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Background: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC., Methods: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C., Results: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C., Conclusions: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination., Trial Registration: NCT03322566. Registered October 26, 2017., (© 2023. The Author(s).)

Background: This phase III OAK trial (NCT02008227) subgroup analysis (data cutoff, January 9, 2019) evaluated the predictive value of 2 PD-L1 IHC tests (VENTANA SP142 and Dako 22C3) for benefit from atezolizumab versus docetaxel by programmed death ligand 1 (PD-L1) status in patients with previously treated metastatic non-small cell lung cancer., Methods: PD-L1 expression was assessed prospectively with SP142 on tumor cells (TC) and tumor-infiltrating immune cells (IC) and retrospectively with 22C3 using a tumor proportion score (TPS) based on TC membrane staining. Efficacy was assessed in the 22C3 biomarker-evaluable population (22C3-BEP) (n = 577; 47.1% of SP142-intention-to-treat population) and non-22C3-BEP (n = 648) in PD-L1 subgroups (high, low, and negative) and according to selection by 1 or both assays., Results: In the 22C3-BEP, overall survival benefits with atezolizumab versus docetaxel were observed across PD-L1 subgroups; benefits were greatest in SP142-defined PD-L1-high (TC3 or IC3: hazard ratio [HR], 0.39 [95% confidence interval (CI), 0.25-0.63]) and 22C3-defined PD-L1-high (TPS ≥ 50%: HR, 0.56 [95% CI, 0.38-0.82]) and low (TPS, 1% to < 50%: HR, 0.55 [95% CI, 0.37-0.82]) groups. Progression-free survival improved with increasing PD-L1 expression for both assays. SP142 and 22C3 assays identified overlapping and unique patient populations in PD-L1-high, positive, and negative subgroups. Overall survival and progression-free survival benefits favored atezolizumab over docetaxel in double PD-L1-positive and negative groups; patients with both SP142- and 22C3-positive tumors derived the greatest benefit., Conclusions: Despite different scoring algorithms and differing sensitivity levels, the SP142 and 22C3 assays similarly predicted atezolizumab benefit at validated PD-L1 thresholds in patients with non-small cell lung cancer., Competing Interests: Disclosure Dr. Gadgeel reports personal fees from Genentech/Roche, AstraZeneca, Merck, Bristol Myers Squibb, Novartis, Daichii-Sanyko, Boehringer-Ingelheim, Xcovery, Jazz Pharmaceuticals, Pfizer, and Janssen, outside the submitted work. Dr. Hirsch reports scientific advisory board for Genentech/Roche, Merck, Bristol Myers Squibb, Novartis, AstraZeneca/Daiichi, Regeneron/Sanofi, and Amgen, outside the submitted work. Dr. Kerr reports personal fees from AbbVie, Amgen, AstraZeneca, Archer Diagnostics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Roche Diagnostics/Ventana, outside the submitted work. Dr. Barlesi reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. Dr. Park has nothing to disclose. Dr. Rittmeyer reports grants from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche, and Novartis, outside the submitted work. Dr. Zou reports employment from Genentech, outside the submitted work. Dr. Bhatia reports employment from Genentech, outside the submitted work. Dr. Koeppen reports employment from Genentech, outside the submitted work. Dr. Paul reports employment from Genentech, outside the submitted work. David Shames reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Yi reports employment and spousal employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. Matheny reports employment from Genentech, during the conduct of the study, and employment from Genentech, outside the submitted work. Dr. Ballinger reports employment from Genentech and stock ownership from Roche, outside the submitted work. Dr. McCleland reports employment from Genentech, outside the submitted work. Dr. Gandara reports personal fees and institutional grants from Genentech, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study., Methods: The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer. FP rates and associated baseline factors were analyzed. FP was defined as either a ≥50% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan)., Results: Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a ≥50% SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), ≥3 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a ≥50% SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92))., Conclusions: FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP., Trial Registration Number: NCT02008227., Competing Interests: Competing interests: Editorial support, funded by the sponsor, was provided by an independent medical writer under the guidance of the authors. DG reports research grants from Amgen, Merck, and Roche/Genentech; personal fees for consulting or advisory roles for Inivata, Lilly, Merck, Roche/Genentech, and Samsung Bioepis; and institutional grants with no personal income for CellMax, Guardant Health, IO Biotech, and Oncocyte. MR reports grants and non-financial support from F. Hoffmann-La Roche during the conduct of the study and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Lilly, Merck, Merck Sharpe and Dohme, Novartis, Pfizer, and Roche outside the submitted work. SP reports personal fees for speaking or attending advisory boards, and has participated in investigation in trials for Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, and Pfizer; and personal fees for speaking or attending advisory boards for AbbVie, Bayer, Biocartis, Bioinvent, Daiichi Sankyo, Debiopharm, Eli Lilly, Foundation Medicine, Janssen, Merrimack, Pharma Mar, Regeneron, Sanofi, Seattle Genetics, and Takeda. DM-S reports grants, personal fees, and non-financial support from Roche/Genentech related to the current work, and from AbbVie, AstraZeneca, Boehringer, Bristol-Myers Squibb, and Pfizer; personal fees and non-financial support from Merck Sharp and Dohme; and personal fees from Novartis and Takeda. JM reports grants, personal fees, and non-financial support from Roche/Genentech related to the current work, and from Bristol-Myers-Squibb; grants or personal fees for participation in advisory boards or speaking for Amgen, AstraZeneca, Lilly/ImClone, Merck Sharp and Dohme, Novartis, and Pierre Fabre; and personal fees and non-financial support for participation in advisory boards or speaking for Pfizer. SMG reports personal fees from Genentech/Roche related to the current work, and from AstraZeneca, Takeda, Boehringer-Ingelheim, Bristol-Myers Squibb, Novocure, Xcovery, and AbbVie. SM is an employee of and has ownership interest in F. Hoffmann-La Roche. AC is an employee of F. Hoffmann-La Roche. DM is an employee of Genentech, Inc. MB is an employee of Genentech, Inc. AR reports personal fees from Roche/Genentech related to this work, and from Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, AstraZeneca, Merck Sharpe and Dohme, Pfizer, AbbVie, and Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680)., Methods: Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis., Results: As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups., Conclusion: First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Introduction : The immune checkpoint inhibitor, pembrolizumab, has revolutionized the treatment of non-small cell lung cancer (NSCLC). It is currently approved and widely used in patients with advanced NSCLC whose tumors have no EGFR or ALK genomic aberrations that express PD-L1 as single-agent treatment and irrespective of PD-L1 expression in combination with platinum-based doublet chemotherapy in the first-line setting. Areas covered : The authors have reviewed articles discussing pembrolizumab and NSCLC in MEDLINE between July 2013 to August 2019 and focus on recent advances in combining pembrolizumab with chemotherapy, radiotherapy and other novel agents in various stages of NSCLC. Expert opinion : Although pembrolizumab has revolutionized the treatment of advanced NSCLC, only a subset of patients benefit from single-agent therapy. Numerous trials combining pembrolizumab with chemotherapy and radiation have shown benefit and a large spectrum of novel combination strategies are being explored for improved synergies. In addition to PD-L1 tumor proportion score, validation of other biomarkers would be beneficial in stratifying patients and improving the predictive value of combining immune check point inhibitors and chemotherapy.

