Cited by 1,745Cancer Immunotherapy and BiomarkersHead and Neck Cancer StudiesNonmelanoma Skin Cancer Studies

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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

Seiwert, Tanguy Y, Burtness, Barbara, Mehra, Ranee, Weiss, Jared, Berger, Raanan, Eder, Joseph Paul, Heath, Karl, McClanahan, Terrill, Lunceford, Jared, Gause, Christine, Cheng, Jonathan D, Chow, Laura Q·2016·The Lancet Oncology

DOI 10.1016/s1470-2045(16)30066-3

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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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BackgroundInfluential
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Background
Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors
Huang, L., Li, Y., Zhang, C., Jiang, A., Zhu, L., Mou, W., Li, K., Zhang, J., Cui, C., Cui, X., et al. (2025) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00819-2 · Cited by 28
Molecular basis, potential biomarkers, and future prospects of OSCC and PD-1/PD-L1 related immunotherapy methods
Cheng, Y., Song, Z., Chen, J., Tang, Z., & Wang, B. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25895 · Cited by 26
“A phase I clinical trial showed that pembrolizumab is relatively safe for the treatment of recurrent or metastatic HNSCC and is well-tolerated by patients [49].”
Background
EGFR Mutation and 11q13 Amplification Are Potential Predictive Biomarkers for Immunotherapy in Head and Neck Squamous Cell Carcinoma
Dou, S., Zhang, L., Wang, C., Yao, Y., Jiang, W. H., Ye, L., Li, J., Wu, S., Sun, D., Gong, X., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.813732 · Cited by 28
“Nonetheless, immunotherapy is applicable in a very limited proportion of patients (approximately 18%) (7, 9), leaving the vast majority vulnerable to trial and error methods for ICI treatment.”
Background
One shoot, three birds: Targeting NEK2 orchestrates chemoradiotherapy, targeted therapy, and immunotherapy in cancer treatment.
Huang, X., Zhang, G., Tang, T., Gao, X., & Liang, T. (2022) · Biochimica et biophysica acta. Reviews on cancer · doi:10.1016/j.bbcan.2022.188696 · Cited by 27
Precision Medicine Gains Momentum: Novel 3D Models and Stem Cell-Based Approaches in Head and Neck Cancer
Affolter, A., Lammert, A., Kern, J., Scherl, C., & Rotter, N. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.666515 · Cited by 34
Keytruda and PD-L1: a Real-World Example of Co-development of a Drug with a Predictive Biomarker
Emancipator, K. (2020) · The AAPS Journal · doi:10.1208/s12248-020-00525-1 · Cited by 31
“A methodical, stepwise, pooled analysis of data from the KEYNOTE-012 and KEYNOTE-055 studies was performed (45); CPS, which showed better sensitivity at lower PD-L1 expression levels, replaced TPS (Fig.”
Method
PD-L1 expression in the microenvironment and the response to checkpoint inhibitors in head and neck squamous cell carcinoma
Evrard, D., Hourseau, M., Couvelard, A., Paradis, V., Gauthier, H., Raymond, É., Halimi, C., Barry, B., & Faivre, S. J. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1844403 · Cited by 37
“Most clinical studies use the IHC 22C3 pharmDx assay (Dako, Carpinteria, CA) with the 22C3 antiPD-L1 antibody (Merck, Kenilworth, NJ) that were validated by the FDA for characterization of NSCLC (Table 2).(15,25,26) Table 2.”
Method
PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma
Smith, H. G., Mansfield, D., Roulstone, V., Kyula, J., McLaughlin, M., Patel, R., Bergerhoff, K. F., Paget, J. T.-E. H., Dillon, M. T., Khan, A., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3767 · Cited by 28
Therapeutic Implications of the Genetic Landscape of Head and Neck Cancer
Cho, J. M., Johnson, D. E., & Grandis, J. R. (2017) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2017.08.005 · Cited by 45
A comparison of weekly paclitaxel and cetuximab with the EXTREME regimen in the treatment of recurrent/metastatic squamous cell head and neck carcinoma.
Nakano, K., Marshall, S., Taira, S., Sato, Y., Tomomatsu, J., Sasaki, T., Shimbashi, W., Fukushima, H., Yonekawa, H., Mitani, H., et al. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.07.022 · Cited by 27
Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies
Flynn, M. J., & Larkin, J. (2017) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2017.1369956 · Cited by 30
“However, overall response rates (ORR) of between 10% and 25% have also been demonstrated in Phase I–III trials in several other tumor types in the refractory setting including in Hodgkin’s lymphoma [16], urothelial [17,18], renal [19], small cell lung [20], platinum-resistant ovarian [21], gastric [22] and anal cancer…”
BackgroundInfluential
Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Review of Current and Emerging Therapeutic Options
Moskovitz, J. M., Moy, J. D., Seiwert, T. Y., & Ferris, R. L. (2017) · The Oncologist · doi:10.1634/theoncologist.2016-0318 · Cited by 31
“Both of these trials evaluate the safety and efficacy in combination with CPI-444, an A2 receptor antagonist, or varlilumab, a CD27 costimulatory agonist (NCT02543645) [50].”
