses: Incyte Therapeutics (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Moderna Lance Leopold Therapeutics (Inst), Sanofi (Inst), Boehringer Ingelheim (Inst), Astellas Employment: Incyte Pharma (Inst) Stock or Other Ownership: Incyte Jeffrey S. Wasser Thomas F. Gajewski Stock or Other Ownership: Johnson & Johnson, Bristol-Myers Squibb, Consulting or Advisory Role: Merck, Roche, Genentech, Jounce Eli Lilly, Biogen, AbbVie, Merck (I), Pfizer (I) Therapeutics, Bayer AG, AbbVie, Aduro Biotech, Evelo Biosciences, Honoraria: Amgen, Novartis FogPharma, Adaptimmune, Five Prime Therapeutics Consulting or Advisory Role: Amgen, Novartis Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Roche Speakers’ Bureau: Novartis (Inst), Genentech (Inst), Incyte (Inst), Seattle Genetics (Inst), Ono Research Funding: Merck, Guardant Health, Incyte, Pfizer Pharmaceutical (Inst) Anthony J. Olszanski Patents, Royalties, Other Intellectual Property: Licensing to Evelo Consulting or Advisory Role: EMD Serono, Takeda Pharmaceuticals, Bioscience (Inst), licensing to Aduro Biotech (Inst) Bristol-Myers Squibb, G1 Therapeutics, Pfizer, Array BioPharma, Iovance Biotherapeutics Research Funding: Takeda Pharmaceuticals (Inst), Immunocore (Inst), EMD Serono (Inst), Amgen (Inst), Incyte (Inst), Kyowa Hakko Kirin (Inst), Eli Lilly (Inst), Advaxis Immunotherapies (Inst), Mirati Therapeutics (Inst), Ignyta (Inst), Novartis (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst), Kura Oncology (Inst) Travel, Accommodations, Expenses: Takeda Pharmaceuticals jco.org © 2018 by American Society of Clinical Oncology Mitchell et al Acknowledgment We thank the site coordinators of the study: Jennifer Kelley and Nichole Smith Audrey (Incyte Corporation); Leonard and Saba Mukarram (The Angeles Clinic and Research Institute); Bernadette Foster and Vipin Khare (Fox Chase Cancer Center); Erin Fisher and Deepa Bhikha (Sarah Cannon Research Institute); Christopher Sampson and Katarzyna Nastri (University of Connecticut School of Medicine); Lauren Zubkoff, Kim Feldhaus, and Villette “Sam” Thorpe (University of Michigan); Lauren Leverage and Mark Jones (University of Pennsylvania); and the site coordinators of the University of Chicago. Editorial assistance was provided by Jane Kovalevich of Complete Healthcare Communications (West Chester, PA), a CHC Group company, and funded by Incyte Corporation. © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Oncology Pubmed Central

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

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© 2018 by American Society of Clinical Oncology
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0732-183X
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10.1200/JCO.2018.78.9602
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� � VOLUME 36 NUMBER 32 NOVEMBER 10, 2018 ORIGIN AL REPORT JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037) Tara C. Mitchell, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, and Thomas F. Gajewski Author affiliations and support information ABSTRACT (if applicable) appear at the end of this article. Purpose Published at jco.org on September 28, Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label Clinical trial information: NCT02178722. phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed Correspondence to: Tara C. Mitchell, MD, death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum Abramson Cancer Center, University of tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: tara. Patients and Methods mitchell@uphs.upenn.edu. Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus © 2018 by American Society of Clinical intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, Oncology. Creative Commons Attribution patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every Non-Commercial No Derivatives 4.0 3 weeks. License. $ = Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum 0732-183X/18/3632w-3223w/$20.00 tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in $ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial ad- enocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors. J Clin Oncol 36:3223-3230. © 2018 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/ that target various immune evasion pathways INTRODUCTION to improve patient response rates and survival. Nivolumab (a PD-1 inhibitor) plus ipilimumab Immunotherapies, such as immune checkpoint (a CTLA-4 inhibitor) provides improved re- inhibitors (ICIs) that target programmed death sponse rates compared with monotherapy but protein 1 (PD-1)/programmed death-ligand 1 is associated with high grade 3/4 treatment- (PD-L1) and cytotoxic T-lymphocyte–associated related adverse events (TRAEs; 33% to 55%) protein 4 (CTLA-4), have resulted in meaningful and immune-related adverse events (AEs; 40% 1 2-5 advances in cancer treatment. However, interest to 45%). Other combination immunother- DOI: https://doi.org/10.1200/JCO.2018. 78.9602 exists in developing combination immunotherapies apies, including epacadostat—apotentand © 2018 by American Society of Clinical Oncology 3223 Mitchell et al highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 Additional eligibility criteria were presence of measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) ; (IDO1) enzyme—plus ICIs, also have been under clinical life expectancy . 