Evolving Role of Immunotherapy in Recurrent Metastatic Head and Neck Cancer

Authors: Xiuning Le MD, PhD 1 , Renata Ferrarotto MD 1 , Trisha Wise-Draper MD, PhD 2 and Maura Gillison MD, PhD 1
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  • 1 Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and
  • 2 Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, Ohio.
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Immunotherapy has revolutionized cancer treatment in the past 2 decades, mostly with immune checkpoint blockade approaches. In squamous cell carcinoma of the head and neck (SCCHN), the initial efficacy of immunotherapy was observed in patients with recurrent or metastatic (R/M) disease who received other prior systemic treatment. As monotherapy, anti–PD-1 therapies induce responses in 13% to 18% of patients. More recently, immunotherapy in combination with cytotoxic chemotherapy demonstrated greater safety and efficacy as first-line systemic treatment compared with chemotherapy alone. In R/M SCCHN, the most important benefit of immunotherapy is the significantly improved overall survival, especially in patients with PD-L1–positive tumors. As of 2019, immunotherapy can be used as first-line or subsequent treatment of R/M SCCHN. Many ongoing trials are evaluating immunotherapy combinations or novel immunotherapy strategies, aiming to improve response rate and overall survival. As new targets are identified and new approaches are leveraged, the role of immunotherapy in R/M SCCHN continues to evolve.

Submitted January 22, 2020; accepted for publication May 12, 2020.

Disclosures: Dr. Le has disclosed that she receives consulting fees from Eli Lilly, AstraZeneca, EMD Serono, and grant/research support from Eli Lilly and Boehringer Ingelheim. Dr. Ferrarotto has disclosed that she receives consulting fees from Regeneron-Sanofi, Ayala Pharma, Klus Pharma, Medscape, and Cellestia Biotech; has received grant/research support from AstraZeneca, Merck, Genentech, Pfizer. Dr. Wise-Draper has disclosed that she receives consulting fees from Shattuck Laboratories, and grant/research support from Bristol-Myers Squibb, Merck, and Tesaro/GlaxoSmithKline. Dr. Gillison has disclosed that she receives consulting fees from Merck, Bristol-Myers Squibb, Roche, Genocea, EMD Serono, Bayer, New Link Genetics, Aspyrian Therapeutics, TRM Oncology, Amgen, AstraZeneca, and Celgene, and grant/research support from Bristol-Myers Squibb and Merck.

Correspondence: Maura Gillison, MD, PhD, Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Email: mgillison@mdanderson.org
  • 1.

    Bray F, Ferlay J, Soerjomataram I, . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Howlader N, Noone AM, Krapcho M, eds. SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Available at: https://seer.cancer.gov/csr/1975_2014/. Based on November 2016 SEER data submission. Posted April 2017.

  • 3.

    Gillison ML, Koch WM, Capone RB, . Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709720.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Gillison ML, Chaturvedi AK, Anderson WF, . Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol 2015;33:32353242.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Shi W, Kato H, Perez-Ordonez B, . Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma. J Clin Oncol 2009;27:62136221.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Tota JE, Best AF, Zumsteg ZS, . Evolution of the oropharynx cancer epidemic in the United States: moderation of increasing incidence in younger individuals and shift in the burden to older individuals. J Clin Oncol 2019;37:15381546.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Chaturvedi AK, D’Souza G, Gillison ML, . Burden of HPV-positive oropharynx cancers among ever and never smokers in the U.S. population. Oral Oncol 2016;60:6167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Ang KK, Harris J, Wheeler R, . Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:2435.

  • 9.

    Carlander AF, Grønhøj Larsen C, Jensen DH, . Continuing rise in oropharyngeal cancer in a high HPV prevalence area: a Danish population-based study from 2011 to 2014. Eur J Cancer 2017;70:7582.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Louie KS, Mehanna H, Sasieni P. Trends in head and neck cancers in England from 1995 to 2011 and projections up to 2025. Oral Oncol 2015;51:341348.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Lydiatt WM, Patel SG, O’Sullian B, . Head and neck cancers-major changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin 2017;67:122–137. doi:10.3322/caac.21389

    • Crossref
    • Export Citation
  • 12.

    Ang KK, Zhang Q, Rosenthal DI, . Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014;32:29402950.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Vermorken JB, Mesia R, Rivera F, . Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:11161127.

  • 14.

    Guigay J, Keilholz U, Mesia R, . TPExtreme randomized trial: TPEx versus Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma [abstract]. J Clin Oncol 2015;33(Suppl):Abstract TPS6087.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Guigay J, Fayette J, Mesia R, . TPExtreme randomized trial: TPEx versus Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 6002.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Weber JS, O’Day S, Urba W, . Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008;26:59505956.

  • 17.

    Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:13501355.

  • 18.

    Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget 2017;8:9767197682.

  • 19.

    Ishida Y, Agata Y, Shibahara K, . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:38873895.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Dong H, Strome SE, Salomao DR, . Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793800.

  • 21.

    Seiwert TY, Burtness B, Mehra R, . 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. Lancet Oncol 2016;17:956965.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Mehra R, Seiwert TY, Gupta S, . Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 2018;119:153159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Bauml J, Seiwert TY, Pfister DG, . Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 2017;35:15421549.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Ferris RL, Blumenschein G Jr, Fayette J, . Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:18561867.

  • 25.

    Ferris RL, Blumenschein G Jr, Fayette J, . Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol 2018;81:4551.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Gillison ML, Blumenschein G Jr, Fayette J, . CheckMate 141: 1-year update and subgroup analysis of nivolumab as first-line therapy in patients with recurrent/metastatic head and neck cancer. Oncologist 2018;23:10791082.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Cohen EEW, Soulières D, Le Tourneau C, . Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 2019;393:156167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Burtness B, Harrington KJ, Greil R, . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:19151928.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Burtness B, Harrington KJ, Greil R, . KEYNOTE-048: phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Ann Oncol 2018;29(Suppl 8):VIII729.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