BackgroundMethodResultInfluentialSelf-citation
Head and neck cancer in 2016: A watershed year for improvements in treatment?
Algazi, A., & Grandis, J. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.196 · Cited by 27
Advancing Head and Neck Cancer Therapies: From Conventional Treatments to Emerging Strategies
Mordzińska-Rak, A., Telejko, I., Adamczuk, G., Trombik, T., Stepulak, A., & Błaszczak, E. (2025) · Biomedicines · doi:10.3390/biomedicines13051046 · Cited by 26
Sunitinib attenuates reactive MDSCs enhancing anti-tumor immunity in HNSCC.
Liu, J., Lin, W.-P., Su, W., Wu, Z.-Z., Yang, Q.-C., Wang, S., Sun, T., Huang, C.-F., Wang, X.-L., & Sun, Z.-S. (2023) · International Immunopharmacology · doi:10.2139/ssrn.4393625 · Cited by 26
Review of biomarkers for response to immunotherapy in HNSCC microenvironment
Chen, S., Yang, Y., He, S., Lian, M., Wang, R., & Fang, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1037884 · Cited by 29
“CXCL9 and CXCL10 are both reported to be significantly expressed in HNSCC, especially in TME and immunotherapy (10, 11).”
BackgroundMethod
Single-cell chemokine receptor profiles delineate the immune contexture of tertiary lymphoid structures in head and neck squamous cell carcinoma
Zhang, B., Li, H., Li, H., Xiong, D., Zhang, L., & Sun, Z. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216105 · Cited by 27
Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies
Meliante, P. G., Barbato, C., Zoccali, F., Ralli, M., Greco, A., VINCENTIIS, M. D., Colizza, A., Petrella, C., Ferraguti, G., Minni, A., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315384 · Cited by 27
Association of Neoadjuvant Pembrolizumab for Oral Cavity Squamous Cell Carcinoma With Adverse Events After Surgery in Treatment-Naive Patients.
Tang, A. L., O'Neil, T., McDermott, S., Tripathi, S., Tikhtman, R. O., Mark, J., Patil, Y. J., Tabangin, M., Altaye, M., Wise-Draper, T., et al. (2022) · JAMA Otolaryngology - Head and Neck Surgery · doi:10.1001/jamaoto.2022.2291 · Cited by 26
FLT3L release by NK cells enhances response to radioimmunotherapy in preclinical models of HNSCC
Bickett, T. E., Knitz, M. M., Darragh, L., Bhatia, S., Court, B. V., Gadwa, J., Bhuvane, S., Piper, M., Nguyen, D., Tu, H., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0971 · Cited by 26
“However, preclinical evidence suggests that these immunotherapies are ineffective at eliminating resistance to radiation (6, 7), and alternate options require further inquiry.”
Background
Treatment beyond progression with anti-PD-1/PD-L1 based regimens in advanced solid tumors: a systematic review
Spagnolo, F., Boutros, A., Cecchi, F., Croce, E., Tanda, E. T., & Queirolo, P. (2021) · BMC Cancer · doi:10.1186/s12885-021-08165-0 · Cited by 31
The Tumor Microenvironment and Immunotherapy of Oropharyngeal Squamous Cell Carcinoma
Welters, M. J. P., Santegoets, S. J. A. M., & van der Burg, S. H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.545385 · Cited by 27
Efficacy of axitinib in metastatic head and neck cancer with novel radiographic response criteria
Swiecicki, P. L., Bellile, E. L., Brummel, C. V., Brenner, J. C., & Worden, F. P. (2020) · Cancer · doi:10.1002/cncr.33226 · Cited by 32
Enhanced Radiation Sensitivity of Human Papillomavirus-Driven Head and Neck Cancer: Focus on Immunological Aspects
Özcan-Wahlbrink, M., Schifflers, C., & Riemer, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02831 · Cited by 26
“Indeed, the KEYNOTE-012 trial, testing the anti-PD-1 antibody pembrolizumab in PD-1-positive HNSCC patients, reported a higher rate of overall responses in patients with HPVpositive tumors (25%) as compared to HPV-negative ones (14%) (74).”
