Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Jun Gong; Alexander Chehrazi-Raffle; Srikanth Reddi; Ravi Salgia

doi:10.1186/s40425-018-0316-z

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Gong, Jun; Chehrazi-Raffle, Alexander; Reddi, Srikanth; Salgia, Ravi 2018-01-23 00:00:00 Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy. Keywords: PD-1 inhibitor, PD-L1 inhibitor, Clinical trials, Biomarkers, Immune checkpoint, Hyperprogressors, Treatment beyond progression, Microbiome, Immune-related toxicity Background hypothesis was developed that PD-1/PD-L1 blockade The programmed cell death protein 1 receptor (PD-1) may be an effective cancer immunotherapy (Fig. 1). receptor was first described in the early 1990s given its Initial phase I studies investigating several human- expression during induction of apoptosis in a T-cell ized monoclonal IgG4 antibodies targeting PD-1 and hybridoma [1, 2]. Since its initial discovery several PD-L1 in advanced solid tumors were soon conducted groups have identified that engagement of PD-1 through and paved way for the development of the first PD-1 its ligand, programmed death ligand 1 (PD-L1), inhibitors, nivolumab and pembrolizumab, approved negatively regulates T-cell-mediated immune responses by the Food and Drug Administration (FDA) [9–11]. [3–6]. Early preclinical evidence suggested that activa- Immune checkpoint inhibitors targeting the PD-1/PD- tion of PD-1/PD-L1 signaling could serve as a mechan- L1 axis are now approved in the treatment of several ism for tumors to evade an antigen-specific T-cell malignancies ranging from classical Hodgkin lymph- immunologic response [6–8]. Consequently, the oma to head and neck squamous cell carcinoma (HNSCC) [12]. Since the approval of pembrolizumab for the treat- * Correspondence: [email protected] ment of advanced melanoma in September 2014, the Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Building 51, Room 101, 1500 E Duarte St, clinical development of PD-1 and PD-L1 inhibitors as Duarte, CA 91010, USA anticancer agents has broadened (Table 1). Presently, the 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. Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 2 of 18 Fig. 1 Mechanism of action of PD-1 and PD-L1 inhibitors. The programmed cell death 1 (PD-1) receptor is expressed on activated T cells, B cells, macrophages, regulatory T cells (Tregs), and natural killer (NK) cells. Binding of PD-1 to its B7 family of ligands, programmed death ligand 1 (PD- L1 or B7-H1) or PD-L2 (B7-DC) results in suppression of proliferation and immune response of T cells. Activation of PD-1/PD-L1 signaling serves as a principal mechanism by which tumors evade antigen-specific T-cell immunologic responses. Antibody blockade of PD-1 or PD-L1 reverses this process and enhances antitumor immune activity. TCR, T-cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell FDA has approved PD-1/PD-L1 inhibitors for the treat- checkpoint inhibitor” and limited to published studies of ment of nine cancer types (Fig. 2). The purpose of this English language up to October 1, 2017. Studies were review is to highlight the clinical development of PD-1 further restricted to registration trials leading to FDA- and PD-L1 inhibitors in cancer therapy to date. In approved indications in cancer therapy. An additional particular, we focus on detailing the registration trials manual search was performed to include preliminary that have led to FDA-approved indications of anti-PD-1 results from abstracts of potential relevance. and anti-PD-L1 therapies in cancer and discuss future considerations important to optimizing their antitumor Melanoma efficacy. Pembrolizumab A literature search was conducted in MEDLINE using On September 4, 2014, pembrolizumab (humanized the following key words: “programmed death 1,” pro- monoclonal IgG4 antibody) became the first PD-1 inhibi- grammed death-ligand 1,”“PD-1,”“PD-L1,”“immune tor to receive approval for patients with advanced or Table 1 Overview of PD-1/PD-L1 inhibitors, mechanisms of action, trial designations and approved companion diagnostics Agent Mechanism of action Trial name(s) FDA-approved PD-L1 companion diagnostic Pembrolizumab PD-1 inhibitor KEYNOTE Primary antibody: 22C3 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: Merck Nivolumab PD-1 inhibitor CheckMate Primary antibody: 28-8 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: BMS Atezolizumab PD-L1 inhibitor IMVigor (UC), POPLAR (NSCLC), OAK (NSCLC) Primary antibody: SP142 (Ventana) IHC scoring: Tumor cell membrane, infiltrating immune cells Therapeutic developer: Genentech Durvalumab PD-L1 inhibitor Study 1108 Primary antibody: SP263 (Ventana) IHC scoring: Tumor cell membrane Therapeutic developer: AstraZeneca Avelumab PD-L1 inhibitor JAVELIN Primary antibody: 73-10 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: Merck, Pfizer PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, FDA Food and Drug Administration, IHC immunohistochemistry, BMS Bristol-Myers Squibb, UC urothelial carcinoma, NSCLC non-small cell lung cancer For research use only Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 3 of 18 Fig. 2 Timeline of FDA approvals for PD-1 and PD-L1 inhibitors in cancer therapy. The Food and Drug Administration approvals of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors detailed by agent, date of approval, and tumor type. NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability-high; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; UC, urothelial carcinoma; MCC, Merkel cell carcinoma unresectable melanoma based on the findings from the 34% in ipilimumab-treated and 45% in ipilimumab-naïve KEYNOTE-001 study [13, 14]. In this phase I multicenter, patients. Pembrolizumab was well tolerated as 14% of all international, open-label, randomized expansion of the patients experienced grade ≥3AEs. KEYNOTE-001 cohort, 173 patients with advanced or On December 18, 2015, pembrolizumab received an unresectable melanoma who had previously failed treat- expanded first-line indication to include previously- ment with ipilimumab and a BRAF inhibitor (if untreated advanced melanoma regardless of BRAF muta- V600 BRAF -mutated) were treated with pembrolizumab tion status following the results of the KEYNOTE-006 [14]. Patients were randomly assigned to treatment with trial [16]. In this international, randomized, open-label pembrolizumab intravenous (IV) at 2 mg/kg every 3 weeks phase 3 study, pembrolizumab 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks. The primary study endpoint or every 3 weeks vs. ipilimumab 3 mg/kg every 3 weeks was overall response rate (ORR) per RECIST 1.1. The was evaluated in patients with advanced, unresectable ORR was 26% in both the pembrolizumab 2 mg/kg and stage III or IV melanoma who had received ≤1 previous 10 mg/kg groups (Table 2). Grade 3-4 drug-related systemic therapy for advanced disease. Primary end- adverse events (AEs) occurred in 15% of the pembrolizu- points were PFS and OS and 6-month PFS for patients mab 2 mg/kg group (most common fatigue 6%) and 8% of who received pembrolizumab every 2 weeks and every the pembrolizumab 10 mg/kg group (1 each of diarrhea, 3 weeks was 47.3% and 46.4%, respectively, compared to rash, dyspnea, hypoxia, maculopapular rash, pancreatitis, 26.5% for those who received ipilimumab (hazard ratio and musculoskeletal pain) [14]. In an update of (HR) for disease progression 0.58 for both pembrolizu- KEYNOTE-001, findings after a median follow-up dur- mab regimens vs. ipilimumab, 95% confidence interval ation of 18 months for all patients were published [15]. (CI) 0.46-0.72 and 0.47-0.72, respectively, p < 0.001). Progression-free survival (PFS) at 6 months was 45%, One-year OS and ORR rates were significantly improved median overall survival (OS) was 25.9 months, and ORR in patients receiving either doses of pembrolizumab Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 4 of 18 Table 2 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in melanoma Study/Agent Tumor (n) Line of therapy Experimental arm Control arm Primary endpoint Ref KEYNOTE-001 Advanced Previously treated Pembrolizumab 2 mg/kg ORR 26% (both doses; 14 (phase I)/ melanoma with ipilimumab or 10 mg/kg every difference 0%, 95% pembrolizumab (n = 173) and/or BRAF inhibitor 3 weeks CI 14-13, p = 0.96) KEYNOTE-006 Advanced First-line (regardless Pembrolizumab 10 mg/kg Ipilimumab 3 mg/kg PFS (6-month) 47.3% vs. 46.4% 16 (phase III)/ melanoma of BRAF mutations every 2 weeks OR every every 3 weeks X4 vs. 26.5% (HR 0.58 for both pembrolizumab (n = 834) status) 3 weeks cycles pembrolizumab regimens vs. ipilimumab 95% CI 0.46-0.72 and 0.47-0.72, respectively, p < 0.001) OS (1-year) 74.1% vs. 68.4% vs. 58.2% (HR pembrolizumab every 2 weeks 0.63, 95% CI 0.47-0.83, p = 0.0005; HR pembrolizumab every 3 weeks 0.69, 95% CI 0.52-0.90, p = 0.0036) KEYNOTE-002 Advanced Refractory to Pembrolizumab 2 mg/kg ICC (paclitaxel+ PFS 2 mg/kg (HR 0.57 95% CI 17 (phase II)/ melanoma ipilimumab and/or every 3 weeks OR 10 carboplatin, paclitaxel, 0.45-0.73, p < 0.001) and pembrolizumab (n = 540) BRAF inhibitor mg/kg every 3 weeks carboplatin, dacarbazine, 10 mg/kg (HR 0.50, 95% CI or temozolomide) 0.39-0.64, p < 0.001) compared to ipilimumab No superiority in OS at this interim analysis ORR 31.7% (95% CI 23.5-40.8) 18 CheckMate 037 Stage IIIC or Second-line Nivolumab 3 mg/kg Dacarbazine 1000 mg/ (phase III)/ IV melanoma every 2 weeks m2 every 3 weeks vs. 10.6% (95% 3.5-23.1) nivolumab (n = 405) OR carboplatin AUC 6 + paclitaxel 175 mg/m every 3 weeks V600 CheckMate 069 BRAF -WT First-line Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every ORR 61% vs. 11% (p < 0.001) 19 phase III)/ unresectable or ipilimumab 3 mg/kg every 3 weeks nivolumab/ipilimumab metastatic 3 weeks X4 cycles then melanoma nivolumab alone every (n = 142) 2 weeks CheckMate 067 Unresectable or First-line Arm 1: Nivolumab Ipilimumab 3 mg/kg every PFS 6.9 mos (HR compared to 20 phase III)/ metastatic 3 mg/kg every 2 weeks 3 weeks ipilimumab 0.57, 99.5% CI nivolumab/ipilimumab melanoma Arm 2: nivolumab 0.43-0.76, p < 0.001 vs. 11.5 mo (n = 945) 1 mg/kg and ipilimumab (HR 0.42, 99.5% CI 0.31-0.57, 3 mg/kg every 3 weeks p < 0.001 compared to for 4 doses followed ipilimumab) vs. 2.9 mos by nivolumab 3 mg/kg of every 2 weeks Order of results refers to the experimental arm and control arm, respectively. In trials with more than one experimental arm, the endpoints are in the same order as documented in the experimental arm column FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, ORR overall response rate, CI confidence interval, PFS progression-free survival, HR hazard ratio, OS overall survival, ICC investigator-choice chemotherapy, AUC area under curve, WT wild-type compared to ipilimumab as well (Table 2). The most carboplatin, paclitaxel, carboplatin, dacarbazine, or temo- common grade 3-5 AEs of special interest were colitis zolomide). There was no statistically significant difference (1.4%, pembrolizumab every 2 weeks), colitis (2.5%) and in OS between both pembrolizumab arms and hepatitis (1.8%, pembrolizumab every 3 weeks), and col- chemotherapy at interim analysis. Doses of pembrolizu- itis (7.0%, ipilimumab) [16]. mab 2 mg/kg (HR 0.57, 95% CI 0.45-0.73, p <0.001) and Furthermore, the FDA approved a labeling update for 10 mg/kg (HR 0.50, 95% CI 0.39-0.64, p < 0.001) showed pembrolizumab in ipilimumab-refractory melanoma based superior median PFS when compared to chemotherapy. on findings from KEYNOTE-002 [17]. This study com- Response rates were 21% in the pembrolizumab 2 mg/kg pared pembrolizumab and investigator-choice chemother- group and 25% in the 10 mg/kg group compared to 4% in apy (ICC) for the treatment of unresectable stage III or the chemotherapy arm (p < 0.0001). Incidence of grade 3- stage IV ipilimumab and/or BRAF inhibitor-refractory 4 treatment-related AEs was higher in those given melanoma. Patients (n = 540) were randomized to receive chemotherapy (26%) than in those given pembrolizumab pembrolizumab 2 mg/kg every 3 weeks, pembrolizumab 2 mg/kg group (11%) and pembrolizumab 2 mg/kg group 10 mg/kg every 3 weeks, or ICC (paclitaxel plus (14%) [17]. Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 5 of 18 Nivolumab were randomized to receive nivolumab 3 mg/kg every 2 On December 22, 2014, nivolumab was first approved as weeks, nivolumab 1 mg/kg and ipilimumab 3 mg/kg second-line treatment of unresectable or metastatic mel- every 3 weeks for 4 doses followed by nivolumab 3 mg/ anoma based on the CheckMate 037 trial [18]. This ran- kg every 2 weeks, or ipilimumab 3 mg/kg. Median PFS domized controlled, open-label, international phase III was 6.9 months in the nivolumab group, 11.5 months in study randomized 272 patients with unresectable stage the combination group, and 2.9 months in the ipilimu- IIIC or IV melanoma progressing after anti-CTLA-4 mab group (Table 2). Longer OS was shown with nivolu- treatment or after anti-CTLA-4 treatment and a BRAF mab and combination therapy compared with V600 inhibitor for BRAF -mutated tumors to IV nivolumab ipilimumab alone across all subgroups (PD-L1 status, V600 3 mg/kg every 2 weeks and 133 to ICC (Table 2). Posi- BRAF status, and metastasis stage). The incidence of tive PD-L1 expression was defined as ≥5% of tumor cells grade ≥ 3 AEs was greater in the combination group exhibiting PD-L1 staining (IHC 28-8 antibody) of any in- (55%) than in nivolumab or ipilimumab alone (16.3% tensity in a section containing ≥100 evaluable cells. The and 27.3%, respectively). The most common grade ≥ 3 ORR was 31.7% in the nivolumab group and 10.6% in AEs in the combination group were diarrhea, colitis, and the chemotherapy group (Table 2). In patients with PD- increased ALT and aspartate aminotransferase (AST) L1 positivity, ORR was 43.6% compared to 9.1% of the whereas the most frequent grade ≥ 3 AEs in the mono- chemotherapy group. Grade ≥ 3 nivolumab-related AEs therapy arms were fatigue and diarrhea. were seen in 9% of patients and included elevated lipase, elevated alanine aminotransferase (ALT), fatigue, and Non-small cell lung cancer anemia. Grade ≥ 3 AEs occurred in 32% of chemotherapy Pembrolizumab patients, the most common of which were neutropenia, On October 2, 2015, pembrolizumab was approved for anemia, and thrombocytopenia. treatment of previously-treated advanced or metastatic The combination of nivolumab and ipilimumab was PD-L1-positive non-small cell lung cancer (NSCLC) V600 later approved as first-line treatment for BRAF -wild- [21]. As part of the KEYNOTE-001 phase I study, 550 type unresectable or metastatic melanoma on October 1, patients were treated with either pembrolizumab at a 2015 based on results from CheckMate 069 [19]. This dose of 2 mg/kg every 2 weeks or 10 mg/kg every 2 or randomized, double-blinded phase III trial, compared 3 weeks (Table 3). The primary endpoints were antitu- nivolumab 1 mg/kg in combination with ipilimumab mor activity per RECIST 1.1 and safety. Of the 61 pa- 3 mg/kg (every 3 weeks X4 cycles then nivolumab alone tients with tumors identified as strongly positive for PD- every 2 weeks) against ipilimumab 3 mg/kg monother- L1 (PD-L1 ≥ 50% based on the companion diagnostic apy (every 3 weeks) as first-line treatment in 142 pa- PD-L1 immunohistochemistry (IHC) 22C3 assay), the tients with advanced melanoma. Objective response ORR for those receiving pembrolizumab 2 mg/kg was V600 occurred in 61% of patients with BRAF -wild-type tu- 28% (95% CI 12.1-49.4%) as compared to 40% (95% CI mors in the combination group compared with 11% of 22.4-61.2) and 41% (95% CI 24.7-59.3%) in patients re- patients in the monotherapy group. Of note, overall re- ceiving pembrolizumab 10 mg/kg every 2 weeks and sponse was independent of PD-L1 status in both the every 3 weeks, respectively. The most commonly occur- combination group (58% for PD-L1-positive (≥5%) tu- ring (> 20%) AEs included fatigue, decreased appetite, mors vs. 55% for PD-L1-negative tumors) and the mono- dyspnea, and cough. Immune-mediated AEs occurred in therapy group (18% for PD-L1- positive tumors and 4% 13% of patients and included pneumonitis, colitis, hypo- V600 for PD-L1 negative tumors). In patients with BRAF - physitis, and thyroid disorders [21]. mutated tumors, the ORR was 52% in the combination Updated long-term OS data for patients with group compared with 10% in the monotherapy group. previously-treated or treatment-naïve advanced or Grade ≥ 3 AEs occurred more frequently in the combin- metastatic NSCLC were subsequently presented for the ation group (54%) than in the monotherapy group phaseIbKEYNOTE-001 study[22].Ascomparedto (24%), the most common of which were colitis, diarrhea, earlier studies that stratified tumor proportion score and elevated ALT. Ipilimumab