Elsevier

The Lancet

Volume 394, Issue 10212, 23–29 November 2019, Pages 1915-1928
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(19)32591-7Get rights and content

Summary

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.

Introduction

Head and neck squamous cell carcinoma (HNSCC) includes cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Locoregional HNSCC is treated with curative intent, although functional sequelae can be severe, and many patients succumb to recurrence or metastasis.1, 2 Standard first-line treatment for recurrent or metastatic disease that is not amenable to local therapy is cetuximab plus chemotherapy with platinum and 5-fluorouracil, which provides median overall survival of about 10 months and is associated with substantial toxicity.3

Immune checkpoint inhibitors have shown efficacy and manageable safety in HNSCC.4, 5, 6, 7, 8 Monotherapy with the programmed cell death 1 (PD-1) inhibitors pembrolizumab and nivolumab improved overall survival compared with standard of care in participants with recurrent or metastatic HNSCC that progressed during or after platinum-based chemotherapy.5, 6 PD-1 ligand 1 (PD-L1) expression on tumour cells and associated immune cells predicted better outcomes for pembrolizumab.5 Chemotherapy is a rational combination partner for immune checkpoint inhibitors in HNSCC because it disrupts tumour architecture (potentially reducing immune exclusion), results in antigen shedding, and induces rapid disease control.9

Here, we aimed to determine whether pembrolizumab as monotherapy or in combination with chemotherapy improves overall survival compared with cetuximab plus chemotherapy in participants with previously untreated recurrent or metastatic HNSCC.

Research in context

Evidence before this study

We searched PubMed on May 28, 2019, using the search terms “PD-1” OR “PD-L1” OR (“MK-3475” OR “pembrolizumab” OR “Keytruda”) OR (“BMS-936558” OR “nivolumab” OR “Opdivo”) OR (“MPDL3280A” OR “atezolizumab” OR “Tecentriq”) OR (“MEDI4736” OR “durvalumab” OR “Imfinzi”) OR (“MSB0010718C” OR “avelumab” OR “Bavencio”) OR (“cetuximab” OR “Erbitux” AND “chemotherapy”) AND “recurrent” OR “metastatic” AND “locally incurable” AND “first line” OR “previously untreated” AND “head and neck squamous cell carcinoma” OR “HNSCC” OR “SCCHN”. There were no limits applied to the search. We also searched the abstracts of the 2017, 2018, and 2019 American Association for Cancer Research Annual Meeting, American Society of Clinical Oncology Annual Meeting, and European Society for Medical Oncology Congress using the same search terms to identify results of any clinical trials that were not yet published in the peer-reviewed literature. We identified a subgroup analysis of the phase 3 CheckMate 141 study of nivolumab versus investigator's choice of therapy for platinum-refractory recurrent or metastatic HNSCC which showed that nivolumab was associated with an overall survival benefit in participants whose disease progressed within 6 months of platinum-based therapy given for locally advanced disease. We did not focus on this report because our study excluded patients whose disease progressed within 6 months of curatively intended systemic therapy given as a component of locoregionally advanced disease management. We also identified several studies of cetuximab given in combination with various chemotherapy regimens and a phase 3 study of bevacizumab plus platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone. We focused on the phase 3 EXTREME study that showed an overall survival benefit for cetuximab in combination with a platinum and 5-fluorouracil because this regimen is the standard for first-line treatment of recurrent or metastatic HNSCC. This regimen was used as the control group in several other studies, including the phase 2 ADVANTAGE study of cilengitide plus cetuximab, a platinum, and 5-fluorouracil, the phase 2 Active8 study of motolimod plus cetuximab, cisplatin, and 5-fluorouracil, and the phase 2 TPExtreme study of cetuximab plus cisplatin and docetaxel.

Added value of this study

The randomised, open-label, phase 3 KEYNOTE-048 study of pembrolizumab given alone or in combination with a chemotherapy regimen of platinum and 5-fluorouracil establishes anti-programmed cell death 1 (PD-1)-based therapy as a first-line treatment option for patients with locally incurable recurrent or metastatic HNSCC. Pembrolizumab monotherapy was associated with a significant overall survival benefit in participants with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 20 or more or 1 or more and had non-inferior overall survival in the total study population compared with standard-of-care therapy with cetuximab, a platinum, and 5-flurouracil. Pembrolizumab given with a platinum and 5-fluorouracil significantly improved overall survival in the PD-L1 CPS of 20 or more population, PD-L1 CPS of 1 or more population, and total population compared with cetuximab, a platinum, and 5-fluorouracil. Compared with standard therapy, the incidence of adverse events of any grade and of grade 3 or worse was lower with pembrolizumab monotherapy and similar with pembrolizumab plus chemotherapy.

Implications of all the available evidence

Our findings of a significant survival benefit for pembrolizumab monotherapy in participants with PD-L1 CPS of 20 or more and of 1 or more and a favourable safety profile relative to standard-of-care therapy suggest that pembrolizumab monotherapy is a new treatment option for patients with PD-L1-positive recurrent or metastatic HNSCC. Our findings of a significant survival benefit for pembrolizumab combined with a platinum and 5-fluorouracil in the total and PD-L1-positive populations along with a manageable safety profile compared with standard therapy suggest that pembrolizumab plus chemotherapy is a new standard-of-care treatment for patients with recurrent or metastatic HNSCC.

Section snippets

Study design and participants

The KEYNOTE-048 study was a randomised, open-label, phase 3 study done at 200 medical centres in 37 countries (appendix pp 2–5). Participants were eligible for enrolment if they were aged 18 years or older; had pathologically confirmed squamous cell carcinoma of the oropharynx, oral cavity, hypopharynx, or larynx that was recurrent or metastatic and not curable by local therapy; had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; had at least one tumour lesion

Results

Between April 20, 2015, and Jan 17, 2017, we screened 1228 individuals for eligibility, 882 of whom were randomly allocated to either pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300; figure 1). Based on consultation between the sponsor and data and safety monitoring committee after three deaths (two from disease progression and one from an adverse event) occurred in the first 14 participants in the pembrolizumab with chemotherapy

Discussion

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

Data sharing

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 [email protected].

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