Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Abstract
Background Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. Methods This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT…
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Virus-specific T cells are highlighted in anti-tumor responses during ICB.
“These findings highlight virus-specific T cells in anti-tumor responses during ICB.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
Clinical studies show enhanced responses to PD-1 blockade in HNSCC patients with human papillomavirus infection compared to those without.
“Clinical studies show enhanced responses to PD-1 blockade in HNSCC patients with human papillomavirus infection compared to those without.78”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
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“Negative 14 (47) 8 (35) 0 (0) 5 (24) 4 (19) 8 (40) 39 (29)”
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“(Figure 4A), all of which had comparable frequencies in the TCGA HPVneg HNSCCs. CDKN2A was hypermethylated in 13 tumors (12%), and hypermethylation was mutually exclusive with other loss of function alterations (Figures 4A and S4A-B, Table S4).”
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“A follow up report of the longterm effects confirmed a durable response and clinical benefits in these treated patients with a 12-month ORR of higher than 71%, survival rate of 38%, and even antitumor responses in some patients lasting for longer than 30 months (Chow et al., 2016; Seiwert et al., 2016; Mehra et al., 2…”
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“On the basis of a six-gene interferon-g gene expression signature analysis of CXCL9, CXCL10, HLA-DRA, IDO1, IFNG, and STAT1, delays in progression and increased clinical response tended to occur among pembrolizumab-treated patients with esophageal carcinoma and higher signature scores, consistent with findings publish…”
ResultSelf-citationImproving head and neck cancer therapies by immunomodulation of the tumour microenvironment
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“Although targeting HPV oncoproteins with antigen-specific immunotherapy using therapeutic vaccines has thus far been ineffective for metastatic disease, immunotherapy with PD-1–targeted agents has shown clinical activity in cervical (19), anal (10), and oropharyngeal (9, 11, 12, 20) cancer.”
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“8%, with no difference among p16-positive and p16-negative.(75) In the Phase II Keynote 055 (on 172 patients), 70% had a treatment-related toxicity but only 12% experienced G3–4 adverse effects.”
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“In fact, the overall survival and duration of response are greater in patients treated with Pembrolizumab than in those treated with conventional therapy [73].”
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“However, the efficacy of immune checkpoint inhibitors in squamous cell tumors (e.g., HNSCC [27, 28], squamous nonsmall cell lung cancer [29], and anal canal [30]) has been established, and nivolumab showed promising activity with a manageable safety profile for patients with treatment-refractory advanced ESCC [31], su…”
BackgroundInfluential
- Authors
- Seiwert, T. Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J. P., Heath, K., McClanahan, T., Lunceford, J., Gause, C., Cheng, J. D., & Chow, L. Q.
- Affiliations
- University of Chicago (US)
- Fox Chase Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Sheba Medical Center (IL)
- Yale Cancer Center (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Washington (US)
- Corresponding author
- Seiwert, Tanguy Y
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 17
- Issue
- 7
- Pages
- 956-965
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2401455386
- Cited by
- 1,745
- References
- 0
- Citations by year
- 2026: 73 · 2025: 136 · 2024: 149 · 2023: 159 · 2022: 165 · 2021: 213 · 2020: 195 · 2019: 190 · 2018: 216 · 2017: 204 · 2016: 44
- FWCI
- 117.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Keywords
- pembrolizumab, PD-1 inhibitors, PD-L1 expression, immune checkpoint inhibitors, antitumour activity, drug safety and tolerability, immune-related adverse events, hyponatremia, elevated liver enzymes, overall response rate
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Squamous Cell, Female, Follow-Up Studies, Head and Neck Neoplasms, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Safety, Survival Rate, Young Adult, Antibodies, Monoclonal, Humanized
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