12 weeks; Eastern Cooperative Oncology Group per- investigation. formance status# 1; ALT, AST, and alkaline phosphatase levels, 2.5 times The intracellular IDO1 enzyme catalyzes the first and rate- the upper limit of normal; and conjugated bilirubin , 2.0 times the upper 6,7 limiting step in the degradation of tryptophan to kynurenine. limit of normal. Exclusion criteria included prior treatment with ICIs Induced by interferon-g, prostaglandin E2, tumor necrosis factor-a, (except prior adjuvant CTLA-4 inhibitors for melanoma) or IDO in- transforming growth factor-b, and other proinflammatory signals, hibitors at any time, investigational device or treatment within 28 days or five half-lives (whichever was longer) before the first dose of study drug, IDO1 primarily is expressed by tumor, endothelial, and dendritic active autoimmune disease, known history of immunodeficiency, and use cells and macrophages within the tumor microenvironment 8,9 of systemic corticosteroids within 7 days before the first dose of study drug. (TME). IDO1-mediated depletion of cellular tryptophan and production of downstream metabolites may result in cell cycle arrest, anergy, and apoptosis of effector T cells and activation Study Design and Treatment In this multicenter, nonrandomized, open-label phase I/II study, of immunosuppressive cells (eg, regulatory T cells, myeloid- 10 11 phase I included a 3 + 3 + 3 epacadostat dose escalation in combination derived suppressor cells, tumor-associated macrophages ), with pembrolizumab, followed by three safety expansion cohorts of up to thereby contributing to immunosuppression within the TME. nine patients each. During dose escalation, patients received oral epaca- Furthermore, IDO1 upregulation may be associated with poor dostat (25, 50, or 100 mg) twice per day in combination with intravenous 12,13 prognosis in patients with advanced cancers. Therefore, pembrolizumab 2 mg/kg every 3 weeks or epacadostat 300 mg twice per IDO1 may represent a potential therapeutic target in various cancers, day with pembrolizumab 200 mg every 3 weeks. The first safety expansion especially in combination with other immunotherapies, including (epacadostat 50 mg twice per day plus pembrolizumab 200 mg every 3 weeks) enrolled patients with melanoma; the second and third ex- ICIs. pansions (epacadostat 100 mg twice per day and 300 mg twice per day, Epacadostat decreases tryptophan metabolism by inhibiting respectively, plus pembrolizumab 200 mg every 3 weeks) included patients IDO1, which results in enhanced proliferation of effector T cells with other eligible tumors. All patients could continue combination and natural killer cells, decreased apoptosis and increased acti- treatment with epacadostat and pembrolizumab for up to 24 months high vation of CD86 dendritic cells, and reduced expansion of followed by optional epacadostat monotherapy until confirmed radio- regulatory T cells. These changes shift the TME away from an graphic disease progression, intolerable toxicity, or withdrawal of consent. immunosuppressive state toward one that supports productive The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization guidelines for immune responses. In preclinical models, epacadostat plus an Good Clinical Practice and was approved by an independent ethics ICI suppressed tumor growth more effectively than single-agent committee or institutional review board at each study site. All patients treatment, primarily through reactivation of antitumor immu- provided written informed consent before initiation of any study pro- nity. Phase I and II clinical studies have shown that single-agent cedures or for any biomarker sample collections. 16,17 epacadostat is well tolerated in patients with advanced cancers, and doses $ 100 mg twice per day provide optimal inhibition of Assessments IDO1 activity and normalization of kynurenine levels. Favorable Safety and tolerability assessments were conducted at all scheduled objective response rate, disease control rate, and progression-free study visits (day 1 of every cycle), at end of treatment, and during follow- survival were observed in immunotherapy-naive patients with up. Laboratory assessments, including liver function tests, were performed melanoma treated with epacadostat plus ipilimumab. In addition weekly for the first 6 weeks. AEs were graded per Common Terminology to these encouraging safety and efficacy findings, interferon-g– Criteria for Adverse Events (version 4.0). AEs of special interest were those induced expression of IDO1 and PD-L1 in the TME supports the with an immune-related cause regardless of attribution to study treatment by the investigator. investigation of epacadostat plus PD-1/PD-L1 inhibitors, such as DLTs were protocol-specified AEs that occurred within the first pembrolizumab. 6 weeks of treatment, regardless of attribution to study drug. Such AEs The primary objectives of the phase I portion of the ECHO- could include grade 4 thrombocytopenia or neutropenia lasting . 