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 language | English (US) |
|---|---|
| Pages (from-to) | 1915-1928 |
| Number of pages | 14 |
| Journal | The Lancet |
| Volume | 394 |
| Issue number | 10212 |
| DOIs | |
| State | Published - Nov 23 2019 |
ASJC Scopus subject areas
- Medicine(all)
Access to Document
Other files and links
Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.
Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
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. / Burtness, Barbara; Harrington, Kevin J.; Greil, Richard; Soulières, Denis; Tahara, Makoto; de Castro, Gilberto; Psyrri, Amanda; Basté, Neus; Neupane, Prakash; Bratland, Åse; Fuereder, Thorsten; Hughes, Brett G.M.; Mesía, Ricard; Ngamphaiboon, Nuttapong; Rordorf, Tamara; Wan Ishak, Wan Zamaniah; Hong, Ruey Long; González Mendoza, René; Roy, Ananya; Zhang, Yayan; Gumuscu, Burak; Cheng, Jonathan D.; Jin, Fan; Rischin, Danny; Lerzo, Guillermo; Tatangelo, Marcelo; Varela, Mirta; Zarba, Juan Jose; Boyer, Michael; Gan, Hui; Gao, Bo; Hughes, Brett; Mallesara, Girish; Taylor, Anne; Burian, Martin; Barrios, Carlos Henrique; de Castro Junior, Dalvaro Oliveira; Castro, Gilberto; Franke, Fabio Andre; Girotto, Gustavo; Lima, Iane Pinto Figueiredo; Nicolau, Ulisses Ribaldo; Pinto, Gustavo Dix Junqueira; Santos, Lucas; Victorino, Ana Paula; Chua, Neil; Couture, Felix; Gregg, Richard; Hansen, Aaron; Hilton, John; McCarthy, Joy; Soulieres, Denis; Ascui, Rodrigo; Gonzalez, Pablo; Villanueva, Luis; Torregroza, Marco; Zambrano, Angela; Holeckova, Petra; Kral, Zdenek; Melichar, Bohuslav; Prausova, Jana; Vosmik, Milan; Andersen, Maria; Gyldenkerne, Niels; Jurgens, Hannes; Putnik, Kadri; Reinikainen, Petri; Gruenwald, Viktor; Laban, Simon; Aravantinos, Gerasimos; Boukovinas, Ioannis; Georgoulias, Vassilis; Kwong, Dora; Al-Farhat, Yousuf; Csoszi, Tibor; Erfan, Jozsef; Horvai, Geza; Landherr, Laszlo; Remenar, Eva; Ruzsa, Agnes; Szota, Judit; Billan, Salem; Gluck, Iris; Gutfeld, Orit; Popovtzer, Aron; Benasso, Marco; Bui, Simona; Ferrari, Vittorio; Licitra, Lisa; Nole, Franco; Fujii, Takashi; Fujimoto, Yasushi; Hanai, Nobuhiro; Hara, Hiroki; Matsumoto, Koji; Mitsugi, Kenji; Monden, Nobuya; Nakayama, Masahiro; Okami, Kenji; Oridate, Nobuhiko; Shiga, Kiyoto; Shimizu, Yasushi; Sugasawa, Masashi; Takahashi, Masanobu; Takahashi, Shunji; Tanaka, Kaoru; Ueda, Tsutomu; Yamaguchi, Hironori; Yamazaki, Tomoko; Yasumatsu, Ryuji; Yokota, Tomoya; Yoshizaki, Tomokazu; Kudaba, Iveta; Stara, Zinaida; Cheah, Soon Keat; Aguilar Ponce, Jose; Gonzalez Mendoza, Rene; Hernandez Hernandez, Carlos; Medina Soto, Francisco; Buter, Jan; Hoeben, Ann; Oosting, S.; Suijkerbuijk, Karijn; Bratland, Aase; Brydoey, Marianne; Alvarez, Renzo; Mas, Luis; Caguioa, Priscilla; Querol, John; Regala, Eugenio Emmanuel; Tamayo, Maria Belen; Villegas, Ellie May; Kawecki, Andrzej; Karpenko, Andrey; Klochikhin, Arkadiy; Smolin, Alexey; Zarubenkov, Oleg; Goh, Boon Cher; Cohen, Graham; du Toit, Johanna; Jordaan, Christa; Landers, Gregory; Ruff, Paul; Szpak, Waldemar; Tabane, Neonyana; Brana, Irene; Iglesias Docampo, Lara; Lavernia, Javier; Mesia, Ricard; Abel, Edvard; Muratidu, Valentina; Nielsen, Niels; Cristina, Valerie; Rothschild, Sacha; Wang, Hung Ming; Yang, Muh Hwa; Yeh, Su Peng; Yen, Chia Jui; Soparattanapaisarn, Nopadol; Sriuranpong, Virote; Aksoy, Sercan; Cicin, Irfan; Ekenel, Meltem; Harputluoglu, Hakan; Ozyilkan, Ozgur; Harrington, Kevin; Agarwala, Sanjiv; Ali, Haythem; Alter, Robert; Anderson, Daniel; Bruce, Justine; Campbell, Nicholas; Conde, Miguel; Deeken, John; Edenfield, William; Feldman, Lawrence; Gaughan, Elizabeth; Goueli, Basem; Halmos, Balazs; Hegde, Upendra; Hunis, Brian; Jotte, Robert; Karnad, Anand; Khan, Saad; Laudi, Noel; Laux, Douglas; Martincic, Danko; McCune, Steven; McGaughey, Dean; Misiukiewicz, Krzysztof; Mulford, Deborah; Nadler, Eric; Nunnink, Johannes; Ohr, James; O'Malley, Meaghan; Patson, Brian; Paul, Doru; Popa, Elizabeta; Powell, Steven; Redman, Rebecca; Rella, Vincent; Rocha Lima, Chaio; Sivapiragasam, Abirami; Su, Yungpo; Sukari, Ammar; Wong, Stuart; Yilmaz, Emrullah; Yorio, Jeffrey.