Introduction: Platinum doublet chemotherapy has represented the standard of care in advanced non-small-cell lung cancer for decades. Targeting platelet-derived growth factor receptors (PDGFR) is a potential mechanism to improve the efficacy of first-line therapy. This randomized phase 1b/2 trial investigated the addition of the anti-PDGFRα monoclonal antibody MEDI-575 to first-line carboplatin/paclitaxel (CP) chemotherapy., Patients and Methods: The phase 1b component was a dose-escalation study combining MEDI-575 with carboplatin area under the plasma concentration versus time curve 6 and paclitaxel 200 mg/m 2 (CPM), with the end point of identifying a recommended phase 2 dose. The phase 2 component randomized patients to CPM or CP, with primary end point of progression-free survival. Secondary end points included overall survival, overall response rate, and adverse event rates., Results: Overall, 99 patients were enrolled and received either CPM (n = 53; 4 phase 1b, 49 phase 2) or CP (n = 46). Demographics were as follows: 63/36 male/female, 78/21 aged ≤ 70/> 70 years; 37/62 squamous/nonsquamous, 42/53 Eastern Cooperative Oncology Group performance status 0/1. The phase 2 portion of the trial did not meet its primary end point: progression-free survival was shorter with CPM (4.6 vs. 5.5 months) than CP. No significant difference was seen in overall response rate (31.7% vs. 22.5%) or median overall survival (10.0 vs. 11.8 months). More serious adverse events were observed in patients receiving CPM (47% vs. 40%); in particular, 9 patients in the CPM group had significant gastrointestinal or respiratory adverse events (including abscess, perforation, and pneumothorax)., Conclusion: The addition of MEDI-575 to CP chemotherapy as first-line treatment of advanced non-small-cell lung cancer did not improve efficacy and resulted in increased toxicity., (Copyright © 2018. Published by Elsevier Inc.)

Background: Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited., Patients and Methods: Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4., Results: One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005)., Discussion: The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007)., Conclusion: The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis., Methods: A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025)., Results: As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events., Conclusions: The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Background: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial., Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review., Results: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group., Conclusions: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).