7 days; 202/KEYNOTE-037 study were to evaluate the dose-limiting nonhematologic grade 4 toxicities; any grade 3/4 AST, ALT, or total bil- toxicities (DLTs), maximum tolerated dose (MTD), safety, and irubin elevation; any other grade 3 nonhematologic toxicity (except tolerability of epacadostat plus pembrolizumab in patients with protocol-defined controllable nausea, vomiting, and rash); or grade $ 2 advanced solid tumors. Exploratory end points were preliminary episcleritis, uveitis, or iritis. The recommended phase II dose (RP2D) was selected on the basis of tolerability during the safety expansion. Per study antitumor activity of this combination, epacadostat pharmacoki- protocol, dose escalation was permitted if there were no more than zero, netics, and pharmacokinetic-based projected pharmacodynamics. one, or three DLTs in three, six, or nine patients, respectively. If four or more of the first six or nine evaluable patients in a dose cohort experienced a DLT, the next-lower dose of epacadostat was deemed the RP2D. PATIENTS AND METHODS Tumor response was assessed at baseline, every 9 weeks for the first 18 months of treatment, and every 12 weeks thereafter. Objective response Patients rate (complete response [CR] or partial response [PR]) and duration of Eligible patients were $ 18 years old with histologically or cyto- response (time from response to disease progression) were determined on logically confirmed stage IIIB, stage IV, or recurrent non–small-cell lung the basis of investigator assessment per RECIST v1.1. Immune-related cancer (NSCLC), melanoma, renal cell cancer (RCC), endometrial ade- RECIST v1.1 was used to guide treatment; if imaging showed progressive nocarcinoma (EA), urothelial carcinoma (UC), triple-negative breast disease, patients could continue study treatment at the investigator’s cancer (TNBC), or squamous cell carcinoma of the head and neck discretion until confirmatory assessment $ 4 weeks later. (SCCHN). All patients progressed on one or more prior lines of therapy or Tumor PD-L1 status was determined at baseline by immunohisto- had no available curative treatment, except for patients with melanoma. chemistry using an investigational version of the PD-L1 IHC 22C3 3224 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors pharmDx assay (Agilent, Carpinteria, CA). PD-L1 positivity was defined as Table 1. Patient Demographics and Baseline Characteristics membranous PD-L1 expression in $ 1% of tumor cells or inflammatory cells in nests of tumor cells (melanoma score) for patients with melanoma; Variable Total, No. (%) $ 1% of viable tumor cells showing partial or complete membrane No. of patients 62 staining at any intensity (tumor proportion score) for patients with Median age, years (range) 59 (30-88) NSCLC; and $ 1% of stained tumor and immune cells relative to total Sex tumor cells (combined positive score) for patients with RCC, EA, UC, Male 35 (56) TNBC, or SCCHN. IDO1 expression in tumor-infiltrating immune cells Female 27 (44) was determined by in situ hybridization using RNAscope technology Race (Advanced Cell Diagnostics, Newark, CA); a histoscore $ 5 was used as an White 56 (90) Black 3 (5) arbitrary cutoff for IDO1-positive status. Asian 2 (3) Blood samples were collected predose and postdose at protocol- Hawaiian/Pacific Islander 1 (2) defined time points for pharmacokinetic assessments of epacadostat and ECOG PS pembrolizumab. Pharmacokinetic-based projected IDO1 inhibition was 0 35 (56) determined from the plasma concentration of epacadostat using a three- 1 27 (44) parameter maximum effect model in which the minimum effect and Tumor type* maximum effect were constrained to be 0% and 100%, respectively, and Melanoma 22 (35) the IC was 0.070 mM. The immunogenicity of pembrolizumab also was 50 Non–small-cell lung cancer 12 (19) evaluated. Renal cell cancer 11 (18) Endometrial adenocarcinoma 7 (11) Urothelial carcinoma 5 (8) Triple-negative breast cancer 3 (5) Statistical Analyses Squamous cell carcinoma of the head and neck 2 (3) To determine epacadostat MTD and RP2D when administered in PD-L1 expression combination with pembrolizumab, planned enrollment was approximately Positive 32 (52) 54 patients (three to nine patients per each of four dose levels, plus nine Negative 11 (18) patients per each safety expansion cohort). Safety and efficacy were Unknown† 19 (31) evaluated in all patients who received one or more doses of study treat- IDO1 expression‡ ment. Pharmacokinetic analyses included patients who provided predose Positive 13 (21) (on cycle 1, day 1) and one or more postdose blood samples. Descriptive Negative 9 (15) statistics were used to summarize findings where appropriate. Unknown§ 40 (65) Pharmacokinetic and pharmacokinetic-based projected pharmaco- Abbreviations: ECOG PS, Eastern Cooperative Oncology Group perfor- dynamic data were analyzed using a model-independent approach (ie, mance status; IDO1, indoleamine 2,3-dioxygenase 1; PD-L1, programmed death- noncompartmental analysis) with commercial software (Phoenix Win- ligand 1. Nonlin 7.0; Certara, Princeton, NJ). Predose (trough) samples were an- *Mismatch repair deficiency status was not collected. †PD-L1 expression was not evaluable at the time of analysis in 14 patients alyzed with an assigned time point of 0. Actual times after dosing for (23%); tumor samples were not submitted or missing in an additional five pa- postdose samples were used for pharmacokinetic analysis where available. tients (8%). Because of limited pharmacokinetic sampling up to 6 to 8 hours postdose, ‡IDO1 positivity in tumor-infiltrating immune cells was determined by