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      Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort

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          Treatment with pembrolizumab, an anti–programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) –positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported.

          Patients and Methods

          Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses.


          Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1–positive versus –negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively.


          Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.

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          Most cited references 33

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          Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large "areas" of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths). © 2014 UICC.
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            Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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              Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

                Author and article information

                J Clin Oncol
                J. Clin. Oncol
                Journal of Clinical Oncology
                American Society of Clinical Oncology
                10 November 2016
                19 September 2016
                19 September 2016
                : 34
                : 32
                : 3838-3845
                Laura Q.M. Chow, University of Washington, Seattle Cancer Care Alliance, Seattle, WA; Robert Haddad, Dana-Farber Cancer Institute, Boston, MA; Shilpa Gupta and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Ranee Mehra, Fox Chase Cancer Center, Philadelphia, PA; Joseph Paul Eder and Barbara Burtness, Yale University Cancer Center, New Haven, CT; Hyunseok Kang, Johns Hopkins University, Baltimore, MD; Jared Weiss, Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, NC; Amy Meister, Marisa Dolled-Filhart, Kumudu Pathiraja, and Jonathan D. Cheng, Merck, Kenilworth, NJ; Tanguy Y. Seiwert, The University of Chicago, Chicago, IL; Makoto Tahara, National Cancer Center Hospital East, Kashiwa; Kei Muro, Aichi Cancer Center Hospital, Nagoya, Japan; Raanan Berger, Sheba Medical Center, Tel Hashomer; Ravit Geva, Sourasky Medical Center, Tel-Aviv, Israel; Se-Hoon Lee and Bhumsuk Keam, Seoul National University Hospital; Hyun Cheol Chung, Yonsei University College of Medicine, Seoul, Korea; and Chia-Chi Lin, National Taiwan University Hospital, Taipei, Taiwan.
                Author notes
                Corresponding author: Laura Q.M. Chow, MD, Department of Medical Oncology, University of Washington, Box 358081, 825 E Eastlake Ave, MS: CE2-109, Seattle, WA 98109-1023; e-mail: lchow@ .
                © 2016 by American Society of Clinical Oncology

                Licensed under the Creative Commons Attribution 4.0 License:

                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 33, Pages: 8
                RC, Rapid Communication
                HNC5, Chemotherapy
                ORIGINAL REPORTS
                Rapid Communication
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