The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
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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The Distinctive Features behind the Aggressiveness of Oral and Cutaneous Squamous Cell Carcinomas
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“In the case of HNSCC, several populations of CAFs have been described that, according to specific markers, can be classified into three subgroups: classical CAFs, normal activated fibroblasts, and elastic fibroblasts.”
BackgroundInfluentialHughes, R., Gebeyehu, R. R., Kalada, J., Lycan, T., Frizzell, B., Kinney, R. D., D'Agostino, R., Bunch, P., Triozzi, P., Zhang, W., et al. (2023) · Future Oncology · doi:10.2217/fon-2022-1146 · Cited by 11
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The Chemokines Initiating and Maintaining Immune Hot Phenotype Are Prognostic in ICB of HNSCC
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“Application of immune checkpoint blockage (ICB) has significantly improved the prognosis of multiple tumors, but exerted limited effects on head and neck squamous cell carcinoma (HNSCC) because less than 30% of the patients got a better prognosis (Curran et al., 2010; Topalian et al., 2012; Seiwert et al., 2016; Clark…”
BackgroundIL-2 complex recovers steroid-induced inhibition in immunochemotherapy for head and neck cancer
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PD-L1 expression in recurrent head and neck squamous cell carcinoma
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“The safety and tolerability of pembrolizumab in relapsing or metastatic SCCHN were also evaluated in the Keynote-012 study [34].”
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“Trials of ICIs in HNSCC, for example, the PD-1 inhibitors pembrolizumab [7] and nivolumab [8], have demonstrated response rates in the region of 20% and improved overall survival in R/M patient groups.”
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Novel Treatment Options in Head and Neck Cancer
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“Specifically, in the setting of HPV-associated oropharyngeal cancer, there has been interest in using circulating tumor HPV DNA (ctHPVDNA) as a biomarker for HPV-associated oropharyngeal squamous cell carcinoma for post-treatment surveillance.”
BackgroundObesity enhances the response to neoadjuvant anti‐PD1 therapy in oral tongue squamous cell carcinoma
Tan, X.-R., Li, G., Deng, H., Xiao, G., Wang, Y.-Q., Zhang, C.-Z., & Chen, Y.-F. (2024) · Cancer Medicine · doi:10.1002/cam4.7346 · Cited by 10
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BackgroundNeoadjuvant chemotherapy for advanced oral cavity cancer
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“14,18,57 Immunotherapy using immune checkpoint inhibitors has demonstrated efficacy in recurrent or metastatic head and neck mucosal SCC. 58,59 These promising results have prompted investigations into the potential impact of immunotherapy in earlier stages of the disease, including in the…”
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“From the pooled 791 patients who participated in clinical trials of PD-1 inhibitors, 11,14,15,32 we identified 46 trAEs, with the most frequent potential irAEs involving the endocrine, cutaneous, and gastrointestinal systems.”
BackgroundClonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response
Nemunaitis, J. J., Stanbery, L., Willoughby, D., Bognar, E., Brun, S., Walter, A., Monk, B. J., Rocconi, R. P., Choucair, K., & Coleman, R. L. (2023) · Cancers · doi:10.3390/cancers15235616 · Cited by 14
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“4 Currently, in the first-line treatment for P/R/M cervical cancer, pembrolizumab is recommended for programmed death-ligand 1 (PD-L1)-positive patients.”
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“However, so far, durable response rates are low and outcomes are generally not superior to the current standards of care for LA HNSCCs [9–13].”
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DDX1 is a prognostic biomarker and correlates with immune infiltrations in hepatocellular carcinoma
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TP53 mutation-associated immune infiltration and a novel risk score model in HNSCC
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Sex-related disparities in outcomes of cholangiocarcinoma patients in treatment trials
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Treatment Options in Early Stage (Stage I and II) of Oropharyngeal Cancer: A Narrative Review
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“The results showed that this signature is significantly associated with the response rate and PFS and, due to its high negative predictive value, is a potential biomarker for the exclusion of patients from immunotherapy [78].”
BackgroundMethodPyroptosis patterns and immune infiltrates characterization in head and neck squamous cell carcinoma
Deng, H.-X., Wei, Z.-Y., Qiu, S.-J., Ye, D., Gu, S., Shen, Y., Shen, Z.-S., Jin, Y., & Zhou, C. (2022) · Journal of clinical laboratory analysis (Print) · doi:10.1002/jcla.24292 · Cited by 10
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“Early studies of pembrolizumab in a similar population (KEYNOTE-012) also used a cut-off point of TC1% (11).”