RNAscope 12-hour postdose concentrations for the visit at steady state (cycle 1, day 8, assay (Advanced Cell Diagnostics, Newark, CA) using an arbitrary histoscore threshold of $ 5%. or cycle 2, day 1) were imputed from the predose concentration on the §IDO1 expression was not available at the time of analysis in 27 patients (44%); same day. tumor samples were missing in an additional 13 patients (21%). RESULTS therapy), and 46 (74%) had discontinued combination treatment (Fig 1). Median epacadostat exposure was 193 days, with a median Patient Disposition and Baseline Characteristics daily dose of 197 mg. Patients received a median of nine pem- Between July 15, 2014, and October 13, 2015, 62 patients were brolizumab doses. Median follow-up was 19 months (range, 11 to enrolled in the phase I portion of the study. Median age was 59 25 months). years (range, 30 to 88 years). Most patients were male (56%) and white (90%) with an Eastern Cooperative Oncology Group per- formance status of 0 (56%; Table 1). Melanoma (22 patients, Safety including 19 who were treatment-naive for advanced or metastatic During dose escalation, eight of 53 patients experienced DLTs. disease), NSCLC (12 patients), and RCC (11 patients) were the At 50 mg twice per day (18 patients), grade 3 arthralgia and grade 3 most frequent tumor types. Thirty-two patients were PD-L1 rash occurred in one patient each. At 100 mg twice per day (15 positive and 11 were PD-L1 negative; 19 had unknown PD-L1 patients), a grade 3 AST increased/grade 2 ALT increased and grade status. Thirteen patients were IDO1 positive and nine were IDO1 2 nervous system disorder occurred in one patient each. At 300 mg negative; 40 had unknown IDO1 status. Among 17 patients twice per day (16 patients), a grade 3 rash occurred in two patients; evaluable for both PD-L1 and IDO1 expression, eight were IDO1 grade 2 brain edema and grade 1 skin erythema (recurrent grade 2 positive and PD-L1 positive. Four patients were treated with rash that required a dose reduction) occurred in one patient each. epacadostat 25 mg twice per day, 20 with 50 mg twice per day, 18 All DLTs resolved with dose modification, drug discontinuation, with 100 mg twice per day, and 20 with 300 mg twice per day (Fig and/or concomitant medications, except in the one patient with 1). As of October 29, 2017, 15 (24%) of 62 patients had completed brain edema who died as a result of disease progression before combination treatment (12 patients completed 2 years of therapy resolution of this event. MTD of epacadostat in combination with and three achieved CR and discontinued after $ 6 months of pembrolizumab was not reached. jco.org © 2018 by American Society of Clinical Oncology 3225 Treatment ongoing Mitchell et al Enrolled (N = 62) 25 mg twice per day 50 mg twice per day 100 mg twice per day 300 mg twice per day (n = 4) (n = 20) (n = 18) (n = 20) Completed* (n = 2; 50%) Completed* (n = 6; 30%) Completed* (n = 4; 22%) Completed* (n = 3; 15%) Discontinued (n = 2; 50%) Discontinued (n = 14; 70%) Discontinued (n = 14; 78%) Discontinued (n = 16; 80%) Disease (n = 2; 50%) Disease (n = 8; 40%) Disease (n = 7; 39%) Disease (n = 9; 45%) progression progression progression progression (n = 0) Adverse (n = 2; 10%) Adverse (n = 4; 22%) Adverse (n = 5; 25%) event event event Patient (n = 1; 5%) Death (n = 2; 11%) Patient (n = 1; 5%) decision decision Patient (n = 1; 6%) Physician (n = 1; 5%) decision Physician (n = 1; 5%) decision decision Treatment (n = 0) Death (n = 1; 5%) ongoing Treatment (n = 1; 5%) Other (n = 1; 5%) ongoing Treatment (n = 0) ongoing Fig 1. CONSORT diagram of the study design and patient disposition. (*) Patients who completed treatment either received 2 years of combination therapy or received $ 6 months of combination treatment and achieved a complete response with two or more doses of pembrolizumab administered beyond the date of initial complete response. Three patients with melanoma met the latter criteria for early stopping of treatment (50 mg twice per day, two patients; 100 mg twice per day, one patient). TRAEs of any grade and grade 3/4 occurred in 84% and 24% patients), and amylase increased (two patients). TRAEs led to dose of patients, respectively (Table 2). TRAEs reported in $ 20% of interruption and reduction in 32% and 19% of patients, re- patients were fatigue (36%), rash (36%), arthralgia (24%), pruritus spectively. Seven patients (11%) discontinued treatment because of (23%), and nausea (21%). Grade 3/4 TRAEs that occurred in more TRAEs (grade 3 arthralgia, grade 3 AST increased, grade 3 lipase than one patient were rash (five patients), lipase increased (five increased, grade 3 aseptic meningitis, grade 2 brain edema, grade 2 Table 2. Summary of Treatment-Related AEs Epacadostat Treatment Group, No. (%) 25 mg Twice Per Day* 50 mg Twice Per Day* 100 mg Twice Per Day* 300 mg Twice Per Day* (n = 4) (n = 20) (n = 18) (n = 20) Total (N = 62) Event All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Treatment-related AEs 4 (100) 1 (25) 14 (70) 2 (10) 16 (89) 5 (28) 18 (90) 7 (35) 52 (84) 15 (24) Fatigue 3 (75) 0 7 (35) 0 6 (33) 0 6 (30) 1 (5) 22 (36) 1 (2) Rash† 2 (50) 0 9 (45) 1 (5) 0 0 11 (55) 4 (20) 22 (36) 5 (8) Arthralgia 2 (50) 0 4 (20) 1 (5) 4 (22) 0 5 (25) 0 15 (24) 1 (2) Pruritus‡ 2 (50) 0 5 (25) 0 0 0 7 (35) 0 14 (23) 0 Nausea 