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Clinical Trial
. 2024 Jul 25;23(Suppl 1):1250.
doi: 10.1186/s12885-022-10427-4.

Pembrolizumab with platinum-based chemotherapy with or without epacadostat as first-line treatment for metastatic non-small cell lung cancer: a randomized, partially double-blind, placebo-controlled phase II study

Michael Boyer  1 , Rina Hui  2 , Damien Urban  3 , Philip Clingan  4 , Wu-Chou Su  5 , Celine Devaux  6 , Shirish Gadgeel  7 , Marina Garassino  8 , Lance Leopold  9 , Jeannie Daniel  9 , Mihaela C Munteanu  9 , Ayman Samkari  10 , Yiwen Luo  10 , Delvys Rodriguez Abreu  11
Affiliations
Clinical Trial

Pembrolizumab with platinum-based chemotherapy with or without epacadostat as first-line treatment for metastatic non-small cell lung cancer: a randomized, partially double-blind, placebo-controlled phase II study

Michael Boyer et al. BMC Cancer. .

Abstract

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.

Keywords: Combination immunotherapy; Epacadostat; Non-small cell lung cancer; Pembrolizumab.

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Conflict of interest statement

MB reports institutional research funding from Amgen, AstraZeneca, BeiGene, Ltd., Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Merck Sharpe & Dohme, and Pfizer; and advisory board participation for AstraZeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Roche. RH reports advisory board participation for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Seagen; and speaker honoraria from Merck Sharp & Dohme, Novartis and Roche. DU reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme (Israel), Roche, and Takeda; consultancy for Merck Sharp & Dohme (Israel), Roche, and Takeda; and other (travel) for AstraZeneca and Takeda. PC and W–CS have nothing to disclose. CD reports advisory committee participation for Bristol-Myers Squibb and Merck. SG reports personal fees from Blueprint, Roche/Genentech, AstraZeneca, Janssen, Bristol Myers-Squibb, Pfizer, Eli Lilly, Novartis, and Daichii; grants and personal fees from Merck; and a role on the IDMC of a phase III trial sponsored by AstraZeneca. MG reports honoraria from AstraZeneca/MedImmune, Bristol-Myers Squibb, GlaxoSmithKline, MSD Oncology, Roche, and Takeda; consulting or advisory roles with AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Daichii Sankyo, GlaxoSmithKline, Incyte, Inivata, Janssen, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Takeda, and Tiziana Life Sciences; Speakers’ Bureau participation with AstraZeneca, Bristol-Myers Squibb, Celgene, Incyte, Lilly, MSD Oncology, Otsuka, Roche, and Takeda; and research funding from Amgen (Inst), AstraZeneca (Inst), AstraZeneca/MedImmune (Inst), Blueprint Medicines (Inst), Bristol-Myers Squibb (Inst), Exelixis (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Ipsen (Inst), Janssen (Inst), Lilly (Inst), MedImmune (Inst), Merck (Inst), MSD (Inst), Novartis (Inst), Pfizer (Inst), Roche/Genentech (Inst), Sanofi (Inst), Spectrum Pharmaceuticals (Inst), and Takeda (Inst); and travel/accommodation/expenses from AstraZeneca, Pfizer, and Roche. LL, MCM, and JD are salaried employees of and own stock in Incyte Corporation. AS and YL are salaried employees of Merck & Co., Inc., Rahway, NJ, USA and own stock in the Company. DRA reports personal fees/honoraria for consultancy and lectures from Roche, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Pfizer, and Novartis; travel expenses from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis; and grant support for institutional studies from Bristol-Myers Squibb.

Figures

Fig. 1
Fig. 1
Patient disposition AE adverse event; PD progressive disease
Fig. 2
Fig. 2
Kaplan–Meier curves for a PFSa and b OS. aBased on BICR assessment per RECIST v1.1. One-sided p-value based on log-rank test stratified by PD-L1 TPS (< 50% vs ≥ 50%) and predominant tumor histology (squamous vs non-squamous), because of small sample size, the strata ‘PD-L1 TPS greater than or equal to 50 percent Non-squamous’ and ‘PD-L1 TPS greater than or equal to 50 percent. Squamous’ were combined into one stratum. BICR blinded independent central review; OS overall survival; PFS progression-free survival; RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1
Fig. 3
Fig. 3
Circulating kynurenine levels at baseline (C1D1) and after one cycle of treatment (C2D1). The number of samples assessed was 83 in the placebo plus pembrolizumab and chemotherapy group, 74 in the epacadostat plus pembrolizumab and chemotherapy group (73 for C1), and 48 in the pembrolizumab plus epacadostat group. C1D1 vs. C2D1 were compared within each treatment arm using paired t-tests. Vertical lines represent maximum and minimum values, horizontal lines represent the median values, bars represent the interquartile range (25th-75th) percentiles, and dots represent outlier values. The dotted line indicates the median kynurenine levels in healthy subjects (1.5 μM) [16]. C cycle; D day; ns not significant
See this image and copyright information in PMC

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