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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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“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]
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“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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“Anti‐PD‐1 antibodies like nivolumab and pembrolizumab have shown persistent responses and improved survival in patients with r/m who received platinum‐based therapy.(47) In 2019, pem-”
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“A phase 1b trial showed that pembrolizumab, a PD1 inhibitor, was a safe, well-tolerated and antitumor drug in patients with recurrent or metastatic HNSCC irrespective of HPV status (48).”
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“The confirmed ORR in both cohorts was 18%, and responses were durable.(12,13) After a median follow-up of 14 months and 9 months in the initial and expansion cohorts, respectively, the median DOR was 53 weeks in the initial cohort and was not reached in the expansion cohort.”
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HPV – Das andere Kopf-Hals-Karzinom
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“In the KEYNOTE-012 study (Pembrolizumab) a response of 32 % was evaluated in HPV-positive head and neck tumors compared to 18 % in HPV-negative tumors [214].”
Rationale for neoadjuvant immunotherapy in head and neck squamous cell carcinoma.
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“brolizumab and nivolumab (both anti-PD-1 antibodies) in this disease [11,12].”
BackgroundBauman, J. E., Cohen, E. E. W., Ferris, R. L., Adelstein, D. J., Brizel, D. M., Ridge, J. A., O’Sullivan, B., Burtness, B. A., Butterfield, L. H., Carson, W. E., et al. (2016) · Cancer · doi:10.1002/cncr.30449 · Cited by 51
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BackgroundMethodInfluentialSelf-citationThe effects of checkpoint inhibition on head and neck squamous cell carcinoma: a systematic review
Ghanizada, M., Jakobsen, K. K., Grønhøj, C., & von Buchwald, C. (2019) · Oral Oncology · doi:10.1016/j.oraloncology.2019.01.018 · Cited by 46
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Immunotherapy for squamous cell carcinoma of the head and neck
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“A phase 1b multi-cohort study (KEYNOTE012) demonstrated a durable objective response rate by treatment with pembrolizumab monotherapy in a subgroup of platinumrefractory SCCHN (32).”
BackgroundClinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma
Gougis, P., Moreau-Bachelard, C., Kamal, M. T., Gan, H. K., Borcoman, É., Torossian, N., Bièche, I., & Tourneau, C. L. (2019) · JNCI Cancer Spectrum · doi:10.1093/jncics/pkz055 · Cited by 63
“In addition, responses may sometimes be durable (123).”
BackgroundImmunotherapies and Future Combination Strategies for Head and Neck Squamous Cell Carcinoma
Cristina, V., Gómez, R. G. H., Szturz, P., Espeli, V. G., & Siano, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215399 · Cited by 52
“In the phase IB KEYNOTE-012 trial, 60 patients with PD-L1 positive (>1%) R/M HNSCC (38% were HPV-positive and 62% were HPV-negative) were treated with pembrolizumab 10 mg/kg intravenously every two weeks [28].”
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“[2] established the basis of the application of pembrolizumab, a PD-1 antibody, in the recurrence and metastasis of refractory head and neck squamous cell carcinoma (HNSCC).”
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PD-L1 Expression is Increased in Metastasizing Squamous Cell Carcinomas and Their Metastases
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“In recent years, clinical trials of immunotherapy for LA-HNSCC have demonstrated the successful use of immunotherapy for recurrent/metastatic HNSCC (Seiwert et al., 2016).”
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“benefited from it, but the response rate in HNSCC patients is only ∼13–20% (4, 5).”
BackgroundPD-1/PD-L1 blockade in cervical cancer: current studies and perspectives
Wang, Y., & Li, G. (2019) · Frontiers of Medicine · doi:10.1007/s11684-018-0674-4 · Cited by 49
Association of Immunotherapy With Durable Survival as Defined by Value Frameworks for Cancer Care
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Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review
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“The overexpression of programmed death-ligand 1 (PD-L1) on tumor cells, which interact with programmed death-1 (PD-1) receptors expressed on T cells, leads to T cell exhaustion and reduced cytotoxic activity [32].”
The Bidirectional Relationship between Pulmonary Tuberculosis and Lung Cancer
Preda, M., Tanase, B., Zob, D., Gheorghe, A., Lungulescu, C., Dumitrescu, E., Stănculeanu, D., Manolescu, L., Popescu, O., Ibraim, E., et al. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20021282 · Cited by 45
“Some diseases do not respond to PD-1 blocking, such as head and neck squamous cell carcinoma, which has response rates as low as 10–15% [28].”
BackgroundInfluentialCurrent status and perspective of tumor immunotherapy for head and neck squamous cell carcinoma
Yu, C., Li, Q., Zhang, Y., Wen, Z., Dong, H., & Mou, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.941750 · Cited by 55
“In the phase I trial KEYNOTE-012, pembrolizumab was 18% effective in the treatment of patients with recurrent metastatic HNSCC (Seiwert et al., 2016), and its safety and durable antitumor activity were confirmed by long-term follow-up (Mehra et al.”
BackgroundTinhofer, I., Braunholz, D., & Klinghammer, K. F. (2020) · Cancers of the Head & Neck · doi:10.1186/s41199-020-00056-4 · Cited by 55
Immunotherapy for head and neck cancer: where are we now and where are we going?
Bauml, J., Aggarwal, C., & Cohen, R. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.03.58 · Cited by 45
“The first trial evaluating the PD-1 inhibitor pembrolizumab in R/M HNSCC was KEYNOTE 012 (3,4).”
BackgroundImmuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities
Baik, C. S., Rubin, E. H., Forde, P. M., Mehnert, J. M., Collyar, D. E., Butler, M. O., Dixon, E. L., & Chow, L. Q. M. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3066 · Cited by 49
“In squamous cell carcinoma of the head and neck (SCCHN), an initial dose of 10mg/kg q2weekswas exploredwith subsequent expansion at the 200 mg q3 week flat dose, which demonstrated efficacy and tolerability with resultant FDA approval of the flat dose (43, 44).”