3 (75) 0 3 (15) 0 3 (17) 0 4 (20) 0 13 (21) 0 Diarrhea 2 (50) 0 3 (15) 0 3 (17) 0 3 (15) 0 11 (18) 0 Pyrexia 0 0 1 (5) 0 1 (6) 0 5 (25) 0 7 (11) 0 AST increased 0 0 2 (10) 0 4 (22) 1 (6) 0 0 6 (10) 1 (2) Dizziness 0 0 4 (20) 0 1 (6) 0 1 (5) 0 6 (10) 0 Vomiting 0 0 1 (5) 0 3 (17) 0 2 (10) 0 6 (10) 0 Chills 0 0 2 (10) 0 2 (11) 0 1 (5) 0 5 (8) 0 Cough 0 0 2 (10) 0 1 (6) 0 2 (10) 0 5 (8) 0 Lipase increased 0 0 0 0 3 (17) 3 (17) 2 (10) 2 (10) 5 (8) 5 (8) Myalgia 0 0 1 (5) 0 2 (11) 0 2 (10) 0 5 (8) 0 ALT increased 0 0 1 (5) 0 3 (17) 0 0 0 4 (7) 0 Back pain 0 0 0 0 1 (6) 0 3 (15) 0 4 (7) 0 Constipation 2 (50) 0 1 (5) 0 0 0 1 (5) 0 4 (7) 0 Decreased appetite 0 0 0 0 0 0 4 (20) 0 4 (7) 0 Musculoskeletal pain 0 0 2 (10) 1 (5) 1 (6) 0 0 0 3 (5) 1 (2) NOTE. Treatment-related AEs are listed by preferred term for events that occurred in $ 5% of the total study population. Grade 3/4 treatment-related AEs not listed in the table were amylase increased (n = 2), stomatitis (n = 1), and aseptic meningitis (n = 1). Abbreviation: AE, adverse event. *Combined with pembrolizumab 2 mg/kg every 3 weeks or 200 mg every 3 weeks. †Rash includes the following Medical Dictionary for Regulatory Activities–preferred terms: rash, rash maculopapular, rash generalized, rash pruritic, erythema, erythema multiforme, rash erythematous, palmar-plantar erythrodysesthesia syndrome, rash follicular, rash pustular, and skin exfoliation. ‡Pruritus includes the following Medical Dictionary for Regulatory Activities–preferred terms: pruritus and pruritus generalized. 3226 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors Table 3. Pharmacokinetic Assessments of Epacadostat Epacadostat*, Mean 6 SD (geometric mean) 25 mg 50 mg 100 mg 300 mg Parameter Twice Per Day Twice Per Day Twice Per Day Twice Per Day Cycle 1, day 1, No. of patients 3 20 18 19 C , mM 0.23 6 0.15 (0.20) 0.54 6 0.22 (0.50) 0.80 6 0.38 (0.72) 2.3 6 1.2 (2.0) max t , hours† 2.0 (1.0-3.2) 2.0 (0.45-4.0) 2.0 (0.83-4.4) 2.0 (0.53-6.0) max AUC , hours $ mM 0.71 6 0.35 (0.65) 1.4 6 0.62 (1.3) 2.4 6 0.82 (2.3) 7.2 6 2.9 (6.7) last Cycle 1, day 8, No. of patients 3 19 16 19 C , mM 0.27 6 0.16 (0.24) 0.50 6 0.24 (0.45) 0.92 6 0.42 (0.81) 2.7 6 1.2 (2.5) max t , hours† 1.0 (1.0-2.0) 2.0 (0.85-4.0) 2.0 (1.0-4.0) 2.0 (0.50-4.1) max t , hours 5.2, 5.5‡ 3.5 6 1.4 (3.3) 3.9 6 1.6 (3.6) 4.0 6 1.4 (3.8) 1/2 AUC , hours $ mM1.2 6 0.17 (1.2) 2.1 6 1.1 (1.8) 3.7 6 1.4 (3.4) 12 6 5.8 (11) 0-t Abbreviations: AUC , area under the steady-state concentration versus time curve over one dosing interval; AUC , area under the concentration versus time 0-t last curve from time zero to the time of the last measurable concentration; C , maximum observed plasma concentration; SD, standard deviation; t , terminal elimination max 1/2 half-life; t , time of observed maximum observed plasma concentration. max *Combined with pembrolizumab 2 mg/kg every 3 weeks or 200 mg every 3 weeks. †Median (range). ‡One of the three patients was excluded because of pathologic plasma epacadostat concentration-time profile at cycle 1, day 8; individual values for the remaining two patients are listed. colitis, and grade 3 fatigue [one patient each]). The grade 3 aseptic each other and consistent with simulated concentration-time meningitis subsequently resolved after hospitalization and treat- profiles for similar doses from a population pharmacokinetic ment (including empirical antibiotic treatment and oral dexa- model of pembrolizumab monotherapy using data from ap- methasone). No TRAEs led to death. AEs of special interest proximately 3,000 patients. occurred in 10 patients (16%): severe skin reactions (five patients Pharmacokinetic-based projected IDO1 inhibition at steady state [all grade $ 3 rash]), hypothyroidism (three patients), colitis (one is plotted in Figure 2 for individual patients grouped by epacadostat patient), and pneumonitis (one patient). dose. Most patients (. 90%) were projected to have achieved $ 50% time-averaged IDO1 inhibition (level of pharmacodynamic activity Pharmacokinetics, Pharmacodynamics, and associated with inhibition of tumor growth seen in nonclinical Immunogenicity models). PD-L1 expression did not seem to have any clear effects on Pharmacokinetic parameters of epacadostat at days 1 and 8 pharmacokinetic-predicted pharmacodynamics. The treatment-emergent antipembrolizumab antibody rate in of cycle 1 are listed in Table 3. Epacadostat plasma exposures (area under the concentration v time curve and maximum the 54 evaluable patients treated with pembrolizumab plus epa- observed plasma concentration) increased in an approximately cadostat was 3.7%. This rate seemed to be similar to that observed dose-proportional manner, with time of observed a maximum in a pembrolizumab monotherapy reference data set (2.1%), observed plasma concentration at approximately 2 hours. Se- although the small number of patients evaluated in this study rum concentrations of pembrolizumab 2 mg/kg and 200 mg makes it difficult to draw conclusions about the effects of epa- every 3 weeks during cycle 1 and at steady state were similar to cadostat on pembrolizumab immunogenicity. 