monotherapy-related (TPS) cutoff of 1-50% and ≥50% PD-L1 staining of grade ≥ 3 AEs were seen in 24% of patients, the most tumor cells, these investigators assessed a PD-L1 stain- common of which were diarrhea and colitis. ing cutoff of ≥1% on tumor cells. Patients received On January 23, 2016, nivolumab and ipilimumab com- either pembrolizumab 2 mg/kg every 3 weeks or bination therapy received an expanded approval for 10 mg/kg every 2 or 3 weeks. Using a PD-L1 TPS cutoff unresectable or metastatic melanoma irrespective of of ≥1%, median OS was 22.1 months (95% CI 17.1-27.2) V600 BRAF mutation status based on results of the for treatment-naive patients and 10.6 months (95% CI CheckMate 067 trial [20]. In this phase III trial, patients 8.6-13.3) for previously-treated patients, supporting the with untreated, unresectable or metastatic melanoma efficacy of pembrolizuamb in patients with a PD-L1 Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 6 of 18 Table 3 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in lung cancer Study/Agent Tumor (n) Line of therapy Experimental arm Control arm Primary endpoint Ref KEYNOTE-001 Advanced PD-L1 positive Pembrolizumab 2 mg/kg every ORR 28% (95% CI 21, (phase Ib)/ NSCLC (≥1%) 3 weeks OR 10 mg/kg every 12.1-49.4%) vs. 40% 22 pembrolizumab (n = 550) progressing after 2 or 3 weeks (95% CI 22.4-61.2) platinum-based vs. 41% (95% CI therapy 24.7-59.3%) for PD-L1 ≥ 50% OS 22.1 mo (treatment-naïve, 95% CI 17.1-27.2) vs. 10.6 mo (previously-treated, 95% CI 8.6-13.3) for PD-L1 ≥ 50% KEYNOTE-024 Metastatic First-line Pembrolizumab 200 mg every ICC (cisplatin/ PFS 10.3 mos vs. 6.0 25 (phase III)/ NSCLC with 3 weeks carboplatin + pemetrexed, mos (HR 0.50, 95% pembrolizumab ≥50% PD-L1 cisplatin/carboplatin + CI 0.37-0.68, expression gemcitabine, or p < 0.001) (n = 305) carboplatin + paclitaxel) KEYNOTE-021 Advanced First line (in Pembrolizumab 200 mg + Carboplatin + pemetrexed ORR 55% vs. 29% 26 (phase II)/ NSCLC combination with carboplatin AUC 5 mg/ml/min + X4 cycles followed by (estimated pembrolizumab (n = 123) platinum-doublet pemetrexed 500 mg/m every indefinite maintenance treatment difference chemotherapy) 3 weeks X4 cycles followed by pemetrexed of 26%, 95% CI pembrolizumab (24 months 9-42%, p = 0.0016) duration) and indefinite maintenance pemetrexed CheckMate 017 Metastatic Previously treated Nivolumab 3 mg/kg every Docetaxel 75 mg/m OS 9.2 mo vs. 6.0 27 (phase III)/ squamous with platinum-based 2 weeks every 2 weeks mos (HR 0.59, 95% nivolumab NSCLC chemo CI 0.44-0.79, (n = 272) p < 0.001) CheckMate 057 Metastatic Previously treated Nivolumab 3 mg/kg every Docetaxel 75 mg/m OS 12.2 mos vs. 9.4 28 (phase III)/ non-squamous with platinum-based 2 weeks every 3 weeks mos (HR 0.73, 96% nivolumab NSCLC (n = 582) chemo CI 0.59-0.89, p =0.002) POPLAR (phase II)/ NSCLC (POPLAR Second-line Atezolizumab 1200 mg every Docetaxel 75 mg/m POPLAR: OS 12.6 mos 29, OAK (phase III)/ n = 287, OAK 3 weeks vs. 9.7 mos (HR 0.7, 30 atezolizumab n = 1225) 95% CI 0.53-0.99, p =0.04) OAK: OS 13.8 mos vs. 9.6 mos (HR 0.73, 95% CI 0.62-0.87, p = 0.0003) FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, NSCLC non-small cell lung cancer, ORR overall response rate, CI confidence interval, OS overall survival, ICC investigator-choice chemotherapy, PFS progression-free survival, HR hazard ratio, AUC area under curve TPS ≥1% [22]. KEYNOTE-001 investigators attempted 36.6%. Toxicities of grade ≥ 3 were reported in 47/495 to define a tumor PD-L1 expression level associated patients (9.5%) and were most commonly dyspnea with an enhanced likelihood of benefit as well as valid- (3.8%), pneumonitis (1.8%), decreased appetite (1%), ate the safety and antitumor activity of pembrolizumab and asthenia (1%) [23]. in patients with advanced NSCLC and PD-L1 ≥ 50% Following KEYNOTE-001, KEYNOTE-010 was a phase expression [23]. Patients received pembrolizumab II/III clinical trial that randomized 1034 patients to pem- 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks brolizumab (2 or 10 mg/kg every 3 weeks) vs. docetaxel and were randomized to either a training group or (75 mg/m ) for PD-L1-positive NSCLC that progressed validation group. In the training group, the PD-L1 cut- after platinum-based chemotherapy or a tyrosine kinase off was selected by immune-related response criteria by inhibitor (TKI) for those with an EGFR-sensitizing muta- investigator review; in the validation group, tion or ALK gene rearrangement [24]. For patients with membranous PD-L1 expression ≥50% was selected as PD-L1 expression ≥1%, median OS for pembrolizumab the cutoff. The ORR was 45.2% in the patients with 2 mg/kg (HR 0.71, 95% CI 0.58-0.88, p = 0.0008) and PD-L1 ≥ 50%, including 43.9% in previously-treated 10 mg/kg (HR 0.61, 95% CI 0.49-0.75, p < 0.0001) and patients and 50.0% in untreated patients. These values median PFS for pembrolizumab 10 mg/kg (HR 0.79, 95% exceeded the response rate in the training group of CI 0.66-0.94, p = 0.004) were significantly improved Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 7 of 18 compared to docetaxel with a trend towards improved docetaxel 75 mg/m every 3 weeks (Table 3). The PFS with pembrolizumab 2 mg/kg. Pembrolizumab at primary endpoint was OS and a key secondary endpoint both doses was superior to docetaxel in OS and PFS in included efficacy based on tumor cell PD-L1 expression those with ≥50% PD-L1 expression. Grade ≥3treatment- levels of 1%, 5% or 10%. Median OS was 9.2 months in related AEs occurred in 13% of the pembrolizumab 2 mg/ the nivolumab group versus 6.0 months in the docetaxel kg group, 16% of the pembrolizumab 10 mg/kg group, group, and OS at 1 year was 42% in the nivolumab and 35% of the docetaxel group. Deaths attributed to group versus 24% in the docetaxel group. PD-L1 expres- treatment occurred in 3 patients in the pembrolizumab sion was not predictive across any of the efficacy end- 2 mg/kg group (2 of pneumonitis and 1 pneumonia), 3 pa- points. Fewer all-grade treatment-related AEs occurred tients in the pembrolizumab 10 mg/kg group (myocardial with nivolumab (58%) than with docetaxel (86%). The infarction, pneumonia, and pneumonitis), and 5 patients most frequently reported AEs were fatigue, decreased in the docetaxel group [24]. appetite, and asthenia with nivolumab compared to neu- On October 24, 2016, pembrolizumab received tropenia, fatigue, and alopecia in the docetaxel arm. approval as first-line treatment for metastatic NSCLC Grade ≥ 3 AEs were found in 7% of patients with nivolu- with ≥50% PD-L1 expression and without EGFR or ALK mab (including colitis and pneumonitis) compared 57% genomic tumor aberrations [25]. In the phase III with docetaxel (including hemotologic toxicity and KEYNOTE-024 trial, 305 patients were randomized to infections). receive either pembrolizumab 200 mg every 3 weeks or The CheckMate 057 trial ushered in the FDA- ICC (platinum-based) for 4-6 cycles. Median PFS was expanded approval of nivolumab in metastatic non- 10.3 months in the pembrolizumab group as compared squamous NSCLC on October 9, 2015 [28]. This phase to 6.0 months in the chemotherapy group (HR 0.50, 95% III trial enrolled 582 patients who had progressed during CI 0.37-0.68, p < 0.001). Grade ≥ 3 treatment-related AEs or after platinum-based doublet chemotherapy to receive occurred in 26.6% of the pembrolizumab group and nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/ 53.3% of the chemotherapy group [25]. m every 3 weeks. The primary endpoint was OS, which On May 10, 2017, pembrolizumab received approval was 12.2 months with nivolumab and 9.4 months with to be given in combination with pemetrexed and carbo- docetaxel (Table 3). Treatment-related AEs occurred platin as first-line treatment of metastatic NSCLC, irre- more frequently with docetaxel (20%) than nivolumab spective of PD-L1 expression [26]. In the phase II (7%). Grade ≥ 3 nivolumab-related AEs include fatigue, KEYNOTE-021 open-label trial, 123 patients with stage nausea, asthenia, and diarrhea; grade ≥ 3 docetaxel- IIIB or IV NSCLC who did not demonstrate targetable related AEs included fatigue, anemia, and asthenia. EGFR mutations or ALK translocations received either pembrolizumab 200 mg plus pemetrexed 500 mg/m Atezolizumab and carboplatin area under the curve (AUC) 5 mg/mL/ On October 18, 2016, atezolizumab (PD-L1 inhibitor) min every 3 weeks for 4 cycles follow by pembrolizumab was approved for previously-treated metastatic NSCLC 200 mg for 24 months and indefinite pemetrexed main- following the results of the POPLAR and OAK trials [29, tenance therapy, or pemetrexed 500 mg/m and carbo- 30]. POPLAR is an ongoing phase II trial that random- platin AUC 5 mg/mL/min followed by indefinite ized 287 patients to receive atezolizumab 1200 mg or pemetrexed maintenance therapy alone. The primary docetaxel 75 mg/m with emphasis placed on PD-L1 endpoint ORR was 55% (33/60 patients) in the pembroli- expression of tumor cells and tumor-infiltrating immune zumab plus chemotherapy group compared to 29% (18/ cells [29]. The primary endpoint was OS and at a mini- 63 patients) in the chemotherapy alone group, equating mum follow-up of 13 months, atezolizumab had signifi- to an estimated treatment difference of 26% (95% CI 9- cantly improved OS compared with docetaxel 42%, p = 0.0016). The most common all-grade (12.6 months vs. 9.7 months, p = 0.04). Increasing OS treatment-related AEs in the pembrolizumab arm vs. improvement was seen in subgroups with greater tumor chemotherapy alone arm were fatigue (64% vs. 40%), cell and immune cell PD-L1 expression. However, unlike nausea (58% vs. 44%), and anemia (32% vs. 53%). OS, improved PFS and ORR was limited to only those patients with the highest levels of PD-L1 expression Nivolumab (tumor cell ≥50% or immune cell ≥10%). The most com- Nivolumab was approved as treatment for metastatic mon atezolizumab-related AEs were pneumonia and squamous NSCLC on March 4, 2015 based on the elevated AST levels. CheckMate 017 trial [27]. In this phase III study, Similarly, OAK is an ongoing phase III trial that ran- patients who progressed during or after 1 prior domized patients with previously-treated advanced platinum-containing chemotherapy regimen were ran- NSCLC to atezolizumab 1200 mg every 3 weeks or domized to receive nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m every 3 weeks [30]. Patients were Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 8 of 18 stratified by PD-L1 expression, number of previous population. In the phase II, open-label KEYNOTE-052 chemotherapy regimens, and histology (squamous vs. trial, patients with locally advanced or metastatic urothe- non-squamous). OS was improved regardless of PD-L1 lial carcinoma who were cisplatin-ineligible received expression (Table 3) though patients with the highest first-line pembrolizumab 200 mg every 3 weeks until PD-L1 expression experienced the greatest benefit from progressive disease, unacceptable toxicity, or 24 months atezolizumab with a median OS of 20.5 months com- of treatment. The primary endpoint was ORR per pared with 8.9 months in the docetaxel group. Grade ≥ 3 RECIST 1.1. Of 370 enrolled patients, the ORR was 27% AEs were observed in 64% of patients in the atezolizu- (95% CI 22-32) in those who had enrolled for ≥4 months. mab cohort and included fatigue and anemia. Docetaxel- Grade ≥ 3 AEs occurred in 52 patients (14%) with 19 related grade ≥ 3 AEs were seen in 86% and were most (5%) discontinuing therapy due to AEs [32]. frequently febrile neutropenia, neutropenia, anemia, and fatigue. Nivolumab The FDA approved nivolumab on February 2, 2017 Durvalumab for locally advanced or metastatic UC following the Although not FDA approved, it is worthwhile to men- results from CheckMate 275 [34]. This phase II study tion that the PD-L1 inhibitor durvalumab was recently enrolled 270 patients who had experienced progres- granted FDA breakthrough designation in the adjuvant sion or recurrence after ≥1 platinum-based chemo- treatment of locally advanced, unresectable NSCLC therapy regimen to receive nivolumab 3 mg/kg every based on the phase III PACIFIC trial [31]. The primary 2 weeks (Table 4). The primary endpoint was ORR in endpoint was PFS, and 713 patients who did not demon- all treated patients stratified by PD-L1 expression strate PD after ≥2 cycles of platinum-based chemother- (28.4% for ≥5%, 23.8% for ≥1%, and 16.1% for < 1%). apy concurrent with definitive RT were randomized to At median follow up of 7 months, OS was durvalumab (10 mg/kg) or placebo within 1-42 days 11.30 months in the PD-L1 ≥ 1% subgroup and after chemoradiotherapy every 2 weeks for up to 1 year. 5.95 months in the PD-L1 < 1% subgroup. Grade 3-4 Durvalumab demonstrated superior PFS (median PFS AEs related to nivolumab included diarrhea and 16.8 months, 95% CI 13.0-18.1) over placebo fatigue. (5.6 months, 95% CI 4.6-7.8) in this setting (HR 0.52, 95% CI 0.42-0.65, p < 0.001). Safety was similar between Atezolizumab both treatment arms with 29.9% of durvalumab patients On May 18, 2016, atezolizumab became the first PD-L1 and 26.1% of placebo patients experiencing grade 3-4 inhibitor approved for locally advanced and metastatic AEs. Improved outcomes were observed in the experi- UC based on results of IMVigor 210 [35]. This phase II mental arm irrespective of PD-L1 status or histology. trial enrolled 310 patients whose disease had progressed after receiving platinum-based chemotherapy to receive Urothelial cancer a fixed dose of atezolizumab 1200 mg every 3 weeks Pembrolizumab (Table 4). PD-L1 status was subdivided by the percent- On May 18, 2017, pembrolizumab received 2 FDA ap- age of PD-L1-positive immune cells in the tumor micro- provals: in patients with locally advanced or metastatic environment (TME): < 1%, ≥1% but < 5%, and ≥5%. The urothelial carcinoma (UC) who have disease progression primary endpoint was ORR. In all patients, ORR was after platinum-containing chemotherapy and in patients 15%, a significant improvement compared to the histor- who are cisplatin-ineligible [32, 33]. In the phase III, ical response rate of 10%. In addition, subgroup analysis international KEYNOTE-045 trial, 542 patients with ad- showed a PD-L1-related response: PD-L1 ≥ 5% showed a vanced UC showing ≥10% PD-L1 expression who had 27% ORR, PD-L1 ≥ 1% showed 18% ORR, and PD < 1% previously failed platinum-based chemotherapy were showed 8% response. Sixteen percent of patients experi- randomized to receive pembrolizumab 200 mg every enced grade 3-4 treatment-related AEs, the most com- 3 weeks or either paclitaxel, docetaxel, or vinflunine mon of which were fatigue, anemia, and hypertension. [33]. Median OS was significantly higher in the pembro- Notably a recent press release for the confirmatory lizumab group compared to chemotherapy though there IMVigor 211 trial reported a failure to meet the study’s was no significant difference in PFS (Table 4). Fewer primary endpoint (see Discussion). grade ≥ 3 AEs occurred with pembrolizumab compared Accelerated approval of atezolizumab in the first-line to the chemotherapy arm (15.0% vs. 49.4). Median OS treatment of cisplatin-ineligible patients with locally ad- was also significantly improved with pembrolizumab vanced and metastatic UC occurred based on a separate compared to chemotherapy (HR 0.57, 95% CI 0.37-0.88, cohort of the IMVigor 210 trial [36]. This phase II, p = 0.005) in those with PD-L1 expression ≥10% but single-arm trial administered atezolizumab 1200 mg there was no difference in PFS between arms in this every 3 weeks to 119 treatment-naïve metastatic UC Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 9 of 18 Table 4 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in urothelial carcinoma and renal cell carcinoma Study/Agent Tumor (n) Line of therapy Experimental Control arm Primary endpoint Ref. arm KEYNOTE-052 Urothelial carcinoma First-line cisplatin- Pembrolizumab ORR 24% (95% CI 20-29) 32 (phase II)/ (n = 370) ineligible 200 mg every pembrolizumab 3 weeks KEYNOTE-045 Urothelial carcinoma Refractory to platinum- Pembrolizumab Paclitaxel 175 mg/m OS 10.3 mos vs. 7.4 mos 33 (phase III)/ (n = 542) based chemotherapy 200 mg every OR docetaxel (HR 0.73, 95% CI 0.59-0.91, pembrolizumab 3 weeks 75 mg/m OR vinflunine p = 0.002) 320 mg/m PFS HR 0.98, 95% CI 0.81-1.19, p = 0.42 CheckMate 275 Advanced urothelial Previously treated Nivolumab ORR 28.4% (95% CI 18.9-39.5) 34 (phase II)/ carcinoma (n = 270) with platinum-based 3 mg/kg every for 81 patients with PD-L1 ≥ 5%, nivolumab chemotherapy 2 weeks 23.8% (95% CI 16.5-32.3) for 122 PD-L1 ≥ 1%, and 16.1% (95% CI 10.5-23.1) for 143 with PD-L1 < 1% IMVigor 210 (phase Urothelial carcinoma Previously treated with Atezolizumab ORR 27% (95% CI 19-37, 35 II)/atezolizumab (n = 315) platinum-based 1200 mg every p < 0.0001) for PD-L1 ≥ 5%, chemotherapy 