In: The Lancet, Vol. 394, No. 10212, 23.11.2019, p. 1915-1928.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048)
T2 - a randomised, open-label, phase 3 study
AU - Burtness, Barbara
AU - Harrington, Kevin J.
AU - Greil, Richard
AU - Soulières, Denis
AU - Tahara, Makoto
AU - de Castro, Gilberto
AU - Psyrri, Amanda
AU - Basté, Neus
AU - Neupane, Prakash
AU - Bratland, Åse
AU - Fuereder, Thorsten
AU - Hughes, Brett G.M.
AU - Mesía, Ricard
AU - Ngamphaiboon, Nuttapong
AU - Rordorf, Tamara
AU - Wan Ishak, Wan Zamaniah
AU - Hong, Ruey Long
AU - González Mendoza, René
AU - Roy, Ananya
AU - Zhang, Yayan
AU - Gumuscu, Burak
AU - Cheng, Jonathan D.
AU - Jin, Fan
AU - Rischin, Danny
AU - Lerzo, Guillermo
AU - Tatangelo, Marcelo
AU - Varela, Mirta
AU - Zarba, Juan Jose
AU - Boyer, Michael
AU - Gan, Hui
AU - Gao, Bo
AU - Hughes, Brett
AU - Mallesara, Girish
AU - Taylor, Anne
AU - Burian, Martin
AU - Barrios, Carlos Henrique
AU - de Castro Junior, Dalvaro Oliveira
AU - Castro, Gilberto
AU - Franke, Fabio Andre
AU - Girotto, Gustavo
AU - Lima, Iane Pinto Figueiredo
AU - Nicolau, Ulisses Ribaldo
AU - Pinto, Gustavo Dix Junqueira
AU - Santos, Lucas
AU - Victorino, Ana Paula
AU - Chua, Neil
AU - Couture, Felix
AU - Gregg, Richard
AU - Hansen, Aaron
AU - Hilton, John
AU - McCarthy, Joy
AU - Soulieres, Denis
AU - Ascui, Rodrigo
AU - Gonzalez, Pablo
AU - Villanueva, Luis
AU - Torregroza, Marco
AU - Zambrano, Angela
AU - Holeckova, Petra
AU - Kral, Zdenek
AU - Melichar, Bohuslav
AU - Prausova, Jana
AU - Vosmik, Milan
AU - Andersen, Maria
AU - Gyldenkerne, Niels
AU - Jurgens, Hannes
AU - Putnik, Kadri
AU - Reinikainen, Petri
AU - Gruenwald, Viktor
AU - Laban, Simon
AU - Aravantinos, Gerasimos
AU - Boukovinas, Ioannis
AU - Georgoulias, Vassilis
AU - Kwong, Dora
AU - Al-Farhat, Yousuf
AU - Csoszi, Tibor
AU - Erfan, Jozsef
AU - Horvai, Geza
AU - Landherr, Laszlo
AU - Remenar, Eva
AU - Ruzsa, Agnes
AU - Szota, Judit
AU - Billan, Salem
AU - Gluck, Iris
AU - Gutfeld, Orit
AU - Popovtzer, Aron
AU - Benasso, Marco
AU - Bui, Simona
AU - Ferrari, Vittorio
AU - Licitra, Lisa
AU - Nole, Franco
AU - Fujii, Takashi
AU - Fujimoto, Yasushi
AU - Hanai, Nobuhiro
AU - Hara, Hiroki
AU - Matsumoto, Koji
AU - Mitsugi, Kenji
AU - Monden, Nobuya
AU - Nakayama, Masahiro
AU - Okami, Kenji
AU - Oridate, Nobuhiko
AU - Shiga, Kiyoto
AU - Shimizu, Yasushi
AU - Sugasawa, Masashi
AU - Takahashi, Masanobu
AU - Takahashi, Shunji
AU - Tanaka, Kaoru
AU - Ueda, Tsutomu
AU - Yamaguchi, Hironori
AU - Yamazaki, Tomoko
AU - Yasumatsu, Ryuji
AU - Yokota, Tomoya
AU - Yoshizaki, Tomokazu
AU - Kudaba, Iveta
AU - Stara, Zinaida
AU - Cheah, Soon Keat
AU - Aguilar Ponce, Jose
AU - Gonzalez Mendoza, Rene
AU - Hernandez Hernandez, Carlos
AU - Medina Soto, Francisco
AU - Buter, Jan
AU - Hoeben, Ann
AU - Oosting, S.
AU - Suijkerbuijk, Karijn
AU - Bratland, Aase
AU - Brydoey, Marianne
AU - Alvarez, Renzo
AU - Mas, Luis
AU - Caguioa, Priscilla
AU - Querol, John
AU - Regala, Eugenio Emmanuel
AU - Tamayo, Maria Belen
AU - Villegas, Ellie May
AU - Kawecki, Andrzej
AU - Karpenko, Andrey
AU - Klochikhin, Arkadiy
AU - Smolin, Alexey
AU - Zarubenkov, Oleg
AU - Goh, Boon Cher
AU - Cohen, Graham
AU - du Toit, Johanna
AU - Jordaan, Christa
AU - Landers, Gregory
AU - Ruff, Paul
AU - Szpak, Waldemar
AU - Tabane, Neonyana
AU - Brana, Irene
AU - Iglesias Docampo, Lara
AU - Lavernia, Javier
AU - Mesia, Ricard
AU - Abel, Edvard
AU - Muratidu, Valentina
AU - Nielsen, Niels
AU - Cristina, Valerie
AU - Rothschild, Sacha
AU - Wang, Hung Ming
