Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
Administration, Intravenous
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
/ administration & dosage
Antineoplastic Agents
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Axitinib
/ administration & dosage
Carcinoma, Renal Cell
/ drug therapy
Female
Humans
Intention to Treat Analysis
Kidney Neoplasms
/ drug therapy
Male
Middle Aged
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Progression-Free Survival
Single-Blind Method
Sunitinib
/ adverse effects
Survival Rate
Journal
The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562
Informations de publication
Date de publication:
21 03 2019
21 03 2019
Historique:
pubmed:
20
2
2019
medline:
28
3
2019
entrez:
20
2
2019
Statut:
ppublish
Résumé
The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group. Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
Sections du résumé
BACKGROUND
The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.
METHODS
In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
RESULTS
After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.
CONCLUSIONS
Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
Identifiants
pubmed: 30779529
doi: 10.1056/NEJMoa1816714
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Axitinib
C9LVQ0YUXG
pembrolizumab
DPT0O3T46P
Sunitinib
V99T50803M
Banques de données
ClinicalTrials.gov
['NCT02853331']
Types de publication
Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1116-1127Investigateurs
Diogo Bastos
(D)
Sergio Jobim de Azevedo
(SJ)
Gisele Marinho
(G)
Andre Marcio Murad
(AM)
Fabio Schutz
(F)
Luis Eduardo Zucca
(LE)
Ricardo Zylberberg
(R)
Sebastien Hotte
(S)
Frederic Pouliot
(F)
Denis Soulières
(D)
Lori Wood
(L)
Jindrich Finek
(J)
Petra Holeckova
(P)
Jana Katolicka
(J)
Eva Kindlova
(E)
Bohuslav Melichar
(B)
Jana Prausova
(J)
Sophie Abadie-Lacourtoisie
(S)
Mostefa Bennamoun
(M)
Christine Chevreau
(C)
Jean Deville
(J)
Claude El Kouri
(C)
Delphine Borchiellini
(D)
Jean-Marc Ferrero
(JM)
Lionnel Geoffrois
(L)
Marine Gross-Goupil
(M)
Valerie Le Brun Ly
(V)
Marc Laplante
(M)
Claude Linassier
(C)
Stephane Oudard
(S)
Sophie Tartas
(S)
Delphine Topart
(D)
Jean-Marc Tourani
(JM)
Jens Bedke
(J)
Martin Boegemann
(M)
Anja Lorch
(A)
Axel Merseburger
(A)
Peter Reichardt
(P)
Margitta Retz
(M)
Manfred Wirth
(M)
Christian Wuelfing
(C)
Peter Arkosy
(P)
Zsolt Horvath
(Z)
Gyorgy Bodoky
(G)
Andras Csejtei
(A)
Tibor Csoszi
(T)
Lajos Geczi
(L)
Janos Revesz
(J)
Agnes Ruzsa
(A)
John McCaffrey
(J)
Raymond S McDermott
(RS)
Satoshi Anai
(S)
Masatoshi Eto
(M)
Takaaki Inoue
(T)
Haruaki Kato
(H)
Go Kimura
(G)
Hiroaki Kobayashi
(H)
Takahiro Kojima
(T)
Naoya Masumori
(N)
Akio Matsubara
(A)
Nobuaki Matsubara
(N)
Hiroaki Matsumoto
(H)
Ryuichi Mizuno
(R)
Noboru Nakaigawa
(N)
Kazuo Nishimura
(K)
Takahiro Osawa
(T)
Naoto Miyajima
(N)
Masafumi Oyama
(M)
Yoshiki Sugimura
(Y)
Masayuki Takahashi
(M)
Toshimi Takano
(T)
Satoshi Tamada
(S)
Yoshihiko Tomita
(Y)
Masao Tsujihata
(M)
Hiroyuki Tsunemori
(H)
Hirotsugu Uemura
(H)
Akito Yamaguchi
(A)
Przemyslaw Langiewicz
(P)
Cezary Szczylik
(C)
Piotr Tomczak
(P)
Pawel Wiechno
(P)
Joanna Wojcik-Tomaszewska
(J)
Joanna Pikiel
(J)
Marek Ziobro
(M)
Boris Alekseev
(B)
Rustem Gafanov
(R)
Petr Karlov
(P)
Vsevolod Matveev
(V)
Dmitry Nosov
(D)
Michail Shkolnik
(M)
Woo Kyun Bae
(WK)
Hyo Jin Lee
(HJ)
Daniel Castellano Gauna
(D)
Maria Juan Fita
(M)
Alejo Rodriguez-Vida
(A)
Cristina Suarez
(C)
Chao-Hsiang Chang
(CH)
Wen-Cheng Chang
(WC)
Cheng Keng Chuang
(CK)
Hsiao-Jen Chung
(HJ)
Yen-Hwa Chang
(YH)
Igor Bondarenko
(I)
Anna Kryzhanivska
(A)
Valerii Sakalo
(V)
Yaroslav Shparyk
(Y)
Viktor Stus
(V)
Ihor Vynnychenko
(I)
Robert Hawkins
(R)
James Larkin
(J)
Thomas Powles
(T)
Matthew Wheater
(M)
Asim Amin
(A)
Leonard Appleman
(L)
Jeanny Aragon-Ching
(J)
Alan Berg
(A)
Steven Dunder
(S)
Daniel Cho
(D)
Gurjyot Doshi
(G)
John Fruehauf
(J)
Chunkit Fung
(C)
Saby George
(S)
Robert Graham
(R)
Hans Hammers
(H)
James Brugarolas
(J)
Audrey Kam
(A)
Nicklas Pfanzelter
(N)
Stephan DiSean Kendall
(SD)
Maurice Markus
(M)
Allen Cohn
(A)
Marc Matrana
(M)
Suresh Nair
(S)
Raul Oyola
(R)
Elizabeth Plimack
(E)
Brian Rini
(B)
Christopher Ryan
(C)
Ian Schnadig
(I)
Bradley Somer
(B)
Jeffrey Sosman
(J)
Benedito Carneiro
(B)
Christoper Sumey
(C)
Srinath Sundararajan
(S)
Parminder Singh
(P)
Ronald Bukowski
(R)
Janice P Dutcher
(JP)
KyungMann Kim
(K)
Timothy M Kuzel
(TM)
Commentaires et corrections
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Informations de copyright
Copyright © 2019 Massachusetts Medical Society.