3 weeks 18% (95% CI 13-24, p = 0.0004) for PD-L1 ≥ 1%, 15% (95% CI 11-20, p = 0.0058) for all patients compared to historical control IMVigor 210 (phase Urothelial carcinoma First-line cisplatin- Atezolizumab ORR 23% (95% CI 16-31) in 36 II)/atezolizumab (n = 119) ineligible 1200 mg every total population 3 weeks Study 1108 (phase Urothelial carcinoma Second-line Durvalumab ORR 17.8% (95% CI 12.7-24.0) 38 II)/durvalumab (n = 191) 10 mg/kg every in all patients, 27.6% (95% CI 2 weeks 19.0-37.5) for PD-L1 ≥ 25%, and 5.1% (95% CI 1.4-12.5) for PD-L1-negative JAVELIN Solid Urothelial carcinoma Second-line Avelumab ORR 17.4% (95% CI 11.9-24.1, 40 Tumor (phase I)/ (n = 249) 10 mg/kg every complete response in 6.2%) for avelumab 2 weeks 61 post-platinum patients ≥6 months of follow-up CheckMate 025 Advanced RCC Second-line Nivolumab Everolimus 10 mg daily OS 25.0 mos vs. 19.6 mos (HR 41 (phase III)/ (n = 821) 3 mg/kg every 0.73, 98.5% CI 0.57-0.93, nivolumab 2 weeks p = 0.002) FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, ORR overall response rate, CI confidence interval, OS overall survival, HR hazard ratio, PFS progression-free survival, RCC renal cell carcinoma with stratification based on PD-L1 expression as in the patients who had progressed on, been ineligible for, or earlier IMVigor 210 trial. The primary endpoint was in- refused prior therapies for advanced disease were en- dependently confirmed ORR per RECIST v1.1. In the rolled to receive the PD-L1 inhibitor durvalumab primary analysis, efficacy did not reach (PD-L1 ≥ 5% sub- 10 mg/kg of every 2 weeks. Patients were initially en- group) the pre-specified ORR of 10% after a median rolled regardless of PD-L1 expression, but enrollment follow-up of 8.5 months. After a 17.2 month median fol- was later restricted to patients with ≥5% PD-L1 expres- low up duration, the ORR increased to 28% in the PD- sion on tumor cells after preliminary data suggested PD- L1 ≥ 5% subgroup, 21% in the ≥1% PD-L1 but < 5% L1 was expressed more commonly on immune cells than group, and 21% in the PD-L1 < 1% group. Interestingly, tumor cells. The primary endpoint was safety and of 42 median OS was 15.9 months in all patients, 12.3 months treated patients, grade ≥ 3 AEs occurred in 3 patients. Of in PD-L1 ≥ 5% patients, and 19.1 months in PD-L1 < 5% note, the ORR was 31.0% in all 42 patients, 46.4% in the patients. The most common grade 3-4 treatment-related PD-L1-positive subgroup, and 0% in the PD-L1-negative AEs were fatigue and elevated AST and ALT. subgroup. In an update of Study 1108, results were presented re- Durvalumab garding the efficacy and tolerability of durvalumab Durvalumab received FDA approval on May 1, 2017 for 10 mg/kg every 2 weeks up to 12 months [38]. High PD- the treatment of platinum-refractory locally advanced or L1 expression was defined as ≥25% of tumor or immune metastatic UC based on results from Study 1108 [37]. In cells (Ventana SP263 assay). The primary endpoint was this phase I/II dose-escalation and expansion study, 61 ORR using RECIST 1.1 (Table 4). Of the 191 treated Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 10 of 18 patients, ORR was 17.8% (95% CI 12.7-24.0) in all pa- chemotherapy [42]. The KEYNOTE-012 open-label, tients, 27.6% (95% CI 19.0-37.5) for PD-L1 ≥ 25%, and multicenter, phase Ib trial studied the efficacy and safety 5.1% (95% CI 1.4-12.5) for PD-L1-negative. Grade 3-4 of pembrolizumab in patients with ≥1% of tumor cells AEs related to treatment were seen in only 6.8% of that were PD-L1-positive. Sixty patients received pem- patients. brolizumab 10 mg/kg every 2 weeks for 24 months and the primary endpoints were safety and ORR per RECIST Avelumab 1.1 (Table 5). The ORR was 18% (95% CI 8-32%) and 10 Avelumab (PD-L1 inhibitor) received accelerated ap- (16.7%) experienced grade ≥ 3 AEs with the most com- proval for locally advanced or metastatic UC following mon being transaminitis, hyponatremia, and rash. the JAVELIN Solid Tumor study [39]. In this phase Ib study, 44 patients with metastatic or locally advanced Nivolumab solid tumors after platinum-based therapy were given es- On November 10, 2016, nivolumab became the first im- calating doses of avelumab 10 mg/kg every 2 weeks. The munotherapy approved by the FDA for HNSCC based primary endpoint was safety and 1 dose-limiting toxicity on results from CheckMate 141 [43]. This phase III trial was reported at dose level 4 in a patient with metastatic randomized 361 patients with disease that recurred or thymoma who developed autoimmune disorder and in- progressed within 6 months of the last dose of creased blood creatine phosphokinase (CPK). Grade 3-4 platinum-containing chemotherapy to nivolumab 3 mg/ treatment-related AEs occurred in 3 patients (6.8%) and kg every 2 weeks or ICC (Table 5). The primary end- included asthenia, AST elevation, elevated CPK, and de- point was OS, which was 7.5 months with nivolumab creased appetite. and 5.1 months with ICC. Estimated 6-month PFS rates In the phase Ib update to the JAVELIN Solid were 19.7% (nivolumab) and 9.9% (ICC). Grade ≥ 3 Tumor study (Table 4), dose-expansion occurred up nivolumab-related AEs occurred in 13% and included fa- to 249 patients with metastatic UC refractory to tigue, anemia, asthenia, and stomatitis. Grade ≥ 3 platinum-based therapy or ineligible for cisplatin- chemotherapy-related AEs were seen in 35% and most therapy [40]. In 161 post-platinum patients with commonly were anemia and neutropenia. ≥6 months of follow-up, responses were seen across PD-L1 expression levels tested (≥5% and < 5% PD-L1 Hodgkin lymphoma tumor cell-staining (25.4% and 13.2%, respectively). Pembrolizumab Immune-related AEs occurred in 34 pts. (13.7%) with On March 15, 2017, pembrolizumab received approval an incidence of grade ≥3eventsin 2.4%. for a hematologic malignancy based on the findings from the KEYNOTE-087 trial (Table 5) [44]. Patients (n Renal cell carcinoma = 210) with relapsed or refractory classical Hodgkin Nivolumab Lymphoma (cHL from 3 cohorts: 1.) after autologous On November 23, 2015, nivolumab became the first PD-1 stem cell transplantation (ASCT) and subsequent bren- inhibitor approved for use in treatment-refractory clear- tuximab vedotin (BV), 2.) after salvage chemotherapy cell renal cell carcinoma (RCC) based on results from and BV with chemoresistant disease, and 3.) after ASCT CheckMate 025 [41]. In this phase III study, 821 patients but without BV after transplantation received pembroli- were randomized to receive nivolumab 3 mg/kg every zumab 200 mg every 3 weeks for a maximum of 2 weeks or oral everolimus 10 mg daily (Table 4). The pri- 24 weeks. The ORR was 73.9% for cohort 1, 64.2% for mary endpoint was OS, which was 25.0 months with nivo- cohort 2, and 70.0% for cohort 3. The most common lumab and 19.6 months with everolimus. Of note, patients grade ≥ 3 treatment-related AE was neutropenia (2.4%). with ≥1% PD-L1 expression demonstrated median OS of 21.8 months with nivolumab and 18.8 months with evero- Nivolumab limus. Similar results were seen in patients with ≥5% PD- On May 17, 2016, nivolumab received the first approval for L1 expression, though interpretation is limited by the aPD-1inhibitor in thetreatment ofahematologic malig- small sample size in this subgroup. The most frequent nancy based on the findings from CheckMate 039 and grade ≥ 3 AEs were fatigue with nivolumab and anemia CheckMate 205 (Table 5) [45, 46]. CheckMate 039 was a with everolimus (19% and 37%, respectively). phase I study consisting of dose-escalation and expansion cohorts of patients with relapsed or refractory hematologic Head and neck cancer cancers treated with nivolumab 1 mg/kg with escalation to Pembrolizumab 3 mg/kg, and patients in the expansion cohort received On August 5, 2016, pembrolizumab received accelerated nivolumab 3 mg/kg at week 1, week 4, and every 2 weeks approval for recurrent or metastatic HNSCC with dis- up to 2 years [45]. The primary endpoint was safety, and of ease progression on or after platinum-containing the 23 patients with cHL enrolled, grade ≥ 3 AEs were seen Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 11 of 18 Table 5 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid cancers Study/Agent Tumor (n) Line of therapy Experimental Control arm Primary endpoint Ref. arm KEYNOTE-012 HNSCC (n = 60) PD-L1 ≥ 1% and Pembrolizumab Safety 45% with serious AEs, 42 (phase Ib)/ refractory to 10 mg/kg every 17% with grade 3-4 AEs (most pembrolizumab platinum chemotherapy 2 weeks common transaminitis, hyponatremia, and rash) ORR 18% (95% CI 8-32%) CheckMate 141 HNSCC (n = 361) Previously treated with Nivolumab ICC: either weekly OS 7.5 mos vs. 5.1 mos (HR 43 (phase III)/ platinum-based 3 mg/kg every cetuximab 0.70, 97.73% CI 0.51-0.96, nivolumab chemotherapy 2 weeks 250 mg/m after a p = 0.01) loading dose of 400 mg/m , weekly methotrexate 40- 60 mg/m ,or weekly docetaxel 30-40 mg/m KEYNOTE-087 cHL (n = 210) Relapsed after ≥3 lines Pembrolizumab ORR 69.0% (95% CI 62.3- 44 (phase II)/ of therapy or refractory 200 mg every 75.2%) pembrolizumab cHL 3 weeks CR 22.4% (95% CI 16.9- 28.6%) CheckMate 039 cHL (n = 80) Previously treated with Nivolumab ORR 66.3% (95% CI 54.8-76.4) 45, (phase I), ASCT or brentuximab 3 mg/kg every 46 CheckMate 205 2 weeks (phase II)/nivolumab Five phase I and II MSI-H or dMMR Treatment-refractory to Pembrolizumab ORR 39.6% 47- trials (including unresectable or all standard therapies 200 mg every 53 KEYNOTE-164 and metastatic solid 3 weeks KEYNOTE-158)/ tumors (n = 149 pembrolizumab across five trials) KEYNOTE-059 (phase II)/ Advanced gastric PD-L1 ≥ 1% and Pembrolizumab ORR 11.2% (95% CI 7.6-15.7) 54 pembrolizumab or gastroesophageal progression on ≥2 200 mg every junction cancer lines of chemotherapy 3 weeks (n = 259) CheckMate 142 Metastatic colorectal Previously treated with Nivolumab ORR 31.1% (95% CI 20.8-42.9) 55 (phase II)/ cancer (n = 74) fluoropyrimidine, 3 mg/kg every nivolumab oxaliplatin, and irinotecan 2 weeks CheckMate 040 Advanced Refractory to one Nivolumab Safety 12/48 patients (25%) 56 (phase 1/2) hepatocellular previous line of therapy 3 mg/kg every grade 3-4 AEs with 3 (6%) carcinoma (n = 262) (including sorafenib), or 2 weeks having treatment-related intolerant of sorafenib serious AEs (pemphigoid, adrenal insufficiency, liver disorder) ORR 20% (95% CI 15-26%) JAVELIN Merkel 200 Merkel cell First-line and beyond Avelumab ORR 31.8% (95.9% 57 (phase II) carcinoma (n = 88) 10 mg/kg every CI 21.9-43.1) 2 weeks FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, HNSCC head and neck squamous cell carcinoma, AEs adverse events, ORR overall response rate, CI confidence interval, ICC investigator-choice chemotherapy, OS overall survival, HR hazard ratio, cHL classical Hodgkin lymphoma, CR complete response, ASCT autologous stem cell transplantation, MSI-H microsatellite instability-high, dMMR defective mismatch repair in 5 patients including myelodysplastic syndrome, pancrea- recent treatment prior to trial recruitment, 31 of 43 pa- titis, and pneumonitis. Results of this trial showed promis- tients achieved objective response after nivolumab treat- ing efficacy of nivolumab in cHL. ment. Grade ≥ 3 AEs were seen in 25%, the most frequent The CheckMate 205 trial was a phase II study enrolling of which were increased lipase and neutropenia. 80 patients with cHL who had relapsed after ASCT or BV to receive nivolumab 3 mg/kg every 2 weeks [46]. The pri- Microsatellite instability or mismatch repair mary endpoint was independently assessed ORR and was deficient cancers 66.3% (53/80 patients) with 52 of the 53 responders hav- Pembrolizumab ing > 50% tumor reduction. Notably, in a post-hoc analysis In the first tissue-agnostic indication for a therapeutic of patients who did not have response to BV as the most agent, pembrolizumab was approved on May 23, 2017 Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 12 of 18 (Table 5) for patients with treatment-refractory unresect- ORR was 20% (95% CI 15-26%) with no maximum- able or metastatic solid tumors that are microsatellite tolerated dose established in the dose-escalation phase. instability-high (MSI-H) or mismatch repair deficient Activity and tolerability did not appear to be affected by (dMMR) [47–53]. Two phase 2 studies have showed PD-L1 status or presence or absence of viral hepatitis ORR of 48% in 29 patients and 50% in 10 patients with (Table 5). Twelve of 48 patients (25%) experienced grade various dMMR cancers, while a pivotal phase 2 study 3-4 AEs with 3 patients (6%) having treatment-related identified an ORR of 40% in 10 dMMR colorectal cancer serious AEs (pemphigoid, adrenal insufficiency, liver (CRC) patients and an ORR of 71% in 7 dMMR non- disorder). CRC patients [48, 52, 53]. As part of the ongoing, global, multicenter phase II studies KEYNOTE-164 and Merkel cell carcinoma KEYNOTE-158, the ORR was 26.2% for 61 MSI-H CRC Avelumab patients and 42.9% for 21 MSI-H non-CRC patients Avelumab, a fully humanized monoclonal IgG1 antibody [47]. In 2 trials evaluating the role pembrolizumab in against PD-L1, was first approved on March 23, 2017 for dMMR tumors, ORR was 50% in 28 dMMR CRC treatment of metastatic Merkel cell carcinoma patients and 53% in 78 patients with various dMMR (untreated and chemotherapy-resistant). This approval tumors [50, 51]. Another single-institution phase II was granted based on the results of the JAVELIN trial, a study reported an ORR of 56% in 9 patients with dMMR single-arm phase II trial in which patients with stage 4 endometrial cancer [49]. Merkel cell carcinoma refractory to ≥1 previous line of chemotherapy received IV avelumab 10 mg/kg every Gastric cancer 2 weeks [57]. The primary endpoint was ORR (Table 5). Pembrolizumab Complete response was observed in 9% of patients and Recently on September 22, 2017, pembrolizumab partial response observed in 23%, at a median follow-up 200 mg every 3 weeks was approved for advanced gas- time of 10.4 months. Among the patients whose tumors troesophageal cancer that is PD-L1 ≥ 1% (IHC 22C3 were assessable for PD-L1 expression (with PD-L1 posi- antibody) and refractory ≥2 lines of chemotherapy based tivity defined as a threshold level of 1% positive cells of on the phase II KEYNOTE-059 trial [54]. Out of 259 any intensity), 34.5% (95% CI, 22.5-48.1) achieved object- patients, the ORR was 11.2% (95% CI 7.6-15.7) with a ive responses. Grade ≥ 3 toxicities were reported in 5% median duration of response of 8.1 months (Table 5). of patients including lymphopenia and isolated labora- Grade 3-5 treatment-related AEs occurred in 43 patients tory abnormalities. (16.6%) leading to discontinuation in 2 patients and death in 2 patients due to renal failure and pleural Discussion effusion. Since the FDA approvals of the first PD-1 inhibitors pembrolizumab and nivolumab in 2014, the clinical Colorectal cancer development of PD-1 and PD-L1 inhibitors as anticancer Nivolumab agents has picked up considerable momentum [13–15, On August 1, 2017, nivolumab was approved in dMMR/ 18]. There are currently 5 PD-1/PD-L1 inhibitors that MSI-H metastatic colorectal cancer (mCRC) refractory are FDA-approved in the treatment of a number of solid to fluoropyrimidine, oxaliplatin, and irinotecan [55]. This tumors (Tables 1, 2, 3, 4 and 5). Approved indications in approval was granted based on results from the Check- this class of immune checkpoint inhibitors have also Mate 142 trial, a phase II trial in which patients received expanded to include hematologic malignancies and spe- nivolumab 3 mg/kg every 2 weeks and were stratified by cific molecular phenotypes irrespective of solid tumor PD-L1 < 1% and PD-L1 ≥ 1%. The primary endpoint was histology (i.e., tissue-agnostic) [45–53, 55]. As the ORR per RECIST 1.1. Of the 74 patients enrolled, 23 number of PD-1/PD-L1 inhibitors undergoing develop- patients (31%) achieved ORR irrespective of PD-L1 ment is expected to rise in the foreseeable future, several levels (Table 5). Nivolumab-related grade ≥ 3 AEs important points of discussion need to be considered in occurred in 12% of patients, most commonly fatigue, order to optimize the anticancer potential of this class of diarrhea, and pruritus. agents. Hepatocellular carcinoma Predictive biomarkers Nivolumab Despite the promising anticancer activity offered by PD- Recently on September 22, 2017, nivolumab 3 mg/kg 1 and PD-L1 inhibitors, predicting tumor responses to every 2 weeks was approved in advanced hepatocellular PD-1/PD-L1 blockade remains a challenge given that carcinoma (HCC) refractory to sorafenib in the phase I/ not all patients derive benefit from this class of immuno- II CheckMate 040 trial [56]. Of 262 eligible patients, therapy. Perhaps the earliest and most widely recognized Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 13 of 18 predictive