AU - Yang, Muh Hwa
AU - Yeh, Su Peng
AU - Yen, Chia Jui
AU - Soparattanapaisarn, Nopadol
AU - Sriuranpong, Virote
AU - Aksoy, Sercan
AU - Cicin, Irfan
AU - Ekenel, Meltem
AU - Harputluoglu, Hakan
AU - Ozyilkan, Ozgur
AU - Harrington, Kevin
AU - Agarwala, Sanjiv
AU - Ali, Haythem
AU - Alter, Robert
AU - Anderson, Daniel
AU - Bruce, Justine
AU - Campbell, Nicholas
AU - Conde, Miguel
AU - Deeken, John
AU - Edenfield, William
AU - Feldman, Lawrence
AU - Gaughan, Elizabeth
AU - Goueli, Basem
AU - Halmos, Balazs
AU - Hegde, Upendra
AU - Hunis, Brian
AU - Jotte, Robert
AU - Karnad, Anand
AU - Khan, Saad
AU - Laudi, Noel
AU - Laux, Douglas
AU - Martincic, Danko
AU - McCune, Steven
AU - McGaughey, Dean
AU - Misiukiewicz, Krzysztof
AU - Mulford, Deborah
AU - Nadler, Eric
AU - Nunnink, Johannes
AU - Ohr, James
AU - O'Malley, Meaghan
AU - Patson, Brian
AU - Paul, Doru
AU - Popa, Elizabeta
AU - Powell, Steven
AU - Redman, Rebecca
AU - Rella, Vincent
AU - Rocha Lima, Chaio
AU - Sivapiragasam, Abirami
AU - Su, Yungpo
AU - Sukari, Ammar
AU - Wong, Stuart
AU - Yilmaz, Emrullah
AU - Yorio, Jeffrey
N1 - Funding Information: In this randomised phase 3 study of participants with untreated recurrent or metastatic HNSCC and compared with cetuximab with chemotherapy (cetuximab plus platinum and 5-fluorouracil), pembrolizumab monotherapy significantly prolonged overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations and had non-inferior overall survival in the total population. Pembrolizumab with chemotherapy (pembrolizumab plus platinum and 5-fluorouracil) significantly prolonged overall survival in the PD-L1 CPS of 20 or more, PD-L1 CPS of 1 or more, and total populations. The overall survival seen in the cetuximab with chemotherapy group was consistent with that of cetuximab with chemotherapy in the phase 3 EXTREME study. 3 Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival or objective response compared with cetuximab with chemotherapy, and the proportion of participants with progressive disease as best response was greater with pembrolizumab alone than with cetuximab with chemotherapy. Progression-free survival and objective response were similar for pembrolizumab with chemotherapy and cetuximab with chemotherapy. Our statistical analysis plan specified one-sided testing only but, numerically, progression-free survival and objective response favoured the cetuximab with chemotherapy group in the CPS of 1 or more and total populations. Although there were no progression-free survival or objective response benefits, pembrolizumab alone and pembrolizumab with chemotherapy were associated with more complete responses and a longer duration of response. Pembrolizumab alone improved median response duration by more than 16 months versus cetuximab with chemotherapy. The improvement in median response duration in the pembrolizumab with chemotherapy group was 2·5 months, which probably reflects a mix of shorter chemotherapy-driven and longer pembrolizumab-driven responses. As seen for immune checkpoint inhibition, 5,6,11,17,18 we report profound overall survival benefits for pembrolizumab monotherapy in participants with PD-L1-positive tumours and for pembrolizumab with chemotherapy in all participants without improvements in progression-free survival or objective response. Substantial survival advantages were seen for pembrolizumab monotherapy in the PD-L1 CPS of 20 or more and CPS of 1 or more populations and for pembrolizumab with chemotherapy in the CPS of 20 or more, CPS of 1 or more, and total populations despite the fact that the overall survival benefit emerged only after about 7 months. The observed survival benefit reflects the remarkable response durability and is partially driven by a subset of patients who remain progression-free at 3 years. The 3-year overall survival benefit in the pembrolizumab alone and pembrolizumab with chemotherapy groups is greater than can be explained by the proportion of patients with a long-term response. This observation raises the possibility that early exposure to pembrolizumab might induce durable alterations in the tumour microenvironment, altering the natural history of the cancer and sensitising it to subsequent therapy. 