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

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 ZhangBurak 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, Kiyoto Shiga, Yasushi Shimizu, Masashi Sugasawa, Masanobu Takahashi, Shunji Takahashi, Kaoru Tanaka, Tsutomu Ueda, Hironori Yamaguchi, Tomoko Yamazaki, Ryuji Yasumatsu, Tomoya Yokota, Tomokazu Yoshizaki, Iveta Kudaba, Zinaida Stara, Soon Keat Cheah, Jose Aguilar Ponce, Rene Gonzalez Mendoza, Carlos Hernandez Hernandez, Francisco Medina Soto, Jan Buter, Ann Hoeben, S. Oosting, Karijn Suijkerbuijk, Aase Bratland, Marianne Brydoey, Renzo Alvarez, Luis Mas, Priscilla Caguioa, John Querol, Eugenio Emmanuel Regala, Maria Belen Tamayo, Ellie May Villegas, Andrzej Kawecki, Andrey Karpenko, Arkadiy Klochikhin, Alexey Smolin, Oleg Zarubenkov, Boon Cher Goh, Graham Cohen, Johanna du Toit, Christa Jordaan, Gregory Landers, Paul Ruff, Waldemar Szpak, Neonyana Tabane, Irene Brana, Lara Iglesias Docampo, Javier Lavernia, Ricard Mesia, Edvard Abel, Valentina Muratidu, Niels Nielsen, Valerie Cristina, Sacha Rothschild, Hung Ming Wang, Muh Hwa Yang, Su Peng Yeh, Chia Jui Yen, Nopadol Soparattanapaisarn, Virote Sriuranpong, Sercan Aksoy, Irfan Cicin, Meltem Ekenel, Hakan Harputluoglu, Ozgur Ozyilkan, Kevin Harrington, Sanjiv Agarwala, Haythem Ali, Robert Alter, Daniel Anderson, Justine Bruce, Nicholas Campbell, Miguel Conde, John Deeken, William Edenfield, Lawrence Feldman, Elizabeth Gaughan, Basem Goueli, Balazs Halmos, Upendra Hegde, Brian Hunis, Robert Jotte, Anand Karnad, Saad Khan, Noel Laudi, Douglas Laux, Danko Martincic, Steven McCune, Dean McGaughey, Krzysztof Misiukiewicz, Deborah Mulford, Eric Nadler, Johannes Nunnink, James Ohr, Meaghan O'Malley, Brian Patson, Doru Paul, Elizabeta Popa, Steven Powell, Rebecca Redman, Vincent Rella, Chaio Rocha Lima, Abirami Sivapiragasam, Yungpo Su, Ammar Sukari, Stuart Wong, Emrullah Yilmaz, Jeffrey Yorio

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1915-1928
Number of pages14
JournalThe Lancet
Volume394
Issue number10212
DOIs
StatePublished - Nov 23 2019

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Burtness, B., Harrington, K. J., Greil, R., Soulières, D., Tahara, M., de Castro, G., Psyrri, A., Basté, N., Neupane, P., Bratland, Å., Fuereder, T., Hughes, B. G. M., Mesía, R., Ngamphaiboon, N., Rordorf, T., Wan Ishak, W. Z., Hong, R. L., González Mendoza, R., Roy, A., ... Yorio, J. (2019). 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, 394(10212), 1915-1928. https://doi.org/10.1016/S0140-6736(19)32591-7