25 mg twice 50 mg 100 mg 300 mg per twice per day twice per day twice per day 100 day 90% IDO1 inhibition 70% IDO1 inhibition Fig 2. Pharmacokinetic-predicted time-- averaged inhibition of indoleamine 2,3-dioxygenase 50% IDO1 inhibition 1 (IDO1) inhibition for individual patients by epacadostat dose. Patients jco.org © 2018 by American Society of Clinical Oncology 3227 Time-Averaged IDO1 Inhibition (%) Mitchell et al KRAS mutation positive, three were PD-L1 positive (tumor pro- Antitumor Activity portion score $ 1%), one was PD-L1 negative, and one was IDO1 Antitumor activity was observed at all epacadostat doses and in negative. Responses were ongoing in four of five patients. several tumor types (Fig 3). Per investigator assessment by RECIST Among the two responders with RCC, each had intermediate v1.1, eight of 62 patients achieved CR as best response (treatment- and favorable Memorial Sloan Kettering Cancer Center risk, and naive melanoma [5 patients] and previously treated for advanced/ one was PD-L1 positive. Both responses were maintained for metastatic melanoma, EA, or UC [one patient each]), and 17 pa- approximately 15 months. tients achieved PR (treatment-naive melanoma [six patients], Thirteen patients across all doses experienced stable disease as NSCLC [five patients], RCC and UC [two patients each], and EA and best response. These included four with melanoma, two with SCCHN [one patient each]). Of 25 patients who achieved an ob- jective response, 14 received epacadostat doses$ 100 mg twice a day. NSCLC, five with RCC, one with TNBC, and one with SCCHN. For the purpose of RP2D evaluation, antitumor activities were Seventeen of 25 responses were ongoing at data cutoff. Among the 12 responders with melanoma, eight had stage observed at all dose levels, and no dose exceeded the MTD. Epacadostat 100 mg twice per day seemed to be better tolerated M1c disease at baseline, three were BRAF mutation positive, six were PD-L1 positive (melanoma score $ 1%), one was PD-L1 than 300 mg twice per day, with lower rates of grade 3/4 TRAEs negative, four were IDO1 positive, and one was IDO1 negative. (28% v 35%), treatment-related dose interruptions (22% v 45%) Responses were ongoing in 10 of 12 patients. By immune-related and reductions (11% v 35%), and AEs of special interest (6% v RECIST criteria, one additional patient achieved PR. 30%). Furthermore, all patients treated with epacadostat 100 mg Among the five responders with NSCLC, three had adeno- twice per day or 300 mg twice per day were projected to have carcinoma histology, one was EGFR mutation positive, two were achieved $ 50% time-averaged IDO1 inhibition; the majority of 25 mg twice per day 50 mg twice per day 100 mg twice per day 300 mg twice per day Melanoma NSCLC RCC EA TNBC UC SCCHN * * † † † * * ** * –25 –50 –75 –100 Patients Fig 3. Change from baseline in target le- B C sions. (A) Best percentage change from baseline in target lesions by tumor type in all 25 mg twice per day 100 25 mg twice per day patients. (B) to (D) Percentage change from 50 mg twice per day 100 mg twice per day baseline in target lesions over time in pa- 100 mg twice per day 300 mg twice per day tients with (B) melanoma, (C) non–small-cell 300 mg twice per day lung cancer (NSCLC), and (D) renal cell cancer 0 0 (RCC). EA, endometrial adenocarcinoma; RECIST, Response Evaluation Criteria in Solid –50 –50 Tumors; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative breast cancer; UC, urothelial carcinoma. (*) –100 { –100 Progressive disease per RECIST version 1.1. 18 36 54 72 90 108 126 144 162 18 36 54 72 90 108 126 144 162 (†) Partial response per RECIST version 1.1. Time (weeks) Time (weeks) 50 mg twice per day 100 mg twice per day 300 mg twice per day –50 –100 18 36 54 72 90 108 126 144 162 Time (weeks) 3228 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Change From Baseline (%) Change From Baseline (%) Best Change From Baseline (%) Change From Baseline (%) Epacadostat Plus Pembrolizumab in Advanced Solid Tumors patients treated with 100 mg twice per day achieved a minimum biomarkers, including PD-L1 and IDO1, with treatment response IDO1 inhibition of $ 50%. On the basis of these considerations, were not feasible in this study because of insufficient patient epacadostat 100 mg twice per day plus pembrolizumab 200 mg numbers. Across various tumor types, patients achieved durable every 3 weeks was selected for additional investigation in phase II. response, with the majority of responses (17 [68%] of 25) ongoing at data cutoff. The preliminary favorable toxicity profile, phar- macokinetics, and pharmacokinetic-predicted pharmacodynamics DISCUSSION along with encouraging clinical activity of epacadostat plus pembrolizumab reported here support additional phase II in- Phase I results of this trial show that epacadostat plus pem- vestigation of the combination, with epacadostat 100 mg twice per brolizumab generally is well tolerated in patients with various day selected as the RP2D. advanced solid tumors; the safety profile is similar to previous At the time of this publication, it has been announced that the experience with pembrolizumab monotherapy. No new safety pivotal phase III ECHO-301/KEYNOTE-252 study (ClinicalTrials. signals were detected for either epacadostat or pembrolizumab. gov identifier: NCT02752074) that was evaluating epacadostat plus TRAEs were primarily grade 1/2 and manageable with dose pembrolizumab in patients with unresectable or metastatic mel- modifications or concomitant medications. Seven