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“Twenty-three out of 28 patients had maintained tumor shrinkage over six months (37).”
BackgroundMa, B., Jiang, H., Luo, Y., Liao, T., Xu, W., Wang, X., Dong, C., Ji, Q., & Wang, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.692079 · Cited by 12
Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer
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“However, the checkpoint blockade immune therapeutics does not respond to all patients and the observed objective response rates are in the range of only 16% to 25% [15, 16].”
Squamous cell carcinoma of the external ear: 170 cases treated with Mohs surgery.
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Baseline monocyte and its classical subtype may predict efficacy of PD-1/PD-L1 inhibitor in cancers
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“A phase 1b clinical trial demonstrated that the overall response rate (ORR) of squamous cell carcinoma of the head and neck (HNSCC) cases receiving pembrolizumab was 18%, and complete response was 5%[37].”
BackgroundMethodModel Informed Dosing Regimen and Phase I Results of the Anti‐PD‐1 Antibody Budigalimab (ABBV‐181)
Powderly, J. D., Spira, A. I., Kondo, S., Doi, T., Luke, J. J., Rasco, D. W., Gao, B., Tanner, M., Cassier, P. A., Gazzah, A., et al. (2020) · Clinical and Translational Science · doi:10.1111/cts.12855 · Cited by 13
Combining immunotherapy and radiotherapy in head and neck squamous cell cancers: which perspectives?
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Genomic Perspective on Mouse Liver Cancer Models
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“Interferon gamma (IFNG) 6 scores that predict response to anti-PD-1 (pembrolizumab) therapy are derived from the average expression of the six genes (Cxc110, Cxcl9, Ido1, Stat1, H2-Ea, and Ifng) where higher mean expression values were associated with better response [79].”
MethodSurvival in Early Phase Immuno-Oncology Trials: Development and Validation of a Prognostic Index
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Leveraging Genomics for Head and Neck Cancer Treatment
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Local Immune Responsiveness of Mice Bearing Premalignant Oral Lesions to PD-1 Antibody Treatment
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“For example, several studies have shown clinically meaningful responses following treatment of patients bearing head and neck squamous cell carcinoma (HNSCC) with antibodies to programmed death receptor-1 (PD-1) [1,2].”
BackgroundInfluentialResponse Evaluation in Head and Neck Oncology: Definition and Prediction
Hoffmann, T. K., Schuler, P., Laban, S., Grässlin, R., Beer, M., Beer, A., Friebe-Hoffmann, U., Bullinger, L., Möller, P., & Wiegel, T. (2017) · ORL · doi:10.1159/000455726 · Cited by 10
Atypical autoimmune adverse effects with checkpoint blockade therapies
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Emerging Immune Checkpoint Inhibitors for the Treatment of Oropharyngeal Squamous Cell Carcinoma
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The European Larynx Organ Preservation Study [MK-3475-C44]
Wichmann, G., Wald, T., Pirlich, M., Napp, J., Münter, I., Asendorf, T., Tostmann, R., Vogt, J., Vogel, K., Meuret, S., et al. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1433238 · Cited by 9
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“…toxicity (hypothyroidism 13/211; 6.2%), which is much lower than the rates observed in clinical trials of pembrolizumab treatment in HNSCC including Keynote-012 (hypothyroidism 10% 21 ), Keynote-048 (pem-brolizumab monotherapy arm, hypothyroidism 18% 16 ), Keynote-040 (hypothyroidism 15% 13 ).”
ResultInfluentialFeng, Y., Li, X., Yang, B., Li, M., Du, Y., Wang, J., Liu, S., Gong, L., Li, L., & Gao, L. (2024) · Oncology Reports · doi:10.3892/or.2024.8738 · Cited by 9
Huang, Y.-F., & Yuan, J. (2024) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2024.2344669 · Cited by 9
“For example, immune-checkpoint inhibitors such as pembrolizumab in metastatic melanoma treatment [19] had dramatic anticancer activity in early-phase SATs and many indications of pembrolizumab achieved the FDA AA [19,40–47].”