BackgroundResult
Systemic treatment in elderly head and neck cancer patients: recommendations for clinical practice
Szturz, P., Bossi, P., & Vermorken, J. B. (2019) · Current Opinion in Otolaryngology & Head & Neck Surgery · doi:10.1097/moo.0000000000000526 · Cited by 32
Current landscape and future directions of biomarkers for predicting responses to immune checkpoint inhibitors
Zhu, Y., Zhao, F., Li, Z., & Yu, J. (2018) · Cancer Management and Research · doi:10.2147/cmar.s167400 · Cited by 29
“15,89 Data were insufficient in other types of virus-infected tumors, such as HPV-infected cervical cancer and EBV-induced malignant tumors.”
Importance of choice of materials and methods in PD‐L1 and TIL assessment in oropharyngeal squamous cell carcinoma
Meulenaere, A. D., Vermassen, T., Creytens, D., Aspeslagh, S., Deron, P., Duprez, F., Rottey, S., Dorpe, J. V., & Ferdinande, L. (2018) · Histopathology · doi:10.1111/his.13650 · Cited by 26
Detailed analysis of adenosine A2a receptor (ADORA2A) and CD73 (5′-nucleotidase, ecto, NT5E) methylation and gene expression in head and neck squamous cell carcinoma patients
Vogt, T. J., Gevensleben, H., Dietrich, J., Kristiansen, G., Bootz, F., Landsberg, J., Goltz, D., & Dietrich, D. (2018) · Oncoimmunology · doi:10.1080/2162402x.2018.1452579 · Cited by 26
Checkpoint inhibitors in the treatment of urological malignancies
POPOVIC, L. S., Matovina-Brko, G., & Popovic, M. (2017) · ESMO Open · doi:10.1136/esmoopen-2017-000165 · Cited by 26
“Since 2010, numerous trials on different tumour types have been conducted and have resulted in the approval of these drugs for the treatment of melanoma, lung cancer, Hodgkin’s lymphoma(14) and head and neck cancers.(15) In urological tumours, nivolumab has been approved for the treatment of metastatic renal cancer (m…”
Background
Real-world treatment patterns and outcomes among individuals receiving first-line pembrolizumab therapy for recurrent/metastatic head and neck squamous cell carcinoma
Black, C. M., Hanna, G. J., Wang, L., Ramakrishnan, K., Goto, D., Turzhitsky, V. M., & Hair, G. M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1160144 · Cited by 24
Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation
van der Heijden, M., Essers, P., de Jong, M. C., de Roest, R. H., Sanduleanu, S., Verhagen, C. V. M., Hamming‐Vrieze, O., Hoebers, F. J. P., Lambin, P., Bartelink, H. G. M. M., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01470 · Cited by 24
The Common Costimulatory and Coinhibitory Signaling Molecules in Head and Neck Squamous Cell Carcinoma
Liao, P., Wang, H., Tang, Y., Tang, Y.-J., & Liang, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02457 · Cited by 27
Novel Delivery Systems for Checkpoint Inhibitors
Lamichhane, P., Deshmukh, R. R., Brown, J. K., Jakubski, S., Parajuli, P., Nolan, T. A., Raja, D. S., Badawy, M., Yoon, T., Zmiyiwsky, M., et al. (2019) · Medicines · doi:10.3390/medicines6030074 · Cited by 29
The Current Landscape of Immune Checkpoint Inhibition for Solid Malignancies
Keung, E. Z.-Y., & Wargo, J. A. (2019) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2019.02.008 · Cited by 24
Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go?
