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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/51301
Title: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study
Authors: Barbara Burtness
Kevin J. Harrington
Richard Greil
Denis Soulières
Makoto Tahara
Gilberto de Castro
Amanda Psyrri
Neus Basté
Prakash Neupane
Åse Bratland
Thorsten Fuereder
Brett G.M. Hughes
Ricard Mesía
Nuttapong Ngamphaiboon
Tamara Rordorf
Wan Zamaniah Wan Ishak
Ruey Long Hong
René González Mendoza
Ananya Roy
Yayan Zhang
Burak Gumuscu
Jonathan D. Cheng
Fan Jin
Danny Rischin
Guillermo Lerzo
Marcelo Tatangelo
Mirta Varela
Juan Jose Zarba
Michael Boyer
Hui Gan
Bo Gao
Brett Hughes
Girish Mallesara
Anne Taylor
Martin Burian
Carlos Henrique Barrios
Dalvaro Oliveira de Castro Junior
Gilberto Castro
Fabio Andre Franke
Gustavo Girotto
Iane Pinto Figueiredo Lima
Ulisses Ribaldo Nicolau
Gustavo Dix Junqueira Pinto
Lucas Santos
Ana Paula Victorino
Neil Chua
Felix Couture
Richard Gregg
Aaron Hansen
John Hilton
Joy McCarthy
Denis Soulieres
Rodrigo Ascui
Pablo Gonzalez
Luis Villanueva
Marco Torregroza
Angela Zambrano
Petra Holeckova
Zdenek Kral
Bohuslav Melichar
Jana Prausova
Milan Vosmik
Maria Andersen
Niels Gyldenkerne
Hannes Jurgens
Kadri Putnik
Petri Reinikainen
Viktor Gruenwald
Simon Laban
Gerasimos Aravantinos
Ioannis Boukovinas
Vassilis Georgoulias
Dora Kwong
Yousuf Al-Farhat
Tibor Csoszi
Jozsef Erfan
Geza Horvai
Laszlo Landherr
Eva Remenar
Agnes Ruzsa
Judit Szota
Salem Billan
Iris Gluck
Orit Gutfeld
Aron Popovtzer
Marco Benasso
Simona Bui
Vittorio Ferrari
Lisa Licitra
Franco Nole
Takashi Fujii
Yasushi Fujimoto
Nobuhiro Hanai
Hiroki Hara
Koji Matsumoto
Kenji Mitsugi
Nobuya Monden
Masahiro Nakayama
Kenji Okami
Nobuhiko Oridate
Oslo University Hospital
National Taiwan University Hospital
Peter Maccallum Cancer Centre
University of Malaya
Royal Brisbane and Women's Hospital
University of Melbourne
UniversitatsSpital Zurich
Yale School of Medicine
Royal Marsden NHS Foundation Trust
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Attikon University Hospital
Paracelsus Medizinische Privatuniversitat
Hospital Universitari Vall d'Hebron
Hospital Universitari de Bellvitge
Medizinische Universitat Wien
National Cancer Center Hospital East
Centre Hospitalier de L'Universite de Montreal
Merck & Co., Inc.
University of Kansas Medical Center
Cancer Cluster Salzburg
Instituto do Câncer do Estado de São Paulo
Unidad de Investigación en Salud de
Keywords: Medicine
Issue Date: 23-Nov-2019
Citation: The Lancet. Vol.394, No.10212 (2019), 1915-1928
Abstract: © 2019 Elsevier Ltd Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45–0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64–0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71–1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63–0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45–0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53–0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. Funding: Merck Sharp & Dohme.
URI: http://repository.li.mahidol.ac.th/dspace/handle/123456789/51301
metadata.dc.identifier.url: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85075142270&origin=inward
ISSN: 1474547X
01406736
Appears in Collections:Scopus 2019

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