19 Support for this hypothesis comes from retrospective analyses 20–25 showing that outcomes of therapy given after immune checkpoint inhibition exceed those predicted by historical data, even in patients whose disease did not respond to checkpoint inhibition. Further clinical and translational analyses and prospective studies are needed to explore this hypothesis. The observed adverse events were as expected based on the known toxicity profiles of the individual treatment components. Pembrolizumab monotherapy had a favourable safety profile compared with cetuximab with chemotherapy. The incidences of grade 3 or worse adverse events and those leading to treatment discontinuation were lower with pembrolizumab alone than with cetuximab with chemotherapy, as was the incidence of treatment-related death. The incidence of grade 3 or worse adverse events and those leading to discontinuation and death were similar in the pembrolizumab with chemotherapy and cetuximab with chemotherapy groups. Pembrolizumab did not exacerbate adverse events associated with chemotherapy or vice versa. Tumour bleeding was not substantially increased with pembrolizumab alone or with pembrolizumab with chemotherapy. This study was powered to compare pembrolizumab monotherapy with cetuximab with chemotherapy and to compare pembrolizumab with chemotherapy with cetuximab with chemotherapy and had 14 primary hypotheses. Per protocol, once a primary hypothesis completed statistical testing, the result was considered definitive. Therefore, the second interim analysis results are the definitive study findings for 11 of 14 primary hypotheses and the final analysis results are the definitive findings for the remaining three hypotheses. Notably, this study was not powered to compare pembrolizumab monotherapy with pembrolizumab with chemotherapy, and the protocol did not specify any comparisons of these two groups. Although outcomes were not directly compared and both pembrolizumab strategies showed a survival benefit, certain findings might direct the choice of pembrolizumab monotherapy or pembrolizumab with chemotherapy. For example, although pembrolizumab monotherapy had a favourable toxicity profile compared with cetuximab with chemotherapy, fewer participants had an objective response and progression-free survival was shorter. Conversely, the proportion of participants with objective response and progression-free survival were similar for pembrolizumab with chemotherapy and cetuximab with chemotherapy. For pembrolizumab monotherapy, greater PD-L1 expression was associated with greater response. Overall, pembrolizumab monotherapy might be preferred for PD-L1-positive cancers that are associated with a lesser symptom burden, whereas pembrolizumab with chemotherapy might be preferred for patients whose symptom burden indicates a greater importance of objective response or those who have low PD-L1 expression or recurrent-only disease. Patient preference will also be an important element in choosing between pembrolizumab monotherapy and pembrolizumab with chemotherapy. Exploratory analyses of clinical characteristics, additional PD-L1 subgroups, and biomarkers beyond PD-L1 expression would be of value in helping to inform the choice of therapy. One limitation of this study is the open-label design, which could have resulted in the higher proportion of participants in the cetuximab with chemotherapy