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.

Autor: Boyer M; Chris O'Brien Lifehouse, University of Sydney, Missenden Road, PO BOX M33, Camperdown, NSW, 2050, Australia. Michael.Boyer@lh.org.au., Hui R; Crown Princess Mary Cancer Centre, Westmead Hospital, University of Sydney, Westmead, NSW, Australia., Urban D; Department of Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Ramat Gan, Israel., Clingan P; Southern Medical Day Care Centre, Wollongong, NSW, Australia., Su WC; Department of Oncology, National Cheng Kung University Hospital, Tainan, Taiwan., Devaux C; Centre Intégré de Santé Et de Services Sociaux de La Montérégie-Centre, Greenfield Park, QC, Canada., Gadgeel S; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA., Garassino M; Department of Medicine, University of Chicago, Chicago, IL, USA., Leopold L; Incyte Corporation, Wilmington, DE, USA., Daniel J; Incyte Corporation, Wilmington, DE, USA., Munteanu MC; Incyte Corporation, Wilmington, DE, USA., Samkari A; Merck & Co., Inc., Rahway, NJ, USA., Luo Y; Merck & Co., Inc., Rahway, NJ, USA., Abreu DR; Department of Medical Oncology, Complejo Hospitalario Universitario Insular-Materno Infantil. Universidad de Las Palmas de Gran Canaria, Gran Canaria, Spain.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2024 Jul 25; Vol. 23 (Suppl 1), pp. 1250. Date of Electronic Publication: 2024 Jul 25.
DOI: 10.1186/s12885-022-10427-4
Abstrakt: 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).)
Databáze: MEDLINE
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