BackgroundSelf-citationXu, Y., Zhu, G., Maroun, C. A., Wu, X., Huang, D., Seiwert, T. Y., Liu, Y., Mandal, R., & Zhang, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.645170 · Cited by 46
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“Although numerous studies have shown that recurrent and metastatic HNSCC patients could benefit from immunotherapy [11-15], most of them are resistant to ICIs, with a 13-18% overall response rate [16].”
BackgroundKatsoulakis, E., Yu, Y., Apte, A., Leeman, J. E., Katabi, N., Morris, L. G. T., Deasy, J. O., Chan, T. A.-T., Lee, N. Y., Riaz, N., et al. (2020) · Oral Oncology · doi:10.1016/j.oraloncology.2020.104877 · Cited by 58
Radiation and Immune Checkpoint Blockade: From Bench to Clinic
Shabason, J. E., & Minn, A. J. (2017) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2017.03.002 · Cited by 44
Understanding the tumor microenvironment in head and neck squamous cell carcinoma
Sadeghirad, H., Shiravand, Y., Radfar, P., Ladwa, R., Perry, C., Han, X., Warkiani, M. E., Adams, M. N., Hughes, B. G. M., O'Byrne, K. J., et al. (2022) · Clinical & Translational Immunology · doi:10.1002/cti2.1397 · Cited by 52
“Instead, the study found that the tumors expressed both M1 and M2 macrophage markers, implying that macrophage differentiation is a continuum rather than two distinct states.33 Chen et al. discovered two types of TME in HNSCC: one with the presence of B cells and M1 macrophages, which was linked to better immunotherap…”
BackgroundInfluentialMetabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma
Huang, H., Li, S., Tang, Q., & Zhu, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.680955 · Cited by 49
PD-L1/PD-1 axis as a potent therapeutic target in breast cancer
Bastaki, S., Irandoust, M., Ahmadi, A., Hojjat‐Farsangi, M., Ambrose, P., Hallaj, S., Edalati, M., Ghalamfarsa, G., Azizi, G., Yousefi, M., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117437 · Cited by 51
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“Recent advances with immune checkpoint inhibitors have produced promising results, but not all patients benefit from anti-PD-1 therapy.(4,5) As a result, there is a tremendous need for more effective and less toxic systemic therapies that further enhance radiotherapy and immunotherapies such as immune checkpoint block…”
BackgroundAmaral, T. M. S., Osewold, M., Presser, D., Meiwes, A., Garbe, C., & Leiter, U. (2019) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.15845 · Cited by 46
Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors
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“Head and Neck Squamous Cell Carcinoma In a randomized, open-label, phase III trial, Ferris et al. explored the use of nivolumab monotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that had progressed within six months after platinum-based chemotherapy.”
BackgroundInfluentialPatel, P., Sun, L., Robbins, Y. L., Clavijo, P. E., Friedman, J., Silvin, C. J., Waes, C. V., Cook, J. A., Mitchell, J. B., & Allen, C. T. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1638207 · Cited by 47
“Response rates in patients with recurrent/metastatic malignancy for PD-1/PD-L1 blockade are 15–20% across multiple large trials.(2,3) Enhanced understanding of why so few patients respond, and how to reverse these mechanisms of resistance in a translationally relevant way may enhance response rates to ICB resulting in…”
BackgroundEder, T., Hess, A. K., Konschak, R., Stromberger, C., Jöhrens, K., Fleischer, V., Hummel, M., Balermpas, P., von der Grün, J., Linge, A., et al. (2019) · European Journal of Cancer · doi:10.1016/j.ejca.2019.04.015 · Cited by 56
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Progresses and Perspectives of Anti-PD-1/PD-L1 Antibody Therapy in Head and Neck Cancers
Yang, B., Liu, T., Qu, Y., Liu, H., Zheng, S. G., Cheng, B., & Sun, J. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00563 · Cited by 47
Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma
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Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer
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“Today, PD-1 inhibitors represent a newly approved therapeutic option for these patients [2, 3].”
Tonella, L., Giannoccaro, M., Alfieri, S., Canevari, S., & Cecco, L. D. (2017) · Current Treatment Options in Oncology · doi:10.1007/s11864-017-0472-2 · Cited by 43
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“%) patients had a grade 3 – 4 TRAE [2].”
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“PD-1 blocking therapy is to exert the tumor-killing ability of T cells by blocking the binding process of PD-1 receptors on the surface of T cells and PD-L1 on the surface of tumor cells [44 – 46].”
BackgroundClinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer
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“Although p16 + HNSCC patients had superior responses to PD-L1/PD-1 inhibitors than their p16( − ) counterparts, this was limited to recurrent and metastatic tumors [50 – 53].”
BackgroundStatins in Cancer Prevention and Therapy
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“Clinical trials and research studies have confirmed pembrolizumab’s efficacy and safety, both as a standalone treatment and combined with chemotherapy for recurrent or metastatic HNSCC [52,53].”
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“Recent trials investigating the efficacy of this first-line immune checkpoint inhibition for recurrent and/or metastatic HNSCC showed that PD-L1 expression is associated with an increased objective response rate in patients with a combined positive score (CPS) of ≥1, with a better response being seen when the CPS was…”
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“Immune checkpoint inhibition constitutes a well-established approach in the treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), malignant melanoma (MM), urothelial carcinoma (UC), head and neck squamous cell carcinoma (HNSCC), and Hodgkin lymphoma (HL) in a relapsed or refractory setting…”
Background
Metadata
- 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 › Dermatology › 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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