Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

BACKGROUND

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

METHODS

KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m

FINDINGS

Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.

INTERPRETATION

The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.

FUNDING

Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests TP reports honoraria and research funding from Merck Sharp and Dohme (a subsidiary of Merck, Kenilworth, NJ, USA), AstraZeneca, and Roche; honoraria from BMS, Seattle Genetics, Ipsen, Merck Sharp and Dohme, Novartis, and Pfizer; fees for a consultant or advisory role for AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck Sharp and Dohme, Novartis, Pfizer, and Seattle Genetics; and travel expenses and accommodations from AstraZeneca and Roche. TC reports research funding from Merck Sharp and Dohme. MO reports research funding from Merck Sharp and Dohme; personal honoraria from Roche, Sanofi Aventis, and Astellas; institutional honoraria from Janssen; fees for a consultant or advisory role for Janssen, Sanofi Aventis, and Astellas; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from BMS, Janssen, and AstraZeneca. NM reports research funding from Merck Sharp and Dohme, Astellas, Chugai, Eli Lilly, Janssen, Pfizer, and Taiho; and fees for a consultant or advisory role for Chugai, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. LG reports research funding from Merck Sharp and Dohme; fees for a consultant or advisory role for Janssen, Merck Sharp and Dohme, and Pfizer; and travel expenses and accommodations from Janssen, and Pfizer. SY-SC reports research funding from Merck Sharp and Dohme; and fees for a consultant or advisory role for AstraZeneca, BMS, and Merck Sharp and Dohme. YF reports research funding from Merck Sharp and Dohme, Tersera, Janssen, Astellas, and IMV; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, Sanofi Aventis, and Tersera; and fees for travel for Sanofi Aventis, and Tersera. SO reports research funding from Merck Sharp and Dohme, BMS, Sanofi Aventis, Pfizer, Novartis, Bayer, and Ipsen; personal honoraria from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen; institutional honoraria from Bayer and Pfizer; and travel expenses and accommodations from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen. CV reports research funding from Merck Sharp and Dohme, and Leo Pharma; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, GSK, Astellas, Ipsen, Roche, and BMS; and travel expenses and accommodations from Roche. RMB reports research funding from Merck Sharp and Dohme; honoraria from Sanofi Aventis, Roche, and Merck Sharp and Dohme; fees for a consultant or advisory role for Sanofi Aventis, Bayer, Janssen, AstraZeneca, Merck Sharp and Dohme, Roche, and Asofarma; and travel expenses and accommodations from Roche, Sanofi Aventis, Astellas, Janssen, Merck Sharp and Dohme, Bayer, Pharmacyclics, Clovis, and Eli Lilly. AF reports research funding from Merck Sharp and Dohme; honoraria from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics; and travel expenses and accommodations from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics. SG reports research funding from Merck Sharp and Dohme, and travel expenses and accommodations from Roche. YL reports research funding from Merck Sharp and Dohme, Sanofi Aventis, and Janssen; personal honoraria from Roche, Astellas, Janssen, Seattle Genetics, AstraZeneca, BMS, Merck Sharp and Dohme, Pfizer, Sanofi Aventis, and Ipsen; institutional honoraria from Janssen and Pfizer; and travel expenses and accommodations from Roche, Janssen, AstraZeneca, Merck Sharp and Dohme, and Sanofi Aventis. AR-V reports research funding from Merck Sharp and Dohme, Pfizer, and Takeda; honoraria from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis; fees for a consultant or advisory role for Astellas, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Ipsen, Clovis, and Roche; and travel expenses and accommodations from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis. RM reports research funding from Merck Sharp and Dohme; honoraria from MedLearning and Flatiron; and fees for a consultant or advisory role for Roche, Seattle Genetics, and Astellas. EYY reports research funding from Merck Sharp and Dohme, Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Pharmacyclics, Seattle Genetics, and Taiho; and fees for a consultant or advisory role for Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. KN, KI, and BHM are employees of Merck Sharp and Dohme and report stock ownership. AA reports research funding from Merck Sharp and Dohme, Clovis, BMS, AstraZeneca, Bayer, Progenics, Janssen, Genentech, Esanik, Ionis, Arcus Biosciences, and Prometheus; honoraria from Merck Sharp and Dohme, BMS, and AstraZeneca; fees for a consultant or advisory role for Merck Sharp and Dohme, BMS, AstraZeneca, Pfizer, and Merck Serono; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from Merck Sharp and Dohme, BMS, and AstraZeneca.