Publication:
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

Issued Date

2019-11-23

Resource Type

Article

ISSN

1474547X
01406736

DOI

10.1016/S0140-6736(19)32591-7

Other identifier(s)

2-s2.0-85075142270

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

The Lancet. Vol.394, No.10212 (2019), 1915-1928

Suggested Citation

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 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. The Lancet. Vol.394, No.10212 (2019), 1915-1928. doi:10.1016/S0140-6736(19)32591-7 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/51301

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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

Author(s)

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

Other Contributor(s)

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

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.

Keyword(s)

Medicine

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https://repository.li.mahidol.ac.th/handle/20.500.14594/51301

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Scopus 2019