biomarker of response to PD-1/PD-L1 block- DNA repair machinery and have shown significantly ade is PD-L1 expression, for which there are 4 FDA- greater responses to PD-1 blockade compared to micro- approved assays of PD-L1 expression by IHC (Table 1) satellite stable (MSS) or mismatch repair-proficient tu- to help guide treatment decisions for nivolumab in mors [47–53, 55]. Tumors harboring POLE mutations advanced NSCLC or melanoma (Dako 28-8), pembroli- represent another phenotype with high tumor muta- zumab in advanced NSCLC (Dako 22C3), atezolizumab tional burden that may predict response to PD-1 block- in advanced urothelial carcinoma or NSCLC (Ventana ade [60, 61]. Other investigations have focused on the SP142), and durvalumab in advanced urothelial carcin- presence of an immune-active TME. Here, a TME asso- oma (Ventana SP263) [20, 24, 27, 28, 35, 37, 38]. A ciated with higher densities of CD8+ tumor-infiltrating recent meta-analysis involving 41 clinical trials and 6664 lymphocytes (TILs) with a Th1 phenotype and more patients with advanced solid tumors investigated the clonal T-cell receptor (TCR) repertoire, higher levels of predictive value of tumor and tumor-infiltrating immune interferon (IFN), IFN-γ-inducible genes, and IFN- cell PD-L1 expression by IHC assays such as Dako 28-8, stimulated chemokines such as CXCL9, CLCL10, and Dako 22C3, Ventana SP142, Ventana SP263, and Dako CXCL11, and high levels of immune checkpoints such clone 73-10 and demonstrated that PD-L1 expression as cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-L1/ was predictive of tumor response across all tumor types PD-L2, PD-1, and indoleamine 2,3-dioxygenase (IDO) (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.85- may predict benefit from anti-PD-1 and anti-PD-L1 2.75, p < 0.001) [58]. Of note, the largest effect reaching therapy [12, 60, 62]. In contrast to the immunologically significance was observed in NSCLC (OR 2.51, 95% CI “hot” TME, “cold” or non-T-cell-inflamed tumors have 1.99-3.17, p < 0.001). However, despite the promising been associated with activated Wnt/β-catenin pathway utility of PD-L1 expression as a biomarker for PD-1/PD- signaling and PTEN deficiency [60, 62]. Features that de- L1 blockade, there is growing concern regarding its true fine an immunologically hot or T-cell-inflamed tumor predictability for response given its highly variable, het- are becoming increasingly complex with evidence to erogeneous, and dynamic expression on tumor or support a role for CD4+ T-cells, T-regulatory cells, and tumor-infiltrating immune cells [12]. Furthermore, tech- myeloid-derived suppressor cells in contributing to a nical differences and variation in screening thresholds TME that is responsive to PD-1/PD-L1 blockade [60, for PD-L1 expression across assays represent additional 62]. limitations. This was shown in a recent multi- Lastly, genetic polymorphisms and composition of the institutional collaborative effort to provide information gut microbiome may also shape an individual’s potential on the analytic comparability of the 4 FDA-approved to respond to immune checkpoint inhibitors, and pro- IHC assays of PD-L1 expression (22C3, 28-8, SP142, and spective studies are underway to investigate these novel SP263) [59]. Out of 39 NSCLC tumors stained, 3/4 concepts [12, 60, 62]. Significant differences in baseline assays showed a comparable percentage of PD-L1- diversity and composition of the gut microbiome stained tumor cells while the SP142 assay showed fewer between responders and nonresponders to anti-PD-1 stained tumor cells overall. There was greater variability therapy in metastatic melanoma patients have been in immune cell staining than tumor cell staining across reported, with enrichment of the Ruminococcaceae fam- all 4 assays. Notably, in 14/38 cases (37%) a different ily of the Clostridiales order in responders whereas the PD-L1 classification would have been made depending Prevotellaceae family of the Bacteroidales order was on which IHC assay and scoring system was used. A lar- enriched in nonresponders [63]. Other studies in melan- ger Phase II effort is currently underway to validate oma mice models have identified that commensal gut these findings. Nevertheless, although PD-L1 expression bacteria such as Bifidobacterium putatively enhance is associated with a higher likelihood of response to PD- response to anti-PD-L1 therapy by modulating immune 1/PD-L1 blockade, it has yet to be proven as the defini- responses through T-cell regulatory pathways [64]. Con- tive biomarker for efficacy and its absence certainly does versely, antibiotics can affect 30% of gut microbiota, and not preclude response to PD-1/PD-L1 inhibitors. retrospective analyses in advanced solid tumor patients The search for the ideal biomarker of response to PD- treated with anti-PD-1/PD-L1 therapy showed that 1/PD-L1 blockade is undergoing active investigation. receipt of antibiotics prior to immunotherapy was a There is increasing evidence to support that high muta- negative predictor of survival on multivariate analysis tional load can predict benefit from immune checkpoint [65]. Future directions of investigation may seek to inhibitors across several tumor types due to the explore the utility of a comprehensive assessment that immunogenic nature of neoantigens generated from an takes into account features of the TME and other increased burden of nonsynonymous mutations [60]. For immune parameters to produce a composite score pre- example, MSI or dMMR tumors are predisposed to dictive of benefit to PD-1/PD-L1 blockade; one such accumulation of frameshift mutations due to defective tool, the Immunoscore, has already been demonstrated Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 14 of 18 as a strong prognostic indicator in CRC with potential Immune-related adverse events to guide immunotherapy strategies [66]. Paramount to the safe and effective administration of anti-PD-1 and anti-PD-L1 therapy is our greater recog- Mechanisms of resistance and hyperprogressors nition and understanding of their potential immune- Blockade of the PD-1/PD-L1 axis results in antitumor activ- related toxicities. A recent meta-analysis of 3450 patients ity due to its ability, in part, to inhibit interferon-induced receiving PD-1/PD-L1 inhibitors demonstrated higher adaptive immune resistance characterized by interferon- risk of all-grade rash, pruritus, hypothyroidism, hyper- induced JAK-STAT signaling that results in activation of thyroidism, colitis, aminotransferase elevations, and interferon regulatory factor 1 (IRF1) and expression of PD- pneumonitis but lower risk of all-grade AEs in general L1 and IDO that allow for cancer cell immune evasion [67]. and lower risk of all-grade fatigue, sensory neuropathy, Innate resistance to anti-PD-1 therapy has been character- diarrhea, hematologic toxicities, anorexia, nausea, and ized by upregulation of genes involved in the regulation of constipation, and treatment discontinuation when com- cell adhesion, extracellular matrix remodeling, mesenchy- pared to chemotherapy [72]. Nevertheless, immune- mal transition, angiogenesis, and wound healing [68]. related toxicities can often be nontrivial resulting in sig- Acquired resistance to checkpoint blockade has been char- nificant risks that outweigh potential benefits of PD-1/ acterized by loss of sensitivity to IFN-γ either through mu- PD-L1 inhibitors. For example, beginning July 2017, the tations or epigenetic silencing of mediators of the IFN-γ// FDA has placed clinical holds on several clinical trials JAK/STAT/IRF1 signaling pathway [67, 69]. In addition, investigating pembrolizumab-, nivolumab-, and onestudywas among thefirst to describetheexistenceof a durvalumab-containing regimens in various hematologic subset of patients (9%) experiencing hyperprogressive dis- malignancies based on findings and safety concerns ease defined as RECIST progression at first evaluation char- identified from the KEYNOTE-183 and KEYNOTE-185 acterized by a ≥ 2-fold increase in tumor growth rate in studies [73–75]. A detailed description of specific response to anti-PD-1/PD-L1 therapy [70]. This novel pat- immune-related AEs and their management is beyond tern of hyperprogression was associated with higher age the scope of this review and has been extensively and worse OS. In a separate study, tumors from 155 reviewed elsewhere; however, there is growing evidence patients with advanced cancers treated with PD-1/PD-L1 that reassuringly shows use of systemic immunosuppres- inhibitors were evaluated by next-generation sequencing to sants may not negatively impact outcomes derived from evaluate potential genomic markers associated with hyper- checkpoint blockade [76–80]. progressive disease defined as time-to-treatment failure (TTF < 2 months, > 50% increase in tumor burden Treatment duration, treatment beyond progression, and compared to pre-immunotherapy imaging, and > 2- response after prior PD-1/PD-L1 blockade fold increase in progression pace [71]. Hyperproges- The optimal duration of treatment with PD-1/PD-L1 sors to single-agent PD-1/PD-L1 blockade were found inhibitors remains undefined but is of increasing rele- to have MDM2 family amplifications or EGFR aberra- vance given the potential for delayed responses and the tions that significantly correlated to a TTF < 2 months uncommon but documented phenomenon of pseudo- on multivariate analysis. progression with immune checkpoint inhibitors [81]. Further understanding of mechanisms of resistance Many randomized clinical trials investigating anti-PD-1 and identification of hyperprogressors are certainly war- therapy across several tumor types have allowed for ranted in large, prospective cohorts to optimize efficacy treatment beyond first progression (TBP) provided that and minimize risk to PD-1/PD-L1 inhibitors. Moreover, patients continued to exhibit investigator-assessed clin- given the complexities of immunoregulatory pathways ical benefit, stable performance status, and tolerance to and host and tumor heterogeneity, combination strat- therapy without substantial adverse effects [81]. egies incorporating PD-1/PD-L1 blockade with vaccines, Available post hoc subgroup analyses of these trials have radiation therapy, stimulators of T-cell activity through demonstrated that 9-48% of patients received TBP ≥4or targeting of CD40/CD40L, OX40/OX40L, and 4-1BB 6 weeks with anti-PD-1 therapy, and of these, 13-33% of (CD137), co-targeting of other immune checkpoints patients experienced > 30% target lesion reduction after such as T-cell immunoglobulin mucin 3 (Tim-3), progression when compared to baseline imaging [81– lymphocyte activation gene 3 protein (LAG3), IDO, and 85]. Compared to non-TBP patients, TBP patients often T-cell immunoglobulin and ITIM domain (TIGIT), showed improved PFS and OS though often with higher adoptive T-cell therapy, epigenetic reprogramming incidence of treatment-related AEs consistent with pro- drugs, chemotherapy, and targeted agents such as vascu- longed exposure to anti-PD-1 therapy. It remains lar endothelial growth factor (VEGF)-directed therapy unclear, however, whether patients who experienced are increasingly being employed in clinical trials to additional benefit with TBP had contributing factors enhance sensitivity to immunotherapy [62]. such as better prognostic features and likely more Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 15 of 18 indolent disease to begin with and whether the small development of PD-1/PD-L1 inhibitors as a form of can- subset of the overall population of patients that benefit cer immunotherapy has seen unprecedented growth. from TBP is worth the increased toxicity, increased cost, There are currently 5 PD-1/PD-L1 inhibitors that are and risk of delaying alternative and more effective ther- approved for the treatment of a spectrum of cancers apies in choosing this approach [81]. Furthermore, many including hematologic malignancies. As the number of randomized clinical trials have employed conventional anti-PD-1 and anti-PD-L1 therapies is expected to rise RECIST criteria to assess the efficacy of PD-1 inhibitors in the foreseeable future, there are several key issues that [82–86]. The novel iRECIST criteria has recently been remain and require further investigation in order to proposed to allow more consistent interpretation of re- optimize the anticancer potential of this class of agents. sponse and progression to cancer immunotherapy [87]. Specifically, predictive biomarkers, mechanisms of For the question of response to PD-1/PD-L1 blockade resistance, immune-related toxicities, hyperprogressors, after prior treatment with PD-1/PD-L1 inhibitors, evi- treatment duration and TBP, and clinical trial design dence is limited but appears to support an unlikely re- represent areas in need of further consideration to sponse with subsequent treatment in this scenario; there optimize benefit and minimize risks from PD-1/PD-L1 are, however, numerous ongoing and pending prospect- blockade. ive clinical trials involving PD-1/PD-L1 blockade that Abbreviations allow prior treatment with PD-1/PD-L1 inhibitors that AEs: Adverse events; ALT: Alanine aminotransferase; ASCT: Autologous stem may provide more information on this topic [88]. Future cell transplantation; AST: Aspartate aminotransferase; AUC: Area under the studies of ideally prospective design are warranted to ad- curve; BV: Brentuximab vedotin; cHL: Classical Hodgkin lymphoma; CI: Confidence interval; CPK: Creatine phosphokinase; CRC: Colorectal dress remaining questions on optimal duration, TBP vs. carcinoma; CTLA-4: Cytotoxic T-lymphocyte antigen 4; dMMR: Mismatch switching to agents of a different class on progression, repair deficient; FDA: Food and drug administration; HCC: Hepatocellular and treatment to progression or best response followed carcinoma; HNSCC: Head and neck squamous cell carcinoma; HR: Hazard ratio; ICC: Investigator-choice chemotherapy; IDO: Indoleamine 2,3- by rechallenge with PD-1/PD-L1 inhibitors. dioxygenase; IFN: Interferon; IHC: Immunohistochemistry; IRF1: Interferon regulatory factor 1; IV: Intravenous; LAG3: Lymphocyte activation gene 3 Clinical trial design protein; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; NSCLC: Non-small cell lung cancer; ORR: Overall response rate; OS: Overall Lastly, several confirmatory phase III trials KEYNOTE- survival; PD-1: Programmed cell death 1; PD-L1: Programmed death-ligand 1; 040, IMVigor211, and CheckMate 026 have failed to meet PFS: Progression-free survival; RCC: Renal cell carcinoma; TBP: Treatment their primary endpoints of PFS or OS despite promising beyond first progression; TCR: T-cell receptor; TIGIT: T-cell immunoglobulin and ITIM domain (TIGIT); TILs: Tumor-infiltrating lymphocytes; TKI: Tyrosine results in prior studies that in some instances resulted in kinase inhibitor; TME: Tumor microenvironment; TPS: Tumor proportion earlier FDA approval [89–91]. Differences in patient selec- score; TTF: Time-to-treatment failure; UC: Urothelial carcinoma; VEGF: Vascular tion and baseline characteristics, variation among bio- endothelial growth factor marker assays and PD-L1 expression cut-off thresholds, Acknowledgments sampling for PD-L1 expression on metastatic lesions vs. The authors thank Clayton Holder for graphical design assistance. archival tissue biopsy, subsequent immunotherapy in the standard of care arms, and outperformance or over- Funding achievement of study assumptions by standard of care Not applicable therapies have been among the many, but not all, potential Availability of data and materials explanations for these recent results [89, 90, 92, 93]. There Not applicable is curiosity regarding the fate of FDA-labeled indications for specific PD-1/PD-L1 inhibitors that were earlier Authors’ contributions approved but dependent on confirmatory phase III trials. JG, AC, and SR – literature search and review, writing, graphical design, and editing; RS – conception and design and editing. All authors read and Nevertheless, these negative trials highlight the import- approved the final manuscript. ance of all aspects of clinical trial design in evaluating the efficacy of immune checkpoint inhibitors and provide Ethics approval and consent to participate invaluable learning for subsequent confirmatory trials. Not applicable Furthermore, others have proposed implementation of Consent for publication iRECIST criteria and incorporation of weighted-log rank Not applicable tests into future study designs as considerations to improve our interpretability of success or failure with PD- Competing interests 1/PD-L1 inhibitors [87, 94]. The authors declare that they have no competing interests. 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Publisher: Springer Journals
Copyright: Copyright © 2018 by The Author(s).