BackgroundXu, X., Luo, S., Zhao, X., Tang, B., Zhang, E., Liu, J., & Duan, L. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.130921 · Cited by 10
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Agelaki, S., Boukovinas, I., Athanasiadis, I., Trimis, G., Dimitriadis, I., Poughias, L., Morais, E., Sabale, U., Benčina, G., & Athanasopoulos, C. (2024) · Cancer Medicine · doi:10.1002/cam4.6916 · Cited by 9
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“Predictive biomarkers have recently been described for immunotherapy in the palliative treatment of patients with recurrent and/or metastatic head and neck cancer (15, 16).”
Kumar, A., Kapoor, A., Noronha, V., Patil, V., Joshi, A., Menon, N., Janu, A., Mahajan, A., Rajendra, A., Agarawal, A., et al. (2023) · South Asian Journal of Cancer · doi:10.1055/s-0044-1788649 · Cited by 9
The applications and techniques of organoids in head and neck cancer therapy
Hao, Q., Tan, X., Zhang, W., Zhou, Y., Chen, S., Zha, D., Wang, S., & Wen, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1191614 · Cited by 10
Xu, P., Cheng, C., Dong, S., Wang, T., Xie, J., & Li, P. (2023) · BMC Cancer · doi:10.1186/s12885-023-10597-9 · Cited by 9
Bibliometric study on the knowledge graph of immunotherapy for head and neck cancer
Wang, J., Gong, Z.-P., & Yu, M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.942777 · Cited by 9
Schmidl, B., Vossenkämper, K.-A., Stark, L., Boxberg, M., Stögbauer, F., Feigl, K., Winter, C., Pickhard, A., Wollenberg, B., & Wirth, M. (2022) · European Archives of Oto-Rhino-Laryngology · doi:10.1007/s00405-022-07775-z · Cited by 9
“In KEYNOTE-012, immunotherapy with Pembrolizumab led to a response of 32% in HPV-positive, and 18% in HPV-negative recurrent or metastatic HNSCC [21, 43].”
BackgroundJiang, S.-T., Ding, X.-Z., Wu, Q.-Q., Cheng, T., Xu, M.-Y., & Huang, J.-F. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.980986 · Cited by 9
“Immunotherapy can activate the host’s natural defense system to identify and remove tumor cells and has shown unparalleled survival benefits in various cancers (5).”
BackgroundBlocker, S., Cook, J., Everitt, J., Austin, W. M., Watts, T., & Mowery, Y. M. (2022) · American Journal of Pathology · doi:10.1016/j.ajpath.2022.06.003 · Cited by 9
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“Following the promising results of the openlabel, multicenter, phase 1b trial KEYNOTE-012, the PD-1 antibody received approval via accelerated process for patients with recurrent and/or metastatic HNSCC (R/M HNSCC) as a second-line treatment option after progression on standard platinum-based therapy (9, 10).”
BackgroundInfluentialKramb, F., Doerfer, C., Meiwes, A., Ramakrishnan, K., Eigentler, T., Garbe, C., Keim, U., & Leiter, U. (2021) · Acta Dermato-Venereologica · doi:10.2340/actadv.v101.751 · Cited by 9
Clancy, K., Hamill, C. S., O'Neill, W., Vu, B., Thuener, J., Gui, S., Li, S., Fowler, N., Rezaee, R., Lavertu, P., et al. (2021) · Cancers · doi:10.3390/cancers13194861 · Cited by 9
“The results from phase I and II trials with pembrolizumb were mixed in R/M OPSCC patients; some studies showed that p16+ status was associated with an improved response rate, while another study reported similar clinical benefit between p16+ and p16- patients [5,15,16].”
ResultPreoperative Immunotherapy in the Multidisciplinary Management of Oral Cavity Cancer
Philips, R. H. W., Han, C. J., Swendseid, B. P., Curry, J., Argiris, A. E., Luginbuhl, A., & Johnson, J. M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.682075 · Cited by 11
“Pembrolizumab and nivolumab, IgG4 monoclonal antibodies that target PD-1, are currently approved for recurrent/metastatic HNSCC based on well documented efficacy in clinical trials (22, 23).”
BackgroundProgress of molecular targeted therapy for head and neck cancer in clinical aspects
Nakano, K. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00032-5 · Cited by 12
“Other biomarkers related to cancer immune are being investigated [68], but an appropriate new marker that can be made available in clinical practice has not been established.”