von der Grün, J., Rödel, F., Brandts, C., Fokas, E., Gückenberger, M., Rödel, C. M., & Balermpas, P. (2019) · Cancers · doi:10.3390/cancers11040472 · Cited by 28
“[36] Ib Keynote-012 NCT01848834 single-arm, multicentric Pembrolizumab † 60 complete”
Background
Anti-tumor immunity induced by ectopic expression of viral antigens is transient and limited by immune escape
Dharmaraj, N., Piotrowski, S. L., Huang, C. L., Newton, J. M., Golfman, L. S., Hanoteau, A., Koshy, S. T., Li, A. W., Pulikkathara, M. X., Zhang, B., et al. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1568809 · Cited by 32
Nanocomplex-based TP53 gene therapy promotes anti-tumor immunity through TP53- and STING-dependent mechanisms
Moore, E., Sun, L. D., Clavijo, P. E., Friedman, J., Harford, J., Saleh, A. D., Waes, C. V., Chang, E., & Allen, C. (2017) · Oncoimmunology · doi:10.1080/2162402x.2017.1404216 · Cited by 25
“HNSCC serves as a particularly attractive target for combination scL-53 and PD-1 mAb treatment given the high rate of TP53 genetic alterations and response rates of 15-20% to PDbased immune checkpoint blockade monotherapy in the recurrent/metastatic setting.(6,30,31)”
Background
Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy
Roussel, H., de Guillebon, E., Biard, L., Mandavit, M., Gibault, L., Fabre, E., Antoine, M., Hofman, P., Beau-Faller, M., Blons, H., et al. (2017) · Oncoimmunology · doi:10.1080/2162402x.2017.1286437 · Cited by 25
Inflammatory Arthritis Due to Immune Checkpoint Inhibitors: Challenges in Diagnosis and Treatment
Cappelli, L. C., Naidoo, J., Bingham, C. O., & Shah, A. A. (2016) · Immunotherapy · doi:10.2217/imt-2016-0117 · Cited by 21
Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit
Kostecki, K. L., Iida, M., Crossman, B. E., Salgia, R., Harari, P. M., Bruce, J. Y., & Wheeler, D. L. (2024) · Cancers · doi:10.3390/cancers16020312 · Cited by 26
“PDL1 is overexpressed in 50–60% of HNCs [122,123], and expression leads to both immune cell apoptosis [26,120] and T cell dysfunction [124,125].”
Background
Digital Slides as an Effective Tool for Programmed Death Ligand 1 Combined Positive Score Assessment and Training: Lessons Learned from the “Programmed Death Ligand 1 Key Learning Program in Head-and-Neck Squamous Cell Carcinoma”
Eccher, A., Fontanini, G., Fusco, N., Girolami, I., Graziano, P., Guerini‐Rocco, E., Martini, M., Morbini, P., Pantanowitz, L., Parwani, A. V., et al. (2021) · Journal of Pathology Informatics · doi:10.4103/jpi.jpi_63_20 · Cited by 27
“[6] Recent trials investigating the efficacy of first‐line immune‐checkpoint inhibition with the anti-PD-1 drug pembrolizumab in recurrent and/or metastatic HNSCC (KEYNOTE-048 and KEYNOTE-012) showed that PD-L1 expression is associated with an increased objective response rate, with better response when CPS ≥20.[7,8]…”
Background
Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation
Rühle, A., Grosu, A., Wiedenmann, N. E., Mix, M. D., Stoian, R., Niedermann, G., Baltas, D., Werner, M., Weber, W., Kayser, G., et al. (2020) · Theranostics · doi:10.7150/thno.48392 · Cited by 24
“Immune checkpoint inhibitors targeting PD-1 such as nivolumab and pembrolizumab have shown promising results in recurrent or metastatic HNSCC patients and have therefore gained approval for these indications [26-30].”
Background
Differential localization of PD-L1 and Akt-1 involvement in radioresistant and radiosensitive cell lines of head and neck squamous cell carcinoma.
Schulz, D., Streller, M., Piendl, G., Brockhoff, G., Reichert, T., Menevse, A. N., Beckhove, P., Hautmann, M. G., Bauer, R. J., & Ettl, T. (2020) · Carcinogenesis · doi:10.1093/carcin/bgz177 · Cited by 24
Combinations of immuno-checkpoint inhibitors predictive biomarkers only marginally improve their individual accuracy
Pallocca, M., Angeli, D., Palombo, F., Sperati, F., Milella, M., Goeman, F., Nicola, F. D., Fanciulli, M., Nisticò, P., Quintarelli, C., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1865-8 · Cited by 22
Induction of the Abscopal Effect with Immunotherapy and Palliative Radiation in Metastatic Head and Neck Squamous Cell Carcinoma: A Case Report and Review of the Literature
Shinde, A., Novak, J., Freeman, M., Glaser, S., & Amini, A. (2019) · Cureus · doi:10.7759/cureus.4201 · Cited by 24
Programmed Cell Death 1 Ligand 1 and Programmed Cell Death 1 Ligand 2 Are Expressed in Conjunctival Invasive Squamous Cell Carcinoma: Therapeutic Implications
Wolkow, N., Jakobiec, F., Afrogheh, A., Eagle, R., Pai, S., & Faquin, W. (2019) · American journal of ophthalmology-glaucoma · doi:10.1016/j.ajo.2018.12.020 · Cited by 24

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: Seiwert, Tanguy Y
Burtness, Barbara
Mehra, Ranee
Berger, Raanan
Eder, Joseph Paul
Lunceford, Jared
Chow, Laura Q
Venue: The Lancet Oncology
Publisher: Elsevier BV
Published: 2016-07
Volume: 17
Issue: 7
Pages: 956-965
ISSN: 1470-2045 (ISSN-L)
DOI: 10.1016/s1470-2045(16)30066-3
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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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

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