group than in the pembrolizumab alone and pembrolizumab with chemotherapy groups who did not receive the assigned therapy. Other limitations are the inconsistent access to second-line PD-1 and PD-L1 inhibitors across the countries that enrolled participants and the lack of statistical power to compare outcomes in the pembrolizumab alone and pembrolizumab with chemotherapy groups. In summary, first-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, had non-inferior overall survival in the total population, was associated with a substantially longer duration of response in all populations, and had a favourable safety profile compared with cetuximab with chemotherapy as first-line therapy for recurrent or metastatic advanced HNSCC. First-line therapy with pembrolizumab in combination with platinum and 5-fluorouracil significantly improved overall survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations, was associated with a longer duration of response, and had a comparable safety profile versus cetuximab with chemotherapy. Based on the observed efficacy and safety, pembrolizumab combined with 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. Contributors BB, KJH, JDC, and FJ conceived, designed, and planned the study. BB, KJH, RG, DS, MT, GdC, AP, NB, PN, ÅB, TF, BGMH, RM, NN, TR, WZWI, R-LH, RGM, and DR acquired the data. AR and YZ did the statistical analysis. BB, AR, and FJ prepared the first draft of the manuscript. All authors interpreted the results, provided critical review and revision of the article, and approved the decision to submit for publication. Declaration of interests BB reports honoraria and travel support for steering committee activities from Boehringer-Ingelheim, Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co; personal fees for serving as an advisor from Amgen, Alligator Biosciences, Aduro, Bayer, AstraZeneca, Celgene, Debiopharm, Cure Biosciences, Maverick Therapeutics, GlaxoSmithKline, VentiRx, Bristol-Myers Squibb, and Genentech/Roche; travel support for advisory activities from Celgene, Debiopharm, Maverick Therapeutics, and Genentech/Roche; honoraria and travel support for data safety monitoring committee activities from IDDI for AstraZeneca/MedImmune; and funding to their institution to support study conduct from Boehringer-Ingelheim and MSD. KJH reports personal fees for serving as an advisory board member from MSD, AstraZeneca, Amgen, Boehringer-Ingelheim, Merck Serono, Mersana, Oncolys, Pfizer, Replimmune, and Vyriad; personal fees for serving as a speaker from MSD, AstraZeneca, Amgen, Merck Serono; and honoraria from MSD, AstraZeneca, Amgen, Boehringer-Ingelheim, Merck Serono, Pfizer, Replimmune, and Vyriad. RG reports honoraria and travel support for serving in a consultant or advisory role from MSD. DS reports personal fees for serving as an advisor and a speaker from MSD. MT reports personal fees from Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, AstraZeneca, Pfizer, Rakuten Aspyrian Therapeutics, Celgene, Amgen, and Bayer, and grants from Bristol-Myers Squibb, Ono Pharmaceutical, AstraZeneca, Pfizer, Rakuten Aspyrian Therapeutics, Bayer, LOXO, and Novartis. GdC reports personal fees for serving as a speaker from MSD, AstraZeneca, Bristol-Myers Squibb, and Merck Serono; personal fees for presentations from AstraZeneca and Teva; travel and accommodation support from MSD, Bristol-Myers Squibb, and Merck Serono; and funding to their institution to support study conduct from MSD, Bristol-Myers Squibb, and Merck Serono. AP reports personal fees for advisory boards from MSD, Bristol-Myers Squibb, Roche, and Genesis; travel support from MSD, Bristol-Myers Squibb, Roche, and Merck Serono; honoraria from MSD, Bristol-Myers Squibb, and Roche; and grants from Bristol-Myers Squibb, Roche, Boehringer-Ingelheim, Pfizer, Merck