Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study

KEYNOTE-040 investigators

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91 Citations (Scopus)

Abstract

Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Original languageEnglish
Pages (from-to)156-167
Number of pages12
JournalThe Lancet
Volume393
Issue number10167
DOIs
Publication statusPublished - 2019 Jan 12

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docetaxel
Methotrexate
Standard of Care
Therapeutics
Platinum
Safety
Survival
Carcinoma, squamous cell of head and neck
pembrolizumab
Cetuximab
Population
Stevens-Johnson Syndrome

ASJC Scopus subject areas

  • Medicine(all)

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Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040) : a randomised, open-label, phase 3 study. / KEYNOTE-040 investigators.

In: The Lancet, Vol. 393, No. 10167, 12.01.2019, p. 156-167.

Research output: Contribution to journalArticle

@article{3fdccadfb2044fd3946e663c843d0604,
title = "Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study",
abstract = "Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73{\%}) of 247 patients in the pembrolizumab group and 207 (83{\%}) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95{\%} CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13{\%}] of 246 vs 85 [36{\%}] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13{\%}] patients) and fatigue with standard of care (in 43 [18{\%}]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.",
author = "{KEYNOTE-040 investigators} and Cohen, {Ezra E.W.} and Denis Souli{\`e}res and {Le Tourneau}, Christophe and Jos{\'e} Dinis and Lisa Licitra and Ahn, {Myung Ju} and Ainara Soria and Machiels, {Jean Pascal} and Nicolas Mach and Ranee Mehra and Barbara Burtness and Pingye Zhang and Jonathan Cheng and Swaby, {Ramona F.} and Harrington, {Kevin J.} and Mirelis Acosta-Rivera and Adkins, {Douglas R.} and Morteza Aghmesheh and Mario Airoldi and Eduardas Aleknavicius and Yousuf Al-Farhat and Algazi, {Alain P.} and Salah Almokadem and Anna Alyasova and Bauman, {Jessica R.} and Marco Benasso and Alfonso Berrocal and Victoria Bray and Burtness, {Barbara Ann} and Francesco Caponigro and Ana Castro and Cescon, {Terrence P.} and Kelvin Chan and Arvind Chaudhry and Bruno Chauffert and Ezra Cohen and Tibor Csoszi and {De Boer}, {J. P.} and Delord, {Jean Pierre} and Andreas Dietz and Jose Dinis and Charlotte Dupuis and Laurence Digue and Jozsef Erfan and {Escobar Alvarez}, Yolanda and Mererid Evans and Fidler, {Mary Jo} and Forster, {Martin David} and Signe Friesland and Shin, {Sang Won}",
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T1 - Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040)

T2 - a randomised, open-label, phase 3 study

AU - KEYNOTE-040 investigators

AU - Cohen, Ezra E.W.

AU - Soulières, Denis

AU - Le Tourneau, Christophe

AU - Dinis, José

AU - Licitra, Lisa

AU - Ahn, Myung Ju

AU - Soria, Ainara

AU - Machiels, Jean Pascal

AU - Mach, Nicolas

AU - Mehra, Ranee

AU - Burtness, Barbara

AU - Zhang, Pingye

AU - Cheng, Jonathan

AU - Swaby, Ramona F.

AU - Harrington, Kevin J.

AU - Acosta-Rivera, Mirelis

AU - Adkins, Douglas R.

AU - Aghmesheh, Morteza

AU - Airoldi, Mario

AU - Aleknavicius, Eduardas

AU - Al-Farhat, Yousuf

AU - Algazi, Alain P.

AU - Almokadem, Salah

AU - Alyasova, Anna

AU - Bauman, Jessica R.

AU - Benasso, Marco

AU - Berrocal, Alfonso

AU - Bray, Victoria

AU - Burtness, Barbara Ann

AU - Caponigro, Francesco

AU - Castro, Ana

AU - Cescon, Terrence P.

AU - Chan, Kelvin

AU - Chaudhry, Arvind

AU - Chauffert, Bruno

AU - Cohen, Ezra

AU - Csoszi, Tibor

AU - De Boer, J. P.

AU - Delord, Jean Pierre

AU - Dietz, Andreas

AU - Dinis, Jose

AU - Dupuis, Charlotte

AU - Digue, Laurence

AU - Erfan, Jozsef

AU - Escobar Alvarez, Yolanda

AU - Evans, Mererid

AU - Fidler, Mary Jo

AU - Forster, Martin David

AU - Friesland, Signe

AU - Shin, Sang Won

PY - 2019/1/12

Y1 - 2019/1/12

N2 - Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.

AB - Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.

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U2 - 10.1016/S0140-6736(18)31999-8

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AN - SCOPUS:85059907778

VL - 393

SP - 156

EP - 167

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10167

ER -