patients (11%) anoma did not meet the primary end point of improving discontinued because of TRAEs. No epacadostat MTD was de- progression-free survival in the overall population compared with termined, and no patients died as a result of TRAEs. The safety pembrolizumab monotherapy. Future results from ECHO-301/ profile observed with epacadostat plus pembrolizumab compares KEYNOTE-252, including analyses of an extensive biomarker favorably with studies of other combination immunotherapies, panel and other pharmacodynamic analyses, will contribute to the such as nivolumab plus ipilimumab or pembrolizumab plus low- understanding of the role of IDO1 inhibition, and epacadostat in dose ipilimumab in advanced cancers. Nivolumab plus ipilimumab combination with PD-1 inhibitors, in cancer therapy. has been associated with higher rates of toxicities in patients with advanced melanoma, including grade 3/4 TRAEs in $ 45% and 3,4,25 drug discontinuations in approximately one third. The pre- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS liminary findings reported here suggest that dual inhibition of the OF INTEREST IDO1 enzyme and PD-1 is feasible with minimal additive 26-28 Disclosures provided by the authors are available with this article at toxicity. jco.org. Analyses of the pharmacokinetic parameters were comparable to previous reports of epacadostat and pembrolizumab mono- therapies, which suggests that the combination does not affect AUTHOR CONTRIBUTIONS the pharmacokinetics of either individual agent in patients with solid tumors. Kynurenine inhibition over time was not directly Conception and design: Tara C. Mitchell, Anthony J. Olszanski, Emmett measured in this study, so the pharmacodynamics were projected V. Schmidt, Janet Maleski, Lance Leopold, Thomas F. Gajewski on the basis of the phase I patient pharmacokinetic data to yield Provision of study materials or patient: David C. Smith, Todd M. Bauer, time-averaged IDO1 inhibition. All patients who received Jason J. Luke epacadostat $ 100 mg twice per day achieved average concen- Collection and assembly of data: Tara C. Mitchell, Omid Hamid, David C. trations at steady state that exceeded the IC associated with Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason optimal target inhibition on the basis of preclinical models. J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Janet Maleski, Lance Leopold, Thomas F. Gajewski Although not powered to evaluate efficacy, the phase I portion Data analysis and interpretation: Tara C. Mitchell, Omid Hamid, David of this study showed that epacadostat plus pembrolizumab had C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason encouraging and durable antitumor activity. Objective responses J. Luke, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, were observed in patients with treatment-naive and previously Lance Leopold, Thomas F. Gajewski treated (cytokine or interferon therapy) melanoma, NSCLC, RCC, Manuscript writing: All authors UC, EA, and SCCHN. Responses were observed in both PD- Final approval of manuscript: All authors L1–positive and –negative patients; however, correlative analyses of Accountable for all aspects of the work: All authors 4. Hodi FS, Chesney J, Pavlick AC, et al: Combined 7. Prendergast GC, Mondal A, Dey S, et al: In- REFERENCES nivolumab and ipilimumab versus ipilimumab alone in flammatory reprogramming with IDO1 inhibitors: patients with advanced melanoma: 2-year overall survival Turning immunologically unresponsive ‘cold’ tumors 1. Abril-Rodriguez G, Ribas A: SnapShot: Im- outcomes in a multicentre, randomised, controlled, phase ‘hot’. Trends Cancer 4:38-58, 2018 mune checkpoint inhibitors. Cancer Cell 31:848-848. 2 trial. Lancet Oncol 17:1558-1568, 2016 8. Theate I, van Baren N, Pilotte L, et al: Exten- e1, 2017 5. 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Li H, Yu J, Liu C, et al: Time dependent dostat plus pembrolizumab versus pembrolizumab in-human phase I study of the oral inhibitor of indo- pharmacokinetics of pembrolizumab in patients with alone in patients with unresectable or metastatic leamine 2,3-dioxygenase-1 epacadostat (INCB024360) solid tumor and its correlation with best overall re- melanoma: Results of the phase 3 ECHO-301/ in patients with advanced solid malignancies. Clin sponse. J Pharmacokinet Pharmacodyn 44:403-414, KEYNOTE-252 study. J Clin Oncol 36, (suppl; abstr Cancer Res 23:3269-3276, 2017 2017 108), 2018 Affiliations Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE. Support Supported by Incyte and Merck & Co. Prior Presentation Presented at the European Society for Medical Oncology Annual Meeting, Copenhagen, Denmark, October 7-11, 2016. nn n 3230 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Epacadostat Plus Pembrolizumab in Advanced Solid Tumors AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO- 202/KEYNOTE-037) The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Tara C. Mitchell Jason J. Luke Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Incyte, Aduro Honoraria: Intellisphere Biotech, Regeneron Consulting or Advisory Role: Amgen, Array BioPharma, Bristol-Myers Research Funding: Merck (Inst), Incyte (Inst), Bristol-Myers Squibb Squibb, Merck, EMD Serono, Benevir Biopharm, Checkmate (Inst), Roche (Inst) Pharmaceuticals, Novartis, AstraZeneca, MedImmune, 