Subject: Medicine & Public Health; Oncology; Immunology
eISSN: 2051-1426
DOI: 10.1186/s40425-018-0316-z
Publisher site: See Article on Publisher Site

Abstract

Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy. Keywords: PD-1 inhibitor, PD-L1 inhibitor, Clinical trials, Biomarkers, Immune checkpoint, Hyperprogressors, Treatment beyond progression, Microbiome, Immune-related toxicity Background hypothesis was developed that PD-1/PD-L1 blockade The programmed cell death protein 1 receptor (PD-1) may be an effective cancer immunotherapy (Fig. 1). receptor was first described in the early 1990s given its Initial phase I studies investigating several human- expression during induction of apoptosis in a T-cell ized monoclonal IgG4 antibodies targeting PD-1 and hybridoma [1, 2]. Since its initial discovery several PD-L1 in advanced solid tumors were soon conducted groups have identified that engagement of PD-1 through and paved way for the development of the first PD-1 its ligand, programmed death ligand 1 (PD-L1), inhibitors, nivolumab and pembrolizumab, approved negatively regulates T-cell-mediated immune responses by the Food and Drug Administration (FDA) [9–11]. [3–6]. Early preclinical evidence suggested that activa- Immune checkpoint inhibitors targeting the PD-1/PD- tion of PD-1/PD-L1 signaling could serve as a mechan- L1 axis are now approved in the treatment of several ism for tumors to evade an antigen-specific T-cell malignancies ranging from classical Hodgkin lymph- immunologic response [6–8]. Consequently, the oma to head and neck squamous cell carcinoma (HNSCC) [12]. Since the approval of pembrolizumab for the treat- * Correspondence: [email protected] ment of advanced melanoma in September 2014, the Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Building 51, Room 101, 1500 E Duarte St, clinical development of PD-1 and PD-L1 inhibitors as Duarte, CA 91010, USA anticancer agents has broadened (Table 1). Presently, the 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. Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 2 of 18 Fig. 1 Mechanism of action of PD-1 and PD-L1 inhibitors. The programmed cell death 1 (PD-1) receptor is expressed on activated T cells, B cells, macrophages, regulatory T cells (Tregs), and natural killer (NK) cells. Binding of PD-1 to its B7 family of ligands, programmed death ligand 1 (PD- L1 or B7-H1) or PD-L2 (B7-DC) results in suppression of proliferation and immune response of T cells. Activation of PD-1/PD-L1 signaling serves as a principal mechanism by which tumors evade antigen-specific T-cell immunologic responses. Antibody blockade of PD-1 or PD-L1 reverses this process and enhances antitumor immune activity. TCR, T-cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell FDA has approved PD-1/PD-L1 inhibitors for the treat- checkpoint inhibitor” and limited to published studies of ment of nine cancer types (Fig. 2). The purpose of this English language up to October 1, 2017. Studies were review is to highlight the clinical development of PD-1 further restricted to registration trials leading to FDA- and PD-L1 inhibitors in cancer therapy to date. In approved indications in cancer therapy. An additional particular, we focus on detailing the registration trials manual search was performed to include preliminary that have led to FDA-approved indications of anti-PD-1 results from abstracts of potential relevance. and anti-PD-L1 therapies in cancer and discuss future considerations important to optimizing their antitumor Melanoma efficacy. Pembrolizumab A literature search was conducted in MEDLINE using On September 4, 2014, pembrolizumab (humanized the following key words: “programmed death 1,” pro- monoclonal IgG4 antibody) became the first PD-1 inhibi- grammed death-ligand 1,”“PD-1,”“PD-L1,”“immune tor to receive approval for patients with advanced or Table 1 Overview of PD-1/PD-L1 inhibitors, mechanisms of action, trial designations and approved companion diagnostics Agent Mechanism of action Trial name(s) FDA-approved PD-L1 companion diagnostic Pembrolizumab PD-1 inhibitor KEYNOTE Primary antibody: 22C3 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: Merck Nivolumab PD-1 inhibitor CheckMate Primary antibody: 28-8 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: BMS Atezolizumab PD-L1 inhibitor IMVigor (UC), POPLAR (NSCLC), OAK (NSCLC) Primary antibody: SP142 (Ventana) IHC scoring: Tumor cell membrane, infiltrating immune cells Therapeutic developer: Genentech Durvalumab PD-L1 inhibitor Study 1108 Primary antibody: SP263 (Ventana) IHC scoring: Tumor cell membrane Therapeutic developer: AstraZeneca Avelumab PD-L1 inhibitor JAVELIN Primary antibody: 73-10 (Dako) IHC scoring: Tumor cell membrane Therapeutic developer: Merck, Pfizer PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, FDA Food and Drug Administration, IHC immunohistochemistry, BMS Bristol-Myers Squibb, UC urothelial carcinoma, NSCLC non-small cell lung cancer For research use only Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 3 of 18 Fig. 2 Timeline of FDA approvals for PD-1 and PD-L1 inhibitors in cancer therapy. The Food and Drug Administration approvals of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors detailed by agent, date of approval, and tumor type. NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability-high; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; UC, urothelial carcinoma; MCC, Merkel cell carcinoma unresectable melanoma based on the findings from the 34% in ipilimumab-treated and 45% in ipilimumab-naïve KEYNOTE-001 study [13, 14]. In this phase I multicenter, patients. Pembrolizumab was well tolerated as 14% of all international, open-label, randomized expansion of the patients experienced grade ≥3AEs. KEYNOTE-001 cohort, 173 patients with advanced or On December 18, 2015, pembrolizumab received an unresectable melanoma who had previously failed treat- expanded first-line indication to include previously- ment with ipilimumab and a BRAF inhibitor (if untreated advanced melanoma regardless of BRAF muta- V600 BRAF -mutated) were treated with pembrolizumab tion status following the results of the KEYNOTE-006 [14]. Patients were randomly assigned to treatment with trial [16]. In this international, randomized, open-label pembrolizumab intravenous (IV) at 2 mg/kg every 3 weeks phase 3 study, pembrolizumab 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks. The primary study endpoint or every 3 weeks vs. ipilimumab 3 mg/kg every 3 weeks was overall response rate (ORR) per RECIST 1.1. The was evaluated in patients with advanced, unresectable ORR was 26% in both the pembrolizumab 2 mg/kg and stage III or IV melanoma who had received ≤1 previous 10 mg/kg groups (Table 2). Grade 3-4 drug-related systemic therapy for advanced disease. Primary end- adverse events (AEs) occurred in 15% of the pembrolizu- points were PFS and OS and 6-month PFS for patients mab 2 mg/kg group (most common fatigue 6%) and 8% of who received pembrolizumab every 2 weeks and every the pembrolizumab 10 mg/kg group (1 each of diarrhea, 3 weeks was 47.3% and 46.4%, respectively, compared to rash, dyspnea, hypoxia, maculopapular rash, pancreatitis, 26.5% for those who received ipilimumab (hazard ratio and musculoskeletal pain) [14]. In an update of (HR) for disease progression 0.58 for both pembrolizu- KEYNOTE-001, findings after a median follow-up dur- mab regimens vs. ipilimumab, 95% confidence interval ation of 18 months for all patients were published [15]. (CI) 0.46-0.72 and 0.47-0.72, respectively, p < 0.001). Progression-free survival (PFS) at 6 months was 45%, One-year OS and ORR rates were significantly improved median overall survival (OS) was 25.9 months, and ORR in patients receiving either doses of pembrolizumab Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 4 of 18 Table 2 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in melanoma Study/Agent Tumor (n) Line of therapy Experimental arm Control arm Primary endpoint Ref KEYNOTE-001 Advanced Previously treated Pembrolizumab 2 mg/kg ORR 26% (both doses; 14 (phase I)/ melanoma with ipilimumab or 10 mg/kg every difference 0%, 95% pembrolizumab (n = 173) and/or BRAF inhibitor 3 weeks CI 14-13, p = 0.96) KEYNOTE-006 Advanced First-line (regardless Pembrolizumab 10 mg/kg Ipilimumab 3 mg/kg PFS (6-month) 47.3% vs. 46.4% 16 (phase III)/ melanoma of BRAF mutations every 2 weeks OR every every 3 weeks X4 vs. 26.5% (HR 0.58 for both pembrolizumab (n = 834) status) 3 weeks cycles pembrolizumab regimens vs. ipilimumab 95% CI 0.46-0.72 and 0.47-0.72, respectively, p < 0.001) OS (1-year) 74.1% vs. 68.4% vs. 58.2% (HR pembrolizumab every 2 weeks 0.63, 95% CI 0.47-0.83, p = 0.0005; HR pembrolizumab every 3 weeks 0.69, 95% CI 0.52-0.90, p = 0.0036) KEYNOTE-002 Advanced Refractory to Pembrolizumab 2 mg/kg ICC (paclitaxel+ PFS 2 mg/kg (HR 0.57 95% CI 17 (phase II)/ melanoma ipilimumab and/or every 3 weeks OR 10 carboplatin, paclitaxel, 0.45-0.73, p < 0.001) and pembrolizumab (n = 540) BRAF inhibitor mg/kg every 3 weeks carboplatin, dacarbazine, 10 mg/kg (HR 0.50, 95% CI or temozolomide) 0.39-0.64, p < 0.001) compared to ipilimumab No superiority in OS at this interim analysis ORR 31.7% (95% CI 23.5-40.8) 18 CheckMate 037 Stage IIIC or Second-line Nivolumab 3 mg/kg Dacarbazine 1000 mg/ (phase III)/ IV melanoma every 2 weeks m2 every 3 weeks vs. 10.6% (95% 3.5-23.1) nivolumab (n = 405) OR carboplatin AUC 6 + paclitaxel 175 mg/m every 3 weeks V600 CheckMate 069 BRAF -WT First-line Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every ORR 61% vs. 11% (p < 0.001) 19 phase III)/ unresectable or ipilimumab 3 mg/kg every 3 weeks nivolumab/ipilimumab metastatic 3 weeks X4 cycles then melanoma nivolumab alone every (n = 142) 2 weeks CheckMate 067 Unresectable or First-line Arm 1: Nivolumab Ipilimumab 3 mg/kg every PFS 6.9 mos (HR compared to 20 phase III)/ metastatic 3 mg/kg every 2 weeks 3 weeks ipilimumab 0.57, 99.5% CI nivolumab/ipilimumab melanoma Arm 2: nivolumab 0.43-0.76, p < 0.001 vs. 11.5 mo (n = 945) 1 mg/kg and ipilimumab (HR 0.42, 99.5% CI 0.31-0.57, 3 mg/kg every 3 weeks p < 0.001 compared to for 4 doses followed ipilimumab) vs. 2.9 mos by nivolumab 3 mg/kg of every 2 weeks Order of results refers to the experimental arm and control arm, respectively. In trials with more than one experimental arm, the endpoints are in the same order as documented in the experimental arm column FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, ORR overall response rate, CI confidence interval, PFS progression-free survival, HR hazard ratio, OS overall survival, ICC investigator-choice chemotherapy, AUC area under curve, WT wild-type compared to ipilimumab as well (Table 2). The most carboplatin, paclitaxel, carboplatin, dacarbazine, or temo- common grade 3-5 AEs of special interest were colitis zolomide). There was no statistically significant difference (1.4%, pembrolizumab every 2 weeks), colitis (2.5%) and in OS between both pembrolizumab arms and hepatitis (1.8%, pembrolizumab every 3 weeks), and col- chemotherapy at interim analysis. Doses of pembrolizu- itis (7.0%, ipilimumab) [16]. mab 2 mg/kg (HR 0.57, 95% CI 0.45-0.73, p <0.001) and Furthermore, the FDA approved a labeling update for 10 mg/kg (HR 0.50, 95% CI 0.39-0.64, p < 0.001) showed pembrolizumab in ipilimumab-refractory melanoma based superior median PFS when compared to chemotherapy. on findings from KEYNOTE-002 [17]. This study com- Response rates were 21% in the pembrolizumab 2 mg/kg pared pembrolizumab and investigator-choice chemother- group and 25% in the 10 mg/kg group compared to 4% in apy (ICC) for the treatment of unresectable stage III or the chemotherapy arm (p < 0.0001). Incidence of grade 3- stage IV ipilimumab and/or BRAF inhibitor-refractory 4 treatment-related AEs was higher in those given melanoma. Patients (n = 540) were randomized to receive chemotherapy (26%) than in those given pembrolizumab pembrolizumab 2 mg/kg every 3 weeks, pembrolizumab 2 mg/kg group (11%) and pembrolizumab 2 mg/kg group 10 mg/kg every 3 weeks, or ICC (paclitaxel plus (14%) [17]. Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 5 of 18 Nivolumab were randomized to receive nivolumab 3 mg/kg every 2 On December 22, 2014, nivolumab was first approved as weeks, nivolumab 1 mg/kg and ipilimumab 3 mg/kg second-line treatment of unresectable or metastatic mel- every 3 weeks for 4 doses followed by nivolumab 3 mg/ anoma based on the CheckMate 037 trial [18]. This ran- kg every 2 weeks, or ipilimumab 3 mg/kg. Median PFS domized controlled, open-label, international phase III was 6.9 months in the nivolumab group, 11.5 months in study randomized 272 patients with unresectable stage the combination group, and 2.9 months in the ipilimu- IIIC or IV melanoma progressing after anti-CTLA-4 mab group (Table 2). Longer OS was shown with nivolu- treatment or after anti-CTLA-4 treatment and a BRAF mab and combination therapy compared with V600 inhibitor for BRAF -mutated tumors to IV nivolumab ipilimumab alone across all subgroups (PD-L1 status, V600 3 mg/kg every 2 weeks and 133 to ICC (Table 2). Posi- BRAF status, and metastasis stage). The incidence of tive PD-L1 expression was defined as ≥5% of tumor cells grade ≥ 3 AEs was greater in the combination group exhibiting PD-L1 staining (IHC 28-8 antibody) of any in- (55%) than in nivolumab or ipilimumab alone (16.3% tensity in a section containing ≥100 evaluable cells. The and 27.3%, respectively). The most common grade ≥ 3 ORR was 31.7% in the nivolumab group and 10.6% in AEs in the combination group were diarrhea, colitis, and the chemotherapy group (Table 2). In patients with PD- increased ALT and aspartate aminotransferase (AST) L1 positivity, ORR was 43.6% compared to 9.1% of the whereas the most frequent grade ≥ 3 AEs in the mono- chemotherapy group. Grade ≥ 3 nivolumab-related AEs therapy arms were fatigue and diarrhea. were seen in 9% of patients and included elevated lipase, elevated alanine aminotransferase (ALT), fatigue, and Non-small cell lung cancer anemia. Grade ≥ 3 AEs occurred in 32% of chemotherapy Pembrolizumab patients, the most common of which were neutropenia, On October 2, 2015, pembrolizumab was approved for anemia, and thrombocytopenia. treatment of previously-treated advanced or metastatic The combination of nivolumab and ipilimumab was PD-L1-positive non-small cell lung cancer (NSCLC) V600 later approved as first-line treatment for BRAF -wild- [21]. As part of the KEYNOTE-001 phase I study, 550 type unresectable or metastatic melanoma on October 1, patients were treated with either pembrolizumab at a 2015 based on results from CheckMate 069 [19]. This dose of 2 mg/kg every 2 weeks or 10 mg/kg every 2 or randomized, double-blinded phase III trial, compared 3 weeks (Table 3). The primary endpoints were antitu- nivolumab 1 mg/kg in combination with ipilimumab mor activity per RECIST 1.1 and safety. Of the 61 pa- 3 mg/kg (every 3 weeks X4 cycles then nivolumab alone tients with tumors identified as strongly positive for PD- every 2 weeks) against ipilimumab 3 mg/kg monother- L1 (PD-L1 ≥ 50% based on the companion diagnostic apy (every 3 weeks) as first-line treatment in 142 pa- PD-L1 immunohistochemistry (IHC) 22C3 assay), the tients with advanced melanoma. Objective response ORR for those receiving pembrolizumab 2 mg/kg was V600 occurred in 61% of patients with BRAF -wild-type tu- 28% (95% CI 12.1-49.4%) as compared to 40% (95% CI mors in the combination group compared with 11% of 22.4-61.2) and 41% (95% CI 24.7-59.3%) in patients re- patients in the monotherapy group. Of note, overall re- ceiving pembrolizumab 10 mg/kg every 2 weeks and sponse was independent of PD-L1 status in both the every 3 weeks, respectively. The most commonly occur- combination group (58% for PD-L1-positive (≥5%) tu- ring (> 20%) AEs included fatigue, decreased appetite, mors vs. 55% for PD-L1-negative tumors) and the mono- dyspnea, and cough. Immune-mediated AEs occurred in therapy group (18% for PD-L1- positive tumors and 4% 13% of patients and included pneumonitis, colitis, hypo- V600 for PD-L1 negative tumors). In patients with BRAF - physitis, and thyroid disorders [21]. mutated tumors, the ORR was 52% in the combination Updated long-term OS data for patients with group compared with 10% in the monotherapy group. previously-treated or treatment-naïve advanced or Grade ≥ 3 AEs occurred more frequently in the combin- metastatic NSCLC were subsequently presented for the ation group (54%) than in the monotherapy group phaseIbKEYNOTE-001 study[22].Ascomparedto (24%), the most common of which were colitis, diarrhea, earlier studies that stratified tumor proportion score and elevated ALT. Ipilimumab monotherapy-related (TPS) cutoff of 1-50% and ≥50% PD-L1 staining of grade ≥ 3 AEs were seen in 24% of patients, the most tumor cells, these investigators assessed a