Serono, Genesis, and KURA. NB reports personal fees from Bristol-Myers Squibb, Nanobiotix, and Merck Serono, and non-financial support from Bristol-Myers Squibb, Nanobiotix, AstraZeneca, Merck Serono, Boehringer Ingelheim, Novartis, MSD, ISA Therapeutics, Debiopharm, and Roche. TF reports honoraria and travel support to support advisory activities from MSD, Merck KGaA, Roche, Bristol-Myers Squibb, and Boehringer-Ingelheim; honoraria for lectures from Accord, AstraZeneca, Novartis, Sanofi, and Boehringer-Ingelheim; research grants from MSD and Merck KGaA; and funding to their institution to support study conduct from MSD, Bristol-Myers Squibb, Merck KGaA, AstraZeneca, Novartis, Sanofi, Roche, Amgen, and Pfizer. BGMH reports personal fees for serving as an advisory board member for MSD, Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca, Eisai, and Boehringer-Ingelheim. RM reports personal fees for serving in an advisory role for AstraZeneca, MSD, Merck, Bristol-Myers Squibb, Roche, and Nanobiotix, and honoraria for conferences from MSD and Bristol-Myers Squibb. NN reports personal fees from Roche, AstraZeneca, Novartis, Amgen, Boehringer-Ingelheim, Eisai, Taiho, and Bristol-Myers Squibb; non-financial support from Roche, Novartis, Amgen, Boehringer-Ingelheim, Eisai, Merck, and Taiho; and funding to their institution to support study conduct from MSD, Pfizer, and AstraZeneca. TR reports personal fees for advisory board membership from MSD. WZWI reports personal fees for advisory board membership from Merck Serono, Eisai Malaysia, MSD Malaysia, Roche Malaysia, Boehringer-Ingelheim, Eli Lilly Malaysia, and Mundipharma Malaysia; travel grants from Merck Serono, Eisai Malaysia, MSD Malaysia, Roche Malaysia, Eli Lilly Malaysia, Mundipharma Malaysia, and Pfizer; and honorarium for lectures from Merck Serono, Eisai Malaysia, MSD Malaysia, Roche Malaysia, Boehringer-Ingelheim, Eli Lilly Malaysia, and Mundipharma Malaysia. R-LH reports non-financial support and consulting fees from MSD. AR, BG, JDC, and FJ are employed by and own stock in MSD. YZ is employed by MSD. DR reports serving as an uncompensated advisor for MSD, Regeneron, Bristol-Myers Squibb, GlaxoSmithKline, and Sanofi; non-financial support from MSD; and grants from Roche, GlaxoSmithKline, Regeneron, and Bristol-Myers Squibb. KJH, RG, DS, MT, AP, NB, PN, ÅB, BGMH, RM, TR, WZWI, R-LH, RGM, and DR report funding to their institution to support study conduct from MSD. Funding Information: Data will be available according to Merck Sharp & Dohme's data sharing policy, which, including restrictions, is available online at EngageZone. Requests for access to the clinical study data can be submitted through EngageZone or via email to dataacess@merck.com . Acknowledgments This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. We thank the participants and their families and caregivers for participating in this trial; all the investigators and site personnel; and the following employees of MSD: Ramona F Swaby for critical review of an earlier version of the manuscript; Emmett V Schmidt for input into the study design; Christine Gause and Joy Ge for statistical expertise and input into the study design; Amy Meister and Kenia Baez for support of study conduct; and Melanie A Leiby for medical writing and editorial assistance. Publisher Copyright: © 2019 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2019/11/23
Y1 - 2019/11/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075142270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075142270&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)32591-7
DO - 10.1016/S0140-6736(19)32591-7
M3 - Article
C2 - 31679945
AN - SCOPUS:85075142270
VL - 394
SP - 1915
EP - 1928
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10212
ER -