BackgroundLuo, D., Kuang, F. L., Du, J., Zhou, M., Peng, F., Gan, Y., Fang, C., Yang, X., Li, B., & Su, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.677609 · Cited by 7
Oral Tongue Cancer in a Patient with Fanconi Anemia: A Case Report and Literature Review
Deng, S., Ye, W., Zhang, S.-C., Zhu, G.-Q., Zhang, P., Song, Y., Duan, F., Lang, J., & Lu, S. (2021) · Cancer Management and Research · doi:10.2147/cmar.s301582 · Cited by 9
“ICIs are recommended to treat recurrent or metastatic HNSCC patients.(51,52) Since other treatment options were limited by”
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Amy, D. P. B., Shalabi, A., Finfter, O., Birenzweig, Y., & Zadik, Y. (2020) · Immunotherapy · doi:10.2217/imt-2019-0162 · Cited by 15
Lactate induces PD-L1 in HRASG12V-positive oropharyngeal squamous cell carcinoma
Verma, A. K., Messerli, S. M., & Miskimins, W. K. (2020) · Oncotarget · doi:10.18632/oncotarget.27348 · Cited by 8
“Furthermore, PD-L1 expression by tumor cells is not always predictive of patient response to PD-1/PD-L1 blockade [17, 31].”
BackgroundCorneli, P., Conforti, C., Retrosi, C., Vezzoni, R., di Meo, N., Piccolo, V., Farinazzo, E., Russo, T. P., Rizzi, G. M., Giuffrida, R., et al. (2020) · Dermatologic Therapy · doi:10.1111/dth.13250 · Cited by 9
“Some trials demonstrated the usefulness of PD-1 antibodies in recurrent and metastatic SCC of the head and neck, suggesting the potential efficacy in cSCC (Ferris et al., 2016; Seiwert et al., 2016).”
Pembrolizumab for the treatment of head and neck squamous cell cancer
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Melanoma-associated antigen A11 reduces erlotinib and afatinib efficacy in head and neck cancer.
Hartmann, S., Zwick, L., Maurus, K., Fuchs, A., Brands, R., Seher, A., Kübler, A., & Müller-Richter, U. (2017) · Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery · doi:10.1016/j.jcms.2017.12.014 · Cited by 9
Immunogenomics: using genomics to personalize cancer immunotherapy
Siniard, R. C., & Harada, S. (2017) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-017-2140-0 · Cited by 10
Actualités sur l’immunothérapie en pathologie des voies aérodigestives supérieures
Outh-Gauer, S., Tourneau, C. L., Broudin, C., Scotté, F., Roussel, H., Hans, S., Mandavit, M., Tartour, É., & Badoual, C. (2017) · Annales de Pathologie · doi:10.1016/j.annpat.2016.12.013 · Cited by 10
Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer
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“Head and neck cancer [14] 2016 Pembro squa”
BackgroundOkuyama, K., Naruse, T., Matsushita, Y., Fujimoto, J., Yanamoto, S., Lei, Y. L., & Hu, J. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02609-6 · Cited by 9
“Subsequent phase III trials, KEY-NOTE-040 and KEYNOTE-048, further established pembrolizumab as a standard first-line therapy for PD-L1–positive disease [9–11].”
Immune biomarkers for head and neck cancer
Sobhani, N., D'Angelo, A., Kugeratski, F. G., Nguyen, T., Morris, R. M., Roudi, R., Kia, N., Pianta, L., Morello, R., Winter, S., et al. (2025) · Cancer Immunology and Immunotherapy · doi:10.1007/s00262-025-04233-7 · Cited by 8
“Several biomarkers are being investigated to predict ICI response, comprising PD-L1 expression, TMB, MSI, TME features, NLR, and IFN-γ signatures [41, 51, 102, 163].”
InfluentialZwing, N., von Voithenberg, L. V., Alberti, L., Gabriel, S., Rodríguez, J. M. M., Feddersen, R., Foy, J.-P., Damiola, F., Gadot, N., Saintigny, P., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011851 · Cited by 8
“10 11 44 Immu-nologically hot tumors and panCK-high tumor regions, identified based on the 27-gene expression signature, showed increased IFN-γ and IFN-α signaling as well as upregulation of components of MHC-I.”
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“The FDA ’ s approval of nivolumab and pembrolizumab in 2016 marked the beginning of an era of immunotherapy for R/M HNSCC patients (9, 10).”
Barham, W. T., Stagg, M. P., Mualla, R., Dileo, M. D., & Kansara, S. (2025) · Cancers · doi:10.3390/cancers17010144 · Cited by 8
“This recommendation follows the results of the KEYNOTE-012 and KEYNOTE-040 trials in platinum-refractory HNSCC patients [51,52].”
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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