PD-L1 stain- common of which were diarrhea and colitis. ing cutoff of ≥1% on tumor cells. Patients received On January 23, 2016, nivolumab and ipilimumab com- either pembrolizumab 2 mg/kg every 3 weeks or bination therapy received an expanded approval for 10 mg/kg every 2 or 3 weeks. Using a PD-L1 TPS cutoff unresectable or metastatic melanoma irrespective of of ≥1%, median OS was 22.1 months (95% CI 17.1-27.2) V600 BRAF mutation status based on results of the for treatment-naive patients and 10.6 months (95% CI CheckMate 067 trial [20]. In this phase III trial, patients 8.6-13.3) for previously-treated patients, supporting the with untreated, unresectable or metastatic melanoma efficacy of pembrolizuamb in patients with a PD-L1 Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 6 of 18 Table 3 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in lung cancer Study/Agent Tumor (n) Line of therapy Experimental arm Control arm Primary endpoint Ref KEYNOTE-001 Advanced PD-L1 positive Pembrolizumab 2 mg/kg every ORR 28% (95% CI 21, (phase Ib)/ NSCLC (≥1%) 3 weeks OR 10 mg/kg every 12.1-49.4%) vs. 40% 22 pembrolizumab (n = 550) progressing after 2 or 3 weeks (95% CI 22.4-61.2) platinum-based vs. 41% (95% CI therapy 24.7-59.3%) for PD-L1 ≥ 50% OS 22.1 mo (treatment-naïve, 95% CI 17.1-27.2) vs. 10.6 mo (previously-treated, 95% CI 8.6-13.3) for PD-L1 ≥ 50% KEYNOTE-024 Metastatic First-line Pembrolizumab 200 mg every ICC (cisplatin/ PFS 10.3 mos vs. 6.0 25 (phase III)/ NSCLC with 3 weeks carboplatin + pemetrexed, mos (HR 0.50, 95% pembrolizumab ≥50% PD-L1 cisplatin/carboplatin + CI 0.37-0.68, expression gemcitabine, or p < 0.001) (n = 305) carboplatin + paclitaxel) KEYNOTE-021 Advanced First line (in Pembrolizumab 200 mg + Carboplatin + pemetrexed ORR 55% vs. 29% 26 (phase II)/ NSCLC combination with carboplatin AUC 5 mg/ml/min + X4 cycles followed by (estimated pembrolizumab (n = 123) platinum-doublet pemetrexed 500 mg/m every indefinite maintenance treatment difference chemotherapy) 3 weeks X4 cycles followed by pemetrexed of 26%, 95% CI pembrolizumab (24 months 9-42%, p = 0.0016) duration) and indefinite maintenance pemetrexed CheckMate 017 Metastatic Previously treated Nivolumab 3 mg/kg every Docetaxel 75 mg/m OS 9.2 mo vs. 6.0 27 (phase III)/ squamous with platinum-based 2 weeks every 2 weeks mos (HR 0.59, 95% nivolumab NSCLC chemo CI 0.44-0.79, (n = 272) p < 0.001) CheckMate 057 Metastatic Previously treated Nivolumab 3 mg/kg every Docetaxel 75 mg/m OS 12.2 mos vs. 9.4 28 (phase III)/ non-squamous with platinum-based 2 weeks every 3 weeks mos (HR 0.73, 96% nivolumab NSCLC (n = 582) chemo CI 0.59-0.89, p =0.002) POPLAR (phase II)/ NSCLC (POPLAR Second-line Atezolizumab 1200 mg every Docetaxel 75 mg/m POPLAR: OS 12.6 mos 29, OAK (phase III)/ n = 287, OAK 3 weeks vs. 9.7 mos (HR 0.7, 30 atezolizumab n = 1225) 95% CI 0.53-0.99, p =0.04) OAK: OS 13.8 mos vs. 9.6 mos (HR 0.73, 95% CI 0.62-0.87, p = 0.0003) FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, NSCLC non-small cell lung cancer, ORR overall response rate, CI confidence interval, OS overall survival, ICC investigator-choice chemotherapy, PFS progression-free survival, HR hazard ratio, AUC area under curve TPS ≥1% [22]. KEYNOTE-001 investigators attempted 36.6%. Toxicities of grade ≥ 3 were reported in 47/495 to define a tumor PD-L1 expression level associated patients (9.5%) and were most commonly dyspnea with an enhanced likelihood of benefit as well as valid- (3.8%), pneumonitis (1.8%), decreased appetite (1%), ate the safety and antitumor activity of pembrolizumab and asthenia (1%) [23]. in patients with advanced NSCLC and PD-L1 ≥ 50% Following KEYNOTE-001, KEYNOTE-010 was a phase expression [23]. Patients received pembrolizumab II/III clinical trial that randomized 1034 patients to pem- 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks brolizumab (2 or 10 mg/kg every 3 weeks) vs. docetaxel and were randomized to either a training group or (75 mg/m ) for PD-L1-positive NSCLC that progressed validation group. In the training group, the PD-L1 cut- after platinum-based chemotherapy or a tyrosine kinase off was selected by immune-related response criteria by inhibitor (TKI) for those with an EGFR-sensitizing muta- investigator review; in the validation group, tion or ALK gene rearrangement [24]. For patients with membranous PD-L1 expression ≥50% was selected as PD-L1 expression ≥1%, median OS for pembrolizumab the cutoff. The ORR was 45.2% in the patients with 2 mg/kg (HR 0.71, 95% CI 0.58-0.88, p = 0.0008) and PD-L1 ≥ 50%, including 43.9% in previously-treated 10 mg/kg (HR 0.61, 95% CI 0.49-0.75, p < 0.0001) and patients and 50.0% in untreated patients. These values median PFS for pembrolizumab 10 mg/kg (HR 0.79, 95% exceeded the response rate in the training group of CI 0.66-0.94, p = 0.004) were significantly improved Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 7 of 18 compared to docetaxel with a trend towards improved docetaxel 75 mg/m every 3 weeks (Table 3). The PFS with pembrolizumab 2 mg/kg. Pembrolizumab at primary endpoint was OS and a key secondary endpoint both doses was superior to docetaxel in OS and PFS in included efficacy based on tumor cell PD-L1 expression those with ≥50% PD-L1 expression. Grade ≥3treatment- levels of 1%, 5% or 10%. Median OS was 9.2 months in related AEs occurred in 13% of the pembrolizumab 2 mg/ the nivolumab group versus 6.0 months in the docetaxel kg group, 16% of the pembrolizumab 10 mg/kg group, group, and OS at 1 year was 42% in the nivolumab and 35% of the docetaxel group. Deaths attributed to group versus 24% in the docetaxel group. PD-L1 expres- treatment occurred in 3 patients in the pembrolizumab sion was not predictive across any of the efficacy end- 2 mg/kg group (2 of pneumonitis and 1 pneumonia), 3 pa- points. Fewer all-grade treatment-related AEs occurred tients in the pembrolizumab 10 mg/kg group (myocardial with nivolumab (58%) than with docetaxel (86%). The infarction, pneumonia, and pneumonitis), and 5 patients most frequently reported AEs were fatigue, decreased in the docetaxel group [24]. appetite, and asthenia with nivolumab compared to neu- On October 24, 2016, pembrolizumab received tropenia, fatigue, and alopecia in the docetaxel arm. approval as first-line treatment for metastatic NSCLC Grade ≥ 3 AEs were found in 7% of patients with nivolu- with ≥50% PD-L1 expression and without EGFR or ALK mab (including colitis and pneumonitis) compared 57% genomic tumor aberrations [25]. In the phase III with docetaxel (including hemotologic toxicity and KEYNOTE-024 trial, 305 patients were randomized to infections). receive either pembrolizumab 200 mg every 3 weeks or The CheckMate 057 trial ushered in the FDA- ICC (platinum-based) for 4-6 cycles. Median PFS was expanded approval of nivolumab in metastatic non- 10.3 months in the pembrolizumab group as compared squamous NSCLC on October 9, 2015 [28]. This phase to 6.0 months in the chemotherapy group (HR 0.50, 95% III trial enrolled 582 patients who had progressed during CI 0.37-0.68, p < 0.001). Grade ≥ 3 treatment-related AEs or after platinum-based doublet chemotherapy to receive occurred in 26.6% of the pembrolizumab group and nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/ 53.3% of the chemotherapy group [25]. m every 3 weeks. The primary endpoint was OS, which On May 10, 2017, pembrolizumab received approval was 12.2 months with nivolumab and 9.4 months with to be given in combination with pemetrexed and carbo- docetaxel (Table 3). Treatment-related AEs occurred platin as first-line treatment of metastatic NSCLC, irre- more frequently with docetaxel (20%) than nivolumab spective of PD-L1 expression [26]. In the phase II (7%). Grade ≥ 3 nivolumab-related AEs include fatigue, KEYNOTE-021 open-label trial, 123 patients with stage nausea, asthenia, and diarrhea; grade ≥ 3 docetaxel- IIIB or IV NSCLC who did not demonstrate targetable related AEs included fatigue, anemia, and asthenia. EGFR mutations or ALK translocations received either pembrolizumab 200 mg plus pemetrexed 500 mg/m Atezolizumab and carboplatin area under the curve (AUC) 5 mg/mL/ On October 18, 2016, atezolizumab (PD-L1 inhibitor) min every 3 weeks for 4 cycles follow by pembrolizumab was approved for previously-treated metastatic NSCLC 200 mg for 24 months and indefinite pemetrexed main- following the results of the POPLAR and OAK trials [29, tenance therapy, or pemetrexed 500 mg/m and carbo- 30]. POPLAR is an ongoing phase II trial that random- platin AUC 5 mg/mL/min followed by indefinite ized 287 patients to receive atezolizumab 1200 mg or pemetrexed maintenance therapy alone. The primary docetaxel 75 mg/m with emphasis placed on PD-L1 endpoint ORR was 55% (33/60 patients) in the pembroli- expression of tumor cells and tumor-infiltrating immune zumab plus chemotherapy group compared to 29% (18/ cells [29]. The primary endpoint was OS and at a mini- 63 patients) in the chemotherapy alone group, equating mum follow-up of 13 months, atezolizumab had signifi- to an estimated treatment difference of 26% (95% CI 9- cantly improved OS compared with docetaxel 42%, p = 0.0016). The most common all-grade (12.6 months vs. 9.7 months, p = 0.04). Increasing OS treatment-related AEs in the pembrolizumab arm vs. improvement was seen in subgroups with greater tumor chemotherapy alone arm were fatigue (64% vs. 40%), cell and immune cell PD-L1 expression. However, unlike nausea (58% vs. 44%), and anemia (32% vs. 53%). OS, improved PFS and ORR was limited to only those patients with the highest levels of PD-L1 expression Nivolumab (tumor cell ≥50% or immune cell ≥10%). The most com- Nivolumab was approved as treatment for metastatic mon atezolizumab-related AEs were pneumonia and squamous NSCLC on March 4, 2015 based on the elevated AST levels. CheckMate 017 trial [27]. In this phase III study, Similarly, OAK is an ongoing phase III trial that ran- patients who progressed during or after 1 prior domized patients with previously-treated advanced platinum-containing chemotherapy regimen were ran- NSCLC to atezolizumab 1200 mg every 3 weeks or domized to receive nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m every 3 weeks [30]. Patients were Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 8 of 18 stratified by PD-L1 expression, number of previous population. In the phase II, open-label KEYNOTE-052 chemotherapy regimens, and histology (squamous vs. trial, patients with locally advanced or metastatic urothe- non-squamous). OS was improved regardless of PD-L1 lial carcinoma who were cisplatin-ineligible received expression (Table 3) though patients with the highest first-line pembrolizumab 200 mg every 3 weeks until PD-L1 expression experienced the greatest benefit from progressive disease, unacceptable toxicity, or 24 months atezolizumab with a median OS of 20.5 months com- of treatment. The primary endpoint was ORR per pared with 8.9 months in the docetaxel group. Grade ≥ 3 RECIST 1.1. Of 370 enrolled patients, the ORR was 27% AEs were observed in 64% of patients in the atezolizu- (95% CI 22-32) in those who had enrolled for ≥4 months. mab cohort and included fatigue and anemia. Docetaxel- Grade ≥ 3 AEs occurred in 52 patients (14%) with 19 related grade ≥ 3 AEs were seen in 86% and were most (5%) discontinuing therapy due to AEs [32]. frequently febrile neutropenia, neutropenia, anemia, and fatigue. Nivolumab The FDA approved nivolumab on February 2, 2017 Durvalumab for locally advanced or metastatic UC following the Although not FDA approved, it is worthwhile to men- results from CheckMate 275 [34]. This phase II study tion that the PD-L1 inhibitor durvalumab was recently enrolled 270 patients who had experienced progres- granted FDA breakthrough designation in the adjuvant sion or recurrence after ≥1 platinum-based chemo- treatment of locally advanced, unresectable NSCLC therapy regimen to receive nivolumab 3 mg/kg every based on the phase III PACIFIC trial [31]. The primary 2 weeks (Table 4). The primary endpoint was ORR in endpoint was PFS, and 713 patients who did not demon- all treated patients stratified by PD-L1 expression strate PD after ≥2 cycles of platinum-based chemother- (28.4% for ≥5%, 23.8% for ≥1%, and 16.1% for < 1%). apy concurrent with definitive RT were randomized to At median follow up of 7 months, OS was durvalumab (10 mg/kg) or placebo within 1-42 days 11.30 months in the PD-L1 ≥ 1% subgroup and after chemoradiotherapy every 2 weeks for up to 1 year. 5.95 months in the PD-L1 < 1% subgroup. Grade 3-4 Durvalumab demonstrated superior PFS (median PFS AEs related to nivolumab included diarrhea and 16.8 months, 95% CI 13.0-18.1) over placebo fatigue. (5.6 months, 95% CI 4.6-7.8) in this setting (HR 0.52, 95% CI 0.42-0.65, p < 0.001). Safety was similar between Atezolizumab both treatment arms with 29.9% of durvalumab patients On May 18, 2016, atezolizumab became the first PD-L1 and 26.1% of placebo patients experiencing grade 3-4 inhibitor approved for locally advanced and metastatic AEs. Improved outcomes were observed in the experi- UC based on results of IMVigor 210 [35]. This phase II mental arm irrespective of PD-L1 status or histology. trial enrolled 310 patients whose disease had progressed after receiving platinum-based chemotherapy to receive Urothelial cancer a fixed dose of atezolizumab 1200 mg every 3 weeks Pembrolizumab (Table 4). PD-L1 status was subdivided by the percent- On May 18, 2017, pembrolizumab received 2 FDA ap- age of PD-L1-positive immune cells in the tumor micro- provals: in patients with locally advanced or metastatic environment (TME): < 1%, ≥1% but < 5%, and ≥5%. The urothelial carcinoma (UC) who have disease progression primary endpoint was ORR. In all patients, ORR was after platinum-containing chemotherapy and in patients 15%, a significant improvement compared to the histor- who are cisplatin-ineligible [32, 33]. In the phase III, ical response rate of 10%. In addition, subgroup analysis international KEYNOTE-045 trial, 542 patients with ad- showed a PD-L1-related response: PD-L1 ≥ 5% showed a vanced UC showing ≥10% PD-L1 expression who had 27% ORR, PD-L1 ≥ 1% showed 18% ORR, and PD < 1% previously failed platinum-based chemotherapy were showed 8% response. Sixteen percent of patients experi- randomized to receive pembrolizumab 200 mg every enced grade 3-4 treatment-related AEs, the most com- 3 weeks or either paclitaxel, docetaxel, or vinflunine mon of which were fatigue, anemia, and hypertension. [33]. Median OS was significantly higher in the pembro- Notably a recent press release for the confirmatory lizumab group compared to chemotherapy though there IMVigor 211 trial reported a failure to meet the study’s was no significant difference in PFS (Table 4). Fewer primary endpoint (see Discussion). grade ≥ 3 AEs occurred with pembrolizumab compared Accelerated approval of atezolizumab in the first-line to the chemotherapy arm (15.0% vs. 49.4). Median OS treatment of cisplatin-ineligible patients with locally ad- was also significantly improved with pembrolizumab vanced and metastatic UC occurred based on a separate compared to chemotherapy (HR 0.57, 95% CI 0.37-0.88, cohort of the IMVigor 210 trial [36]. This phase II, p = 0.005) in those with PD-L1 expression ≥10% but single-arm trial administered atezolizumab 1200 mg there was no difference in PFS between arms in this every 3 weeks to 119 treatment-naïve metastatic UC Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 9 of 18 Table 4 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in urothelial carcinoma and renal cell carcinoma Study/Agent Tumor (n) Line of therapy Experimental Control arm Primary endpoint Ref. arm KEYNOTE-052 Urothelial carcinoma First-line cisplatin- Pembrolizumab ORR 24% (95% CI 20-29) 32 (phase II)/ (n = 370) ineligible 200 mg every pembrolizumab 3 weeks KEYNOTE-045 Urothelial carcinoma Refractory to platinum- Pembrolizumab Paclitaxel 175 mg/m OS 10.3 mos vs. 7.4 mos 33 (phase III)/ (n = 542) based chemotherapy 200 mg every OR docetaxel (HR 0.73, 95% CI 0.59-0.91, pembrolizumab 3 weeks 75 mg/m OR vinflunine p = 0.002) 320 mg/m PFS HR 0.98, 95% CI 0.81-1.19, p = 0.42 CheckMate 275 Advanced urothelial Previously treated Nivolumab ORR 28.4% (95% CI 18.9-39.5) 34 (phase II)/ carcinoma (n = 270) with platinum-based 3 mg/kg every for 81 patients with PD-L1 ≥ 5%, nivolumab chemotherapy 2 weeks 23.8% (95% CI 16.5-32.3) for 122 PD-L1 ≥ 1%, and 16.1% (95% CI 10.5-23.1) for 143 with PD-L1 < 1% IMVigor 210 (phase Urothelial carcinoma Previously treated with Atezolizumab ORR 27% (95% CI 19-37, 35 II)/atezolizumab (n = 315) platinum-based 1200 mg every p < 0.0001) for PD-L1 ≥ 5%, chemotherapy 3 weeks 18% (95% CI 13-24, p = 0.0004) for PD-L1 ≥ 1%, 15% (95% CI 11-20, p = 0.0058) for all patients compared to historical control IMVigor 210 (phase Urothelial carcinoma First-line