7 Hills Pharma, Castle Biosciences, Actym Therapeutics, Gilead Sciences, Janssen Omid Hamid Pharmaceuticals, NewLink Genetics, RefleXion Medical, Syndax, Tempest Consulting or Advisory Role: Amgen, Novartis, Roche, Bristol-Myers Therapeutics Squibb, Merck Research Funding: Merck, Bristol-Myers Squibb, Boston Biomedical, Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Novartis, Amgen, MedImmune, Incyte, Celldex, Genentech, Roche, Pharmacyclics, Five Array BioPharma Prime Therapeutics, Corvus Pharmaceuticals, Delcath Systems, AbbVie, Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Immunocore, Palleon Pharmaceuticals, Checkmate Pharmaceuticals, Celldex (Inst), Genentech (Inst), Immunocore (Inst), Incyte (Inst), Merck Macrogenics, Novartis, Tesaro (Inst), Merck Serono (Inst), MedImmune (Inst), Novartis (Inst), Pfizer Travel, Accommodations, Expenses: Amgen, Bristol-Myers Squibb, Array (Inst), Rinat Neuroscience (Inst), Roche (Inst) BioPharma, AstraZeneca, MedImmune, Benevir Biopharm, Castle Biosciences, Checkmate Pharmaceuticals, EMD Serono, Gilead Sciences, David C. Smith Janssen Pharmaceuticals, Merck, Novartis, RefleXion Medical Research Funding: Agensys (Inst), Atterocor (Inst), Bayer AG (Inst), Boston Biomedical (Inst), Exelixis (Inst), Incyte (Inst), Eli Lilly (Inst), Ani S. Balmanoukian MedImmune (Inst), Novartis (Inst), OncoMed Pharmaceuticals (Inst), Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Merck, AstraZeneca Seattle Genetics (Inst), Bristol-Myers Squibb (Inst), Medarex (Inst), ESSA Pharma (Inst), Genentech (Inst), Medivation (Inst), Astellas Pharma Emmett V. Schmidt (Inst), Merck (Inst) Employment: Merck Stock or Other Ownership: Merck, Merck (I) Todd M. Bauer Employment: Tennessee Oncology, Sarah Cannon Research Institute Yufan Zhao Consulting or Advisory Role: Ignyta (Inst), Guardant Health, Loxo Employment: Incyte, Amgen Oncology, Pfizer Stock or Other Ownership: Incyte, Amgen Research Funding: Daiichi Sankyo (Inst), MedPacto (Inst), Incyte (Inst), Xiaohua Gong Mirati Therapeutics (Inst), MedImmune (Inst), AbbVie (Inst), Employment: Incyte AstraZeneca (Inst), Leap Therapeutics (Inst), MabVax Therapeutics (Inst), Stock or Other Ownership: Incyte Stemline Therapeutics (Inst), Merck (Inst), Eli Lilly (Inst), Travel, Accommodations, Expenses: Incyte GlaxoSmithKline (Inst), Novartis (Inst), Pfizer (Inst), Principia Biopharma (Inst), Genentech (Inst), Roche (Inst), Deciphera Pharmaceuticals (Inst), Janet Maleski Merrimack (Inst), Immunogen (Inst), Millennium Pharmaceuticals (Inst), Employment: Incyte Ignyta (Inst), Calithera Bioscience (Inst), Kolltan Pharmaceuticals (Inst), Stock or Other Ownership: Incyte Peloton Therapeutics (Inst), Immunocore (Inst), Roche (Inst), Aileron Travel, Accommodations, Expenses: Incyte Therapeutics (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Moderna Lance Leopold Therapeutics (Inst), Sanofi (Inst), Boehringer Ingelheim (Inst), Astellas Employment: Incyte Pharma (Inst) Stock or Other Ownership: Incyte Jeffrey S. Wasser Thomas F. Gajewski Stock or Other Ownership: Johnson & Johnson, Bristol-Myers Squibb, Consulting or Advisory Role: Merck, Roche, Genentech, Jounce Eli Lilly, Biogen, AbbVie, Merck (I), Pfizer (I) Therapeutics, Bayer AG, AbbVie, Aduro Biotech, Evelo Biosciences, Honoraria: Amgen, Novartis FogPharma, Adaptimmune, Five Prime Therapeutics Consulting or Advisory Role: Amgen, Novartis Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Roche Speakers’ Bureau: Novartis (Inst), Genentech (Inst), Incyte (Inst), Seattle Genetics (Inst), Ono Research Funding: Merck, Guardant Health, Incyte, Pfizer Pharmaceutical (Inst) Anthony J. Olszanski Patents, Royalties, Other Intellectual Property: Licensing to Evelo Consulting or Advisory Role: EMD Serono, Takeda Pharmaceuticals, Bioscience (Inst), licensing to Aduro Biotech (Inst) Bristol-Myers Squibb, G1 Therapeutics, Pfizer, Array BioPharma, Iovance Biotherapeutics Research Funding: Takeda Pharmaceuticals (Inst), Immunocore (Inst), EMD Serono (Inst), Amgen (Inst), Incyte (Inst), Kyowa Hakko Kirin (Inst), Eli Lilly (Inst), Advaxis Immunotherapies (Inst), Mirati Therapeutics (Inst), Ignyta (Inst), Novartis (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst), Kura Oncology (Inst) Travel, Accommodations, Expenses: Takeda Pharmaceuticals jco.org © 2018 by American Society of Clinical Oncology Mitchell et al Acknowledgment We thank the site coordinators of the study: Jennifer Kelley and Nichole Smith Audrey (Incyte Corporation); Leonard and Saba Mukarram (The Angeles Clinic and Research Institute); Bernadette Foster and Vipin Khare (Fox Chase Cancer Center); Erin Fisher and Deepa Bhikha (Sarah Cannon Research Institute); Christopher Sampson and Katarzyna Nastri (University of Connecticut School of Medicine); Lauren Zubkoff, Kim Feldhaus, and Villette “Sam” Thorpe (University of Michigan); Lauren Leverage and Mark Jones (University of Pennsylvania); and the site coordinators of the University of Chicago. Editorial assistance was provided by Jane Kovalevich of Complete Healthcare Communications (West Chester, PA), a CHC Group company, and funded by Incyte Corporation. © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Journal

Journal of Clinical Oncology – Pubmed Central

Published: Sep 28, 2018

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