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Clinical Trial
. 2024 Jul 25;23(Suppl 1):1252.
doi: 10.1186/s12885-023-10727-3.

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study

Andrea Necchi  1   2 , Michiel S Van der Heijden  3 , Dmytro Trukhin  4 , Avivit Peer  5 , Howard Gurney  6 , Boris Y Alekseev  7 , Francis X Parnis  8   9 , Raya Leibowitz  10   11 , Maria De Santis  12   13 , Petros Grivas  14 , Jason Clark  15 , Mihaela Munteanu  15 , Ritesh Kataria  16 , Calvin Jia  16 , Arjun V Balar #  17 , Ronald de Wit #  18
Affiliations
Clinical Trial

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study

Andrea Necchi et al. BMC Cancer. .

Abstract

Background: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.

Methods: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).

Results: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).

Conclusions: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.

Trial registration: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

Keywords: Epacadostat; IDO1; Immune checkpoint inhibition; Immunotherapy; PD-L1; PD1; Pembrolizumab; Randomized controlled study; Urinary tract neoplasms; Urothelial carcinoma.

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Conflict of interest statement

AN has received honoraria from Roche, Merck, AstraZeneca, Janssen, Bristol-Myers Squibb, and Foundation Medicine; served in a consulting or advisory role for Merck, Roche, Bayer, Astra Zeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, and Ferring; received research funding to the institution from Merck, AstraZeneca, and Ipsen; received support for travel/accommodations/expenses from Merck, AstraZeneca, and Ipsen, and declares spousal employment and stock ownership with Bayer. MSVdH has received funding to the institute from AstraZeneca, Bristol-Myers Squibb, Roche; served in an advisory role for AstraZeneca, Bristol-Myers Squibb, Roche, Seattle Genetics, MSD/Merck & Co., Inc., Janssen and Astellas, all paid to institute. DT reports no conflicts of interest to disclose. AP has served in an advisory role for AstraZeneca, Bristol-Myers Squibb, Roche, MSD/Merck & Co., Janssen, Pfizer, Teva, Astellas, Bayer, and Eisai. HG received honoraria from Pfizer; served in a consulting or advisory role for Pfizer, Ipsen, Bristol-Myers Squibb, AstraZeneca, Janssen-Cilag, Merck Sharp & Dohme, and Roche; and has received support for travel/accommodations from AstraZeneca. BYA received personal fees for consulting, advisory boards, lectures and personal grants and institutional grants for trials from Astrazeneca, Astellas, Bayer, BMS, Eisai, Ferring, Janssen, Ipsen, Merck, MSD, Pfizer, Roche, and Sanofi. FXP is an advisory board member for Bayer and Janssen. RL has served in a consulting/advisory role for Pfizer, Bristol-Myers Squibb, MSD, Roche, Isotopia, AstraZeneca, Bayer, Astellas, and Janssen. MDS reports consulting for Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, EISAI, ESSA, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck & Co., Inc., Novartis, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and SeaGen. PG reports consulting to 4D Pharma, Aadi Bioscience, Asieris Pharmaceuticals, Astellas Pharma, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Mirati Therapeutics, MSD, Pfizer, PureTech, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, QED Therapeutics, Merck KGaA, and UroGen Pharma; his institution has received research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm Group, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Mirati Therapeutics, MSD, Pfizer, QED Therapeutics, and Merck KGaA. JC and MM are salaried employees of and own stock in Incyte Corporation. RK and CJ are salaried employees of and own stock in Merck & Co., Inc. AVB reports consulting/advisory roles for Genentech, Incyte, Janssen, Merck & Co., Inc., Pfizer, AstraZeneca/Medimmune, Nektar, Seattle Genetics, and Immunomedics; contracted research for Genentech (institution), Merck & Co., Inc. (institution), AstraZeneca/Medimmune (institution), Nektar, Seattle Genetics (institution), and Immunomedics (institution); speaking engagements for Genentech, Merck & Co., Inc., and AstraZeneca/Medimmune; steering and/or scientific advisory committee membership for Merck & Co., Inc., and Nektar; and equity and scientific advisory board membership for EpiVax Oncology. RdW reports consulting/advisory roles for Merck, Sanofi, Astellas, Bayer, and Janssen; speaker fees from Merck and Sanofi; and research grants (institution) from Sanofi and Bayer.

Figures

Fig. 1
Fig. 1
Patient disposition. AE adverse event
Fig. 2
Fig. 2
Maximum percentage change from baseline in tumor size per investigator assessment (intent-to-treat analysis). a Epacadostat plus pembrolizumab. b Placebo plus pembrolizumab
Fig. 3
Fig. 3
Pharmacodynamic effect of epacadostat 100 mg twice daily dosing as shown by change from baseline in circulating kynurenine levels. The number of samples assessed was 43 in the placebo plus pembrolizumab group (36 for C2) and 34 in the epacadostat plus pembrolizumab group. Statistical analyses were conducted using paired t-tests within each treatment arm. The dotted line indicates the median kynurenine level in healthy subjects (1.5 μM) [25]. C cycle, D day, ns not significant
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