cisplatin- Atezolizumab ORR 23% (95% CI 16-31) in 36 II)/atezolizumab (n = 119) ineligible 1200 mg every total population 3 weeks Study 1108 (phase Urothelial carcinoma Second-line Durvalumab ORR 17.8% (95% CI 12.7-24.0) 38 II)/durvalumab (n = 191) 10 mg/kg every in all patients, 27.6% (95% CI 2 weeks 19.0-37.5) for PD-L1 ≥ 25%, and 5.1% (95% CI 1.4-12.5) for PD-L1-negative JAVELIN Solid Urothelial carcinoma Second-line Avelumab ORR 17.4% (95% CI 11.9-24.1, 40 Tumor (phase I)/ (n = 249) 10 mg/kg every complete response in 6.2%) for avelumab 2 weeks 61 post-platinum patients ≥6 months of follow-up CheckMate 025 Advanced RCC Second-line Nivolumab Everolimus 10 mg daily OS 25.0 mos vs. 19.6 mos (HR 41 (phase III)/ (n = 821) 3 mg/kg every 0.73, 98.5% CI 0.57-0.93, nivolumab 2 weeks p = 0.002) FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, ORR overall response rate, CI confidence interval, OS overall survival, HR hazard ratio, PFS progression-free survival, RCC renal cell carcinoma with stratification based on PD-L1 expression as in the patients who had progressed on, been ineligible for, or earlier IMVigor 210 trial. The primary endpoint was in- refused prior therapies for advanced disease were en- dependently confirmed ORR per RECIST v1.1. In the rolled to receive the PD-L1 inhibitor durvalumab primary analysis, efficacy did not reach (PD-L1 ≥ 5% sub- 10 mg/kg of every 2 weeks. Patients were initially en- group) the pre-specified ORR of 10% after a median rolled regardless of PD-L1 expression, but enrollment follow-up of 8.5 months. After a 17.2 month median fol- was later restricted to patients with ≥5% PD-L1 expres- low up duration, the ORR increased to 28% in the PD- sion on tumor cells after preliminary data suggested PD- L1 ≥ 5% subgroup, 21% in the ≥1% PD-L1 but < 5% L1 was expressed more commonly on immune cells than group, and 21% in the PD-L1 < 1% group. Interestingly, tumor cells. The primary endpoint was safety and of 42 median OS was 15.9 months in all patients, 12.3 months treated patients, grade ≥ 3 AEs occurred in 3 patients. Of in PD-L1 ≥ 5% patients, and 19.1 months in PD-L1 < 5% note, the ORR was 31.0% in all 42 patients, 46.4% in the patients. The most common grade 3-4 treatment-related PD-L1-positive subgroup, and 0% in the PD-L1-negative AEs were fatigue and elevated AST and ALT. subgroup. In an update of Study 1108, results were presented re- Durvalumab garding the efficacy and tolerability of durvalumab Durvalumab received FDA approval on May 1, 2017 for 10 mg/kg every 2 weeks up to 12 months [38]. High PD- the treatment of platinum-refractory locally advanced or L1 expression was defined as ≥25% of tumor or immune metastatic UC based on results from Study 1108 [37]. In cells (Ventana SP263 assay). The primary endpoint was this phase I/II dose-escalation and expansion study, 61 ORR using RECIST 1.1 (Table 4). Of the 191 treated Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 10 of 18 patients, ORR was 17.8% (95% CI 12.7-24.0) in all pa- chemotherapy [42]. The KEYNOTE-012 open-label, tients, 27.6% (95% CI 19.0-37.5) for PD-L1 ≥ 25%, and multicenter, phase Ib trial studied the efficacy and safety 5.1% (95% CI 1.4-12.5) for PD-L1-negative. Grade 3-4 of pembrolizumab in patients with ≥1% of tumor cells AEs related to treatment were seen in only 6.8% of that were PD-L1-positive. Sixty patients received pem- patients. brolizumab 10 mg/kg every 2 weeks for 24 months and the primary endpoints were safety and ORR per RECIST Avelumab 1.1 (Table 5). The ORR was 18% (95% CI 8-32%) and 10 Avelumab (PD-L1 inhibitor) received accelerated ap- (16.7%) experienced grade ≥ 3 AEs with the most com- proval for locally advanced or metastatic UC following mon being transaminitis, hyponatremia, and rash. the JAVELIN Solid Tumor study [39]. In this phase Ib study, 44 patients with metastatic or locally advanced Nivolumab solid tumors after platinum-based therapy were given es- On November 10, 2016, nivolumab became the first im- calating doses of avelumab 10 mg/kg every 2 weeks. The munotherapy approved by the FDA for HNSCC based primary endpoint was safety and 1 dose-limiting toxicity on results from CheckMate 141 [43]. This phase III trial was reported at dose level 4 in a patient with metastatic randomized 361 patients with disease that recurred or thymoma who developed autoimmune disorder and in- progressed within 6 months of the last dose of creased blood creatine phosphokinase (CPK). Grade 3-4 platinum-containing chemotherapy to nivolumab 3 mg/ treatment-related AEs occurred in 3 patients (6.8%) and kg every 2 weeks or ICC (Table 5). The primary end- included asthenia, AST elevation, elevated CPK, and de- point was OS, which was 7.5 months with nivolumab creased appetite. and 5.1 months with ICC. Estimated 6-month PFS rates In the phase Ib update to the JAVELIN Solid were 19.7% (nivolumab) and 9.9% (ICC). Grade ≥ 3 Tumor study (Table 4), dose-expansion occurred up nivolumab-related AEs occurred in 13% and included fa- to 249 patients with metastatic UC refractory to tigue, anemia, asthenia, and stomatitis. Grade ≥ 3 platinum-based therapy or ineligible for cisplatin- chemotherapy-related AEs were seen in 35% and most therapy [40]. In 161 post-platinum patients with commonly were anemia and neutropenia. ≥6 months of follow-up, responses were seen across PD-L1 expression levels tested (≥5% and < 5% PD-L1 Hodgkin lymphoma tumor cell-staining (25.4% and 13.2%, respectively). Pembrolizumab Immune-related AEs occurred in 34 pts. (13.7%) with On March 15, 2017, pembrolizumab received approval an incidence of grade ≥3eventsin 2.4%. for a hematologic malignancy based on the findings from the KEYNOTE-087 trial (Table 5) [44]. Patients (n Renal cell carcinoma = 210) with relapsed or refractory classical Hodgkin Nivolumab Lymphoma (cHL from 3 cohorts: 1.) after autologous On November 23, 2015, nivolumab became the first PD-1 stem cell transplantation (ASCT) and subsequent bren- inhibitor approved for use in treatment-refractory clear- tuximab vedotin (BV), 2.) after salvage chemotherapy cell renal cell carcinoma (RCC) based on results from and BV with chemoresistant disease, and 3.) after ASCT CheckMate 025 [41]. In this phase III study, 821 patients but without BV after transplantation received pembroli- were randomized to receive nivolumab 3 mg/kg every zumab 200 mg every 3 weeks for a maximum of 2 weeks or oral everolimus 10 mg daily (Table 4). The pri- 24 weeks. The ORR was 73.9% for cohort 1, 64.2% for mary endpoint was OS, which was 25.0 months with nivo- cohort 2, and 70.0% for cohort 3. The most common lumab and 19.6 months with everolimus. Of note, patients grade ≥ 3 treatment-related AE was neutropenia (2.4%). with ≥1% PD-L1 expression demonstrated median OS of 21.8 months with nivolumab and 18.8 months with evero- Nivolumab limus. Similar results were seen in patients with ≥5% PD- On May 17, 2016, nivolumab received the first approval for L1 expression, though interpretation is limited by the aPD-1inhibitor in thetreatment ofahematologic malig- small sample size in this subgroup. The most frequent nancy based on the findings from CheckMate 039 and grade ≥ 3 AEs were fatigue with nivolumab and anemia CheckMate 205 (Table 5) [45, 46]. CheckMate 039 was a with everolimus (19% and 37%, respectively). phase I study consisting of dose-escalation and expansion cohorts of patients with relapsed or refractory hematologic Head and neck cancer cancers treated with nivolumab 1 mg/kg with escalation to Pembrolizumab 3 mg/kg, and patients in the expansion cohort received On August 5, 2016, pembrolizumab received accelerated nivolumab 3 mg/kg at week 1, week 4, and every 2 weeks approval for recurrent or metastatic HNSCC with dis- up to 2 years [45]. The primary endpoint was safety, and of ease progression on or after platinum-containing the 23 patients with cHL enrolled, grade ≥ 3 AEs were seen Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 11 of 18 Table 5 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid cancers Study/Agent Tumor (n) Line of therapy Experimental Control arm Primary endpoint Ref. arm KEYNOTE-012 HNSCC (n = 60) PD-L1 ≥ 1% and Pembrolizumab Safety 45% with serious AEs, 42 (phase Ib)/ refractory to 10 mg/kg every 17% with grade 3-4 AEs (most pembrolizumab platinum chemotherapy 2 weeks common transaminitis, hyponatremia, and rash) ORR 18% (95% CI 8-32%) CheckMate 141 HNSCC (n = 361) Previously treated with Nivolumab ICC: either weekly OS 7.5 mos vs. 5.1 mos (HR 43 (phase III)/ platinum-based 3 mg/kg every cetuximab 0.70, 97.73% CI 0.51-0.96, nivolumab chemotherapy 2 weeks 250 mg/m after a p = 0.01) loading dose of 400 mg/m , weekly methotrexate 40- 60 mg/m ,or weekly docetaxel 30-40 mg/m KEYNOTE-087 cHL (n = 210) Relapsed after ≥3 lines Pembrolizumab ORR 69.0% (95% CI 62.3- 44 (phase II)/ of therapy or refractory 200 mg every 75.2%) pembrolizumab cHL 3 weeks CR 22.4% (95% CI 16.9- 28.6%) CheckMate 039 cHL (n = 80) Previously treated with Nivolumab ORR 66.3% (95% CI 54.8-76.4) 45, (phase I), ASCT or brentuximab 3 mg/kg every 46 CheckMate 205 2 weeks (phase II)/nivolumab Five phase I and II MSI-H or dMMR Treatment-refractory to Pembrolizumab ORR 39.6% 47- trials (including unresectable or all standard therapies 200 mg every 53 KEYNOTE-164 and metastatic solid 3 weeks KEYNOTE-158)/ tumors (n = 149 pembrolizumab across five trials) KEYNOTE-059 (phase II)/ Advanced gastric PD-L1 ≥ 1% and Pembrolizumab ORR 11.2% (95% CI 7.6-15.7) 54 pembrolizumab or gastroesophageal progression on ≥2 200 mg every junction cancer lines of chemotherapy 3 weeks (n = 259) CheckMate 142 Metastatic colorectal Previously treated with Nivolumab ORR 31.1% (95% CI 20.8-42.9) 55 (phase II)/ cancer (n = 74) fluoropyrimidine, 3 mg/kg every nivolumab oxaliplatin, and irinotecan 2 weeks CheckMate 040 Advanced Refractory to one Nivolumab Safety 12/48 patients (25%) 56 (phase 1/2) hepatocellular previous line of therapy 3 mg/kg every grade 3-4 AEs with 3 (6%) carcinoma (n = 262) (including sorafenib), or 2 weeks having treatment-related intolerant of sorafenib serious AEs (pemphigoid, adrenal insufficiency, liver disorder) ORR 20% (95% CI 15-26%) JAVELIN Merkel 200 Merkel cell First-line and beyond Avelumab ORR 31.8% (95.9% 57 (phase II) carcinoma (n = 88) 10 mg/kg every CI 21.9-43.1) 2 weeks FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, HNSCC head and neck squamous cell carcinoma, AEs adverse events, ORR overall response rate, CI confidence interval, ICC investigator-choice chemotherapy, OS overall survival, HR hazard ratio, cHL classical Hodgkin lymphoma, CR complete response, ASCT autologous stem cell transplantation, MSI-H microsatellite instability-high, dMMR defective mismatch repair in 5 patients including myelodysplastic syndrome, pancrea- recent treatment prior to trial recruitment, 31 of 43 pa- titis, and pneumonitis. Results of this trial showed promis- tients achieved objective response after nivolumab treat- ing efficacy of nivolumab in cHL. ment. Grade ≥ 3 AEs were seen in 25%, the most frequent The CheckMate 205 trial was a phase II study enrolling of which were increased lipase and neutropenia. 80 patients with cHL who had relapsed after ASCT or BV to receive nivolumab 3 mg/kg every 2 weeks [46]. The pri- Microsatellite instability or mismatch repair mary endpoint was independently assessed ORR and was deficient cancers 66.3% (53/80 patients) with 52 of the 53 responders hav- Pembrolizumab ing > 50% tumor reduction. Notably, in a post-hoc analysis In the first tissue-agnostic indication for a therapeutic of patients who did not have response to BV as the most agent, pembrolizumab was approved on May 23, 2017 Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 12 of 18 (Table 5) for patients with treatment-refractory unresect- ORR was 20% (95% CI 15-26%) with no maximum- able or metastatic solid tumors that are microsatellite tolerated dose established in the dose-escalation phase. instability-high (MSI-H) or mismatch repair deficient Activity and tolerability did not appear to be affected by (dMMR) [47–53]. Two phase 2 studies have showed PD-L1 status or presence or absence of viral hepatitis ORR of 48% in 29 patients and 50% in 10 patients with (Table 5). Twelve of 48 patients (25%) experienced grade various dMMR cancers, while a pivotal phase 2 study 3-4 AEs with 3 patients (6%) having treatment-related identified an ORR of 40% in 10 dMMR colorectal cancer serious AEs (pemphigoid, adrenal insufficiency, liver (CRC) patients and an ORR of 71% in 7 dMMR non- disorder). CRC patients [48, 52, 53]. As part of the ongoing, global, multicenter phase II studies KEYNOTE-164 and Merkel cell carcinoma KEYNOTE-158, the ORR was 26.2% for 61 MSI-H CRC Avelumab patients and 42.9% for 21 MSI-H non-CRC patients Avelumab, a fully humanized monoclonal IgG1 antibody [47]. In 2 trials evaluating the role pembrolizumab in against PD-L1, was first approved on March 23, 2017 for dMMR tumors, ORR was 50% in 28 dMMR CRC treatment of metastatic Merkel cell carcinoma patients and 53% in 78 patients with various dMMR (untreated and chemotherapy-resistant). This approval tumors [50, 51]. Another single-institution phase II was granted based on the results of the JAVELIN trial, a study reported an ORR of 56% in 9 patients with dMMR single-arm phase II trial in which patients with stage 4 endometrial cancer [49]. Merkel cell carcinoma refractory to ≥1 previous line of chemotherapy received IV avelumab 10 mg/kg every Gastric cancer 2 weeks [57]. The primary endpoint was ORR (Table 5). Pembrolizumab Complete response was observed in 9% of patients and Recently on September 22, 2017, pembrolizumab partial response observed in 23%, at a median follow-up 200 mg every 3 weeks was approved for advanced gas- time of 10.4 months. Among the patients whose tumors troesophageal cancer that is PD-L1 ≥ 1% (IHC 22C3 were assessable for PD-L1 expression (with PD-L1 posi- antibody) and refractory ≥2 lines of chemotherapy based tivity defined as a threshold level of 1% positive cells of on the phase II KEYNOTE-059 trial [54]. Out of 259 any intensity), 34.5% (95% CI, 22.5-48.1) achieved object- patients, the ORR was 11.2% (95% CI 7.6-15.7) with a ive responses. Grade ≥ 3 toxicities were reported in 5% median duration of response of 8.1 months (Table 5). of patients including lymphopenia and isolated labora- Grade 3-5 treatment-related AEs occurred in 43 patients tory abnormalities. (16.6%) leading to discontinuation in 2 patients and death in 2 patients due to renal failure and pleural Discussion effusion. Since the FDA approvals of the first PD-1 inhibitors pembrolizumab and nivolumab in 2014, the clinical Colorectal cancer development of PD-1 and PD-L1 inhibitors as anticancer Nivolumab agents has picked up considerable momentum [13–15, On August 1, 2017, nivolumab was approved in dMMR/ 18]. There are currently 5 PD-1/PD-L1 inhibitors that MSI-H metastatic colorectal cancer (mCRC) refractory are FDA-approved in the treatment of a number of solid to fluoropyrimidine, oxaliplatin, and irinotecan [55]. This tumors (Tables 1, 2, 3, 4 and 5). Approved indications in approval was granted based on results from the Check- this class of immune checkpoint inhibitors have also Mate 142 trial, a phase II trial in which patients received expanded to include hematologic malignancies and spe- nivolumab 3 mg/kg every 2 weeks and were stratified by cific molecular phenotypes irrespective of solid tumor PD-L1 < 1% and PD-L1 ≥ 1%. The primary endpoint was histology (i.e., tissue-agnostic) [45–53, 55]. As the ORR per RECIST 1.1. Of the 74 patients enrolled, 23 number of PD-1/PD-L1 inhibitors undergoing develop- patients (31%) achieved ORR irrespective of PD-L1 ment is expected to rise in the foreseeable future, several levels (Table 5). Nivolumab-related grade ≥ 3 AEs important points of discussion need to be considered in occurred in 12% of patients, most commonly fatigue, order to optimize the anticancer potential of this class of diarrhea, and pruritus. agents. Hepatocellular carcinoma Predictive biomarkers Nivolumab Despite the promising anticancer activity offered by PD- Recently on September 22, 2017, nivolumab 3 mg/kg 1 and PD-L1 inhibitors, predicting tumor responses to every 2 weeks was approved in advanced hepatocellular PD-1/PD-L1 blockade remains a challenge given that carcinoma (HCC) refractory to sorafenib in the phase I/ not all patients derive benefit from this class of immuno- II CheckMate 040 trial [56]. Of 262 eligible patients, therapy. Perhaps the earliest and most widely recognized Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 13 of 18 predictive biomarker of response to PD-1/PD-L1 block- DNA repair machinery and have shown significantly ade is PD-L1 expression, for which there are 4 FDA- greater responses to PD-1 blockade compared to micro- approved assays of PD-L1 expression by IHC (Table 1) satellite stable (MSS) or mismatch repair-proficient tu- to help guide treatment decisions for nivolumab in mors [47–53, 55]. Tumors harboring POLE mutations advanced NSCLC or melanoma (Dako 28-8), pembroli- represent another phenotype with high tumor muta- zumab in advanced NSCLC (Dako 22C3), atezolizumab tional burden that may predict response to PD-1 block- in advanced urothelial carcinoma or NSCLC (Ventana ade [60, 61]. Other investigations have focused on the SP142), and durvalumab in advanced urothelial carcin- presence of an immune-active TME. Here, a TME asso- oma (Ventana SP263) [20, 24, 27, 28, 35, 37, 38]. A ciated with higher densities of CD8+ tumor-infiltrating recent meta-analysis involving 41 clinical trials and 6664 lymphocytes (TILs) with a Th1 phenotype and more patients with advanced solid tumors investigated the clonal T-cell receptor (TCR) repertoire, higher levels of predictive value of tumor and tumor-infiltrating immune interferon (IFN), IFN-γ-inducible genes, and IFN- cell PD-L1 expression by IHC assays such as Dako 28-8, stimulated chemokines such as CXCL9, CLCL10, and Dako 22C3, Ventana SP142, Ventana SP263, and Dako CXCL11, and high levels of immune checkpoints such clone 73-10 and demonstrated that PD-L1 expression as cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-L1/ was predictive of tumor response across all tumor types PD-L2, PD-1, and indoleamine 2,3-dioxygenase (IDO) (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.85- may predict benefit from anti-PD-1 and anti-PD-L1 2.75, p < 0.001) [58]. Of note, the largest effect reaching therapy [12, 60, 62]. In contrast to the immunologically significance was observed in NSCLC (OR 2.51, 95% CI “hot” TME, “cold” or non-T-cell-inflamed tumors have 1.99-3.17, p < 0.001). However, despite the promising been associated with activated Wnt/β-catenin pathway utility of PD-L1 expression as a biomarker for PD-1/PD- signaling and PTEN deficiency [60, 62]. Features that de- L1 blockade, there is growing concern regarding its true fine an immunologically hot or T-cell-inflamed tumor predictability for response given its highly variable, het- are becoming increasingly complex with evidence to erogeneous, and dynamic expression on tumor or support a role for CD4+ T-cells, T-regulatory cells, and tumor-infiltrating immune cells [12]. Furthermore, tech- myeloid-derived suppressor cells in contributing to a nical differences and variation in screening thresholds TME that is responsive to PD-1/PD-L1 blockade [60, for PD-L1 expression across assays represent additional 62]. limitations. This was shown in a recent multi- Lastly, genetic polymorphisms and composition of the institutional collaborative effort to provide information gut microbiome may also shape an individual’s potential on the analytic comparability of the 4 FDA-approved to respond to immune checkpoint inhibitors, and pro- IHC assays of PD-L1 expression (22C3, 28-8, SP142, and spective studies are underway to investigate these novel SP263) [59]. Out of 39 NSCLC tumors stained, 3/4 concepts [12, 60, 62]. Significant differences in baseline assays showed a comparable percentage of PD-L1- diversity and composition of the gut microbiome stained tumor cells while the SP142 assay showed fewer between responders and nonresponders to anti-PD-1 stained tumor cells overall. There was greater variability therapy in metastatic melanoma patients have been in immune cell staining than tumor cell staining across reported, with enrichment of the Ruminococcaceae fam- all 4 assays. Notably, in 14/38 cases (37%) a different ily of the Clostridiales order in responders whereas the PD-L1 classification would have been made depending Prevotellaceae family of the Bacteroidales order was on which IHC assay and scoring system was used. A lar- enriched in nonresponders [63]. Other studies in melan- ger Phase II effort is currently underway to validate oma mice models have identified that commensal gut these findings. Nevertheless, although PD-L1 expression bacteria such as Bifidobacterium putatively enhance is associated with a higher likelihood of response to PD- response to anti-PD-L1 therapy by modulating immune 1/PD-L1 blockade, it has yet to be proven as the defini- responses through T-cell regulatory pathways [64]. Con- tive biomarker for efficacy and its absence certainly does versely, antibiotics can affect 30% of gut microbiota, and not preclude response to PD-1/PD-L1 inhibitors. retrospective analyses in advanced solid tumor patients The search for the ideal biomarker of response to PD- treated with anti-PD-1/PD-L1 therapy showed that 1/PD-L1 blockade is undergoing active investigation. receipt of antibiotics prior to immunotherapy was a There is increasing evidence to support that high muta- negative predictor of survival on multivariate analysis tional load can predict benefit from immune checkpoint [65]. Future directions of investigation may seek to inhibitors across several tumor types due to the explore the utility of a comprehensive assessment that immunogenic nature of neoantigens generated from an takes into account features of the TME and other increased burden of nonsynonymous mutations [60]. For immune parameters to produce a composite score pre- example, MSI or dMMR tumors are predisposed to dictive of benefit to PD-1/PD-L1 blockade; one such accumulation of frameshift mutations due to defective tool, the Immunoscore, has already been demonstrated Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 14 of 18 as a strong prognostic indicator in CRC with potential Immune-related adverse events to guide immunotherapy strategies [66]. Paramount to the safe and effective administration of anti-PD-1 and anti-PD-L1 therapy is our greater recog- Mechanisms of resistance and hyperprogressors nition and understanding of their potential immune- Blockade of the PD-1/PD-L1 axis results in antitumor activ- related toxicities. A recent meta-analysis of 3450 patients ity due to its ability, in part, to inhibit interferon-induced receiving PD-1/PD-L1 inhibitors demonstrated higher adaptive immune resistance characterized by interferon- risk of all-grade rash, pruritus, hypothyroidism, hyper- induced JAK-STAT signaling that results in activation of thyroidism, colitis, aminotransferase elevations, and interferon regulatory factor 1 (IRF1) and expression of PD- pneumonitis but lower risk of all-grade AEs in general L1 and IDO that allow for cancer cell immune evasion [67]. and lower risk of all-grade fatigue, sensory neuropathy, Innate resistance to anti-PD-1 therapy has been character- diarrhea, hematologic toxicities, anorexia, nausea, and ized by upregulation of genes involved in the regulation of constipation, and treatment discontinuation when com- cell adhesion, extracellular matrix remodeling, mesenchy- pared to chemotherapy [72]. Nevertheless, immune- mal transition, angiogenesis, and wound healing [68]. related toxicities can often be nontrivial resulting in sig- Acquired resistance to checkpoint blockade has been char- nificant risks that outweigh potential benefits of PD-1/ acterized by loss of sensitivity to IFN-γ either through mu- PD-L1 inhibitors. For example, beginning July 2017, the tations or epigenetic silencing of mediators of the IFN-γ// FDA has placed clinical holds on several clinical trials JAK/STAT/IRF1 signaling pathway [67, 69]. In addition, investigating pembrolizumab-, nivolumab-, and onestudywas among thefirst to describetheexistenceof a durvalumab-containing regimens in various hematologic subset of patients (9%) experiencing hyperprogressive dis- malignancies based on findings and safety concerns ease defined as RECIST progression at first evaluation char- identified from the KEYNOTE-183 and KEYNOTE-185 acterized by a ≥ 2-fold increase in tumor growth rate in studies [73–75]. A detailed description of specific response to anti-PD-1/PD-L1 therapy [70]. This novel pat- immune-related AEs and their management is beyond tern of hyperprogression was associated with higher age the scope of this review and has been extensively and worse OS. In a separate study, tumors from 155 reviewed elsewhere; however, there is growing evidence patients with advanced cancers treated with PD-1/PD-L1 that reassuringly shows use of systemic immunosuppres- inhibitors were evaluated by next-generation sequencing to sants may not negatively impact outcomes derived from evaluate potential genomic markers associated with hyper- checkpoint blockade [76–80]. progressive disease defined as time-to-treatment failure (TTF < 2 months, > 50% increase in tumor burden Treatment duration, treatment beyond progression, and compared to pre-immunotherapy imaging, and > 2- response after prior PD-1/PD-L1 blockade fold increase in progression pace [71]. Hyperproges- The optimal duration of treatment with PD-1/PD-L1 sors to single-agent PD-1/PD-L1 blockade were found inhibitors remains undefined but is of increasing rele- to have MDM2 family amplifications or EGFR aberra- vance given the potential for delayed responses and the tions that significantly correlated to a TTF < 2 months uncommon but documented phenomenon of pseudo- on multivariate analysis. progression with immune checkpoint inhibitors [81]. Further understanding of mechanisms of resistance Many randomized clinical trials investigating anti-PD-1 and identification of hyperprogressors are certainly war- therapy across several tumor types have allowed for ranted in large, prospective cohorts to optimize efficacy treatment beyond first progression (TBP) provided that and minimize risk to PD-1/PD-L1 inhibitors. Moreover, patients continued to exhibit investigator-assessed clin- given the complexities of immunoregulatory pathways ical benefit, stable performance status, and tolerance to and host and tumor heterogeneity, combination strat- therapy without substantial adverse effects [81]. egies incorporating PD-1/PD-L1 blockade with vaccines, Available post hoc subgroup analyses of these trials have radiation therapy, stimulators of T-cell activity through demonstrated that 9-48% of patients received TBP ≥4or targeting of CD40/CD40L, OX40/OX40L, and 4-1BB 6 weeks with anti-PD-1 therapy, and of these, 13-33% of (CD137), co-targeting of other immune checkpoints patients experienced > 30% target lesion reduction after such as T-cell immunoglobulin mucin 3 (Tim-3), progression when compared to baseline imaging [81– lymphocyte activation gene 3 protein (LAG3), IDO, and 85]. Compared to non-TBP patients, TBP patients often T-cell immunoglobulin and ITIM domain (TIGIT), showed improved PFS and OS though often with higher adoptive T-cell therapy, epigenetic reprogramming incidence of treatment-related AEs consistent with pro- drugs, chemotherapy, and targeted agents such as vascu- longed exposure to anti-PD-1 therapy. It remains lar endothelial growth factor (VEGF)-directed therapy unclear, however, whether patients who experienced are increasingly being employed in clinical trials to additional benefit with TBP had contributing factors enhance sensitivity to immunotherapy [62]. such as better prognostic features and likely more Gong et al. Journal for ImmunoTherapy of Cancer (2018) 6:8 Page 15 of 18 indolent disease to begin with and whether the small development of PD-1/PD-L1 inhibitors as a form of can- subset of the overall population of patients that benefit cer immunotherapy has seen unprecedented growth. from TBP is worth the increased toxicity, increased cost, There are currently 5 PD-1/PD-L1 inhibitors that are and risk of delaying alternative and more effective ther- approved for the treatment of a spectrum of cancers apies in choosing this approach [81]. Furthermore, many including hematologic malignancies. As the number of randomized clinical trials have employed conventional anti-PD-1 and anti-PD-L1 therapies is expected to rise RECIST criteria to assess the efficacy of PD-1 inhibitors in the foreseeable future, there are several key issues that [82–86]. The novel iRECIST criteria has recently been remain and require further investigation in order to proposed to allow more consistent interpretation of re- optimize the anticancer potential of this class of agents. sponse and progression to cancer immunotherapy [87]. Specifically, predictive biomarkers, mechanisms of For the question of response to PD-1/PD-L1 blockade resistance, immune-related toxicities, hyperprogressors, after prior treatment with PD-1/PD-L1 inhibitors, evi- treatment duration and TBP, and clinical trial design dence is limited but appears to support an unlikely re- represent areas in need of further consideration to sponse with subsequent treatment in this scenario; there optimize benefit and minimize risks from PD-1/PD-L1 are, however, numerous ongoing and pending prospect- blockade. ive clinical trials involving PD-1/PD-L1 blockade that Abbreviations allow prior treatment with PD-1/PD-L1 inhibitors that AEs: Adverse events; ALT: Alanine aminotransferase; ASCT: Autologous stem may provide more information on this topic [88]. Future cell transplantation; AST: Aspartate aminotransferase; AUC: Area under the studies of ideally prospective design are warranted to ad- curve; BV: Brentuximab vedotin; cHL: Classical Hodgkin lymphoma; CI: Confidence interval; CPK: Creatine phosphokinase; CRC: Colorectal dress remaining questions on optimal duration, TBP vs. carcinoma; CTLA-4: Cytotoxic T-lymphocyte antigen 4; dMMR: Mismatch switching to agents of a different class on progression, repair deficient; FDA: Food and drug administration; HCC: Hepatocellular and treatment to progression or best response followed carcinoma; HNSCC: Head and neck squamous cell carcinoma; HR: Hazard ratio; ICC: Investigator-choice chemotherapy; IDO: Indoleamine 2,3- by rechallenge with PD-1/PD-L1 inhibitors. dioxygenase; IFN: Interferon; IHC: Immunohistochemistry; IRF1: Interferon regulatory factor 1; IV: Intravenous; LAG3: Lymphocyte activation gene 3 Clinical trial design protein; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; NSCLC: Non-small cell lung cancer; ORR: Overall response rate; OS: Overall Lastly, several confirmatory phase III trials KEYNOTE- survival; PD-1: Programmed cell death 1; PD-L1: Programmed death-ligand 1; 040, IMVigor211, and CheckMate 026 have failed to meet PFS: Progression-free survival; RCC: Renal cell carcinoma; TBP: Treatment their primary endpoints of PFS or OS despite promising beyond first progression; TCR: T-cell receptor; TIGIT: T-cell immunoglobulin and ITIM domain (TIGIT); TILs: Tumor-infiltrating lymphocytes; TKI: Tyrosine results in prior studies that in some instances resulted in kinase inhibitor; TME: Tumor microenvironment; TPS: Tumor proportion earlier FDA approval [89–91]. Differences in patient selec- score; TTF: Time-to-treatment failure; UC: Urothelial carcinoma; VEGF: Vascular tion and baseline characteristics, variation among bio- endothelial growth factor marker assays and PD-L1 expression cut-off thresholds, Acknowledgments sampling for PD-L1 expression on metastatic lesions vs. The authors thank Clayton Holder for graphical design assistance. archival tissue biopsy, subsequent immunotherapy in the standard of care arms, and outperformance or over- Funding achievement of study assumptions by standard of care Not applicable therapies have been among the many, but not all, potential Availability of data and materials explanations for these recent results [89, 90, 92, 93]. There Not applicable is curiosity regarding the fate of FDA-labeled indications for specific PD-1/PD-L1 inhibitors that were earlier Authors’ contributions approved but dependent on confirmatory phase III trials. JG, AC, and SR – literature search and review, writing, graphical design, and editing; RS – conception and design and editing. All authors read and Nevertheless, these negative trials highlight the import- approved the final manuscript. ance of all aspects of clinical trial design in evaluating the efficacy of immune checkpoint inhibitors and provide Ethics approval and consent to participate invaluable learning for subsequent confirmatory trials. Not applicable Furthermore, others have proposed implementation of Consent for publication iRECIST criteria and incorporation of weighted-log rank Not applicable tests into future study designs as considerations to improve our interpretability of success or failure with PD- Competing interests 1/PD-L1 inhibitors [87, 94]. The authors declare that they have no competing interests. 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Journal for ImmunoTherapy of Cancer – Springer Journals

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Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

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Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

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