Elsevier

The Lancet

Volume 393, Issue 10167, 12–18 January 2019, Pages 156-167
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(18)31999-8Get rights and content

Summary

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.

Introduction

Despite multimodal therapy including platinum-based chemoradiotherapy, more than 50% of patients with locoregionally advanced squamous cell carcinoma of the head and neck have recurrence or develop metastases (or both) within 3 years of treatment.1, 2, 3 Platinum-based combination chemotherapy regimens and cetuximab are commonly used in the first-line recurrent and metastatic settings.1, 2 The EXTREME regimen, which consists of platinum, fluorouracil, and cetuximab, is approved in many countries for first-line treatment of patients whose disease progressed more than 6 months after receiving a platinum-containing chemoradiotherapy regimen administered with curative intent.4 Until 2017, treatment options for recurrent and metastatic disease following progression on a platinum-based regimen were limited to single-agent chemotherapy or cetuximab, which yield a median overall survival of 7 months or less.1, 2, 5, 6, 7

Inhibitors of the programmed death 1 (PD-1) pathway, which is implicated in tumour immune escape, have emerged as valid treatment options in patients with squamous cell carcinoma of the head and neck on the basis of their antitumour activity and safety profiles.8, 9, 10, 11, 12, 13, 14 The anti-PD-1 monoclonal antibody pembrolizumab had a manageable safety profile and produced objective responses in 16–18% of patients with recurrent or metastatic head-and-neck squamous cell carcinoma in the phase 1b KEYNOTE-0128, 9 and phase 2 KEYNOTE-05512 studies. On the basis of these data, we initiated the international, randomised, open-label, phase 3 KEYNOTE-040 trial to compare the efficacy and safety of pembrolizumab with those of an investigator's choice of methotrexate, docetaxel, or cetuximab (standard of care) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck that progressed during or after platinum-based chemotherapy.

Research in context

Evidence before this study

We searched PubMed on April 11, 2018, using the terms “PD-1”, “PD-L1”, “MK-3475”, “lambrolizumab”, “pembrolizumab”, “Keytruda”, “BMS-936558”, “nivolumab”, “Opdivo”, “MPDL3280A”, “atezolizumab”, “Tecentriq”, “MEDI4736”, “durvalumab”, “Imfinzi”, “MSB0010718C”, “avelumab”, or “Bavencio” and “head and neck cancer”. We applied no time limits or language restrictions to the search. We also searched the abstracts for the 2016 and 2017 American Society of Clinical Oncology Annual Meeting and the 2016 and 2017 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 one randomised phase 3 trial of anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monotherapy for squamous cell carcinoma of the head and neck—the CheckMate 141 study of nivolumab versus investigator's choice of docetaxel, methotrexate, or cetuximab for patients with recurrent or metastatic disease following platinum-based chemotherapy. Phase 1 and phase 2 studies of anti-PD-1 or anti-PD-L1 monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck were identified, including the phase 1 KEYNOTE-012 and phase 2 KEYNOTE-055 studies of pembrolizumab, a phase 1 study of atezolizumab (NCT01375842), and the phase 2 HAWK study of durvalumab.

Added value of this study

To our knowledge, these data are the first published report of a randomised, controlled trial of pembrolizumab as therapy for recurrent or metastatic squamous cell carcinoma of the head and neck. Pembrolizumab provides a clinically meaningful prolongation of overall survival and has a favourable safety profile compared with standard-of-care therapy with methotrexate, docetaxel, or cetuximab. There was a clear relationship between higher PD-L1 expression and the benefit of pembrolizumab relative to standard-of-care therapy. Receipt of an immune checkpoint inhibitor by patients in the standard-of-care group appeared to decrease the treatment effect of pembrolizumab, a finding that has implications for future oncology studies, particularly those done in patients with cancer for which immune checkpoint inhibitors have received regulatory approval.

Implications of all the available evidence

Anti-PD-1 and anti-PD-L1 monotherapy have a favourable benefit-to-risk profile in patients with recurrent or metastatic squamous cell carcinoma of the head and neck that progress after platinum-based chemotherapy. The benefit of pembrolizumab monotherapy appears to be greater in patients whose tumours express PD-L1 than in patients whose tumours do not express the ligand. The survival benefit and safety profile of monotherapy with anti-PD-1 and anti-PD-L1 therapies in the recurrent or metastatic setting support the evaluation of monotherapy in earlier stages of disease and the evaluation of combination regimens that include PD-1 and PD-L1 inhibitors.

Section snippets

Study design and participants

This randomised, open-label, phase 3 study was done at 97 medical centres in 20 countries. Patients were eligible for enrolment if they met the following criteria: aged 18 years or older; had histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, incurable by local therapies; had disease progression during or after platinum-containing treatment for recurrent or metastatic disease (or both) or had recurrence or progression within

Results

Between Dec 24, 2014, and May 13, 2016, 495 patients were randomly allocated to pembrolizumab (n=247) or to investigator's choice of standard-of-care therapy (n=248) at one of 97 sites in 20 countries. Of these participants, 246 in the pembrolizumab group and 234 in the standard-of-care group received study treatment (figure 1). Baseline demographics and disease characteristics were generally balanced between the two treatment groups (table 1). A PD-L1 combined positive score of 1 or higher was

Discussion

In the randomised, open-label, phase 3 KEYNOTE-040 trial, pembrolizumab prolonged overall survival compared with investigator's choice of methotrexate, docetaxel, or cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The benefit of pembrolizumab compared with standard-of-care therapy was greater in patients with PD-L1 expression on their tumours or in the tumour microenvironment than in those without PD-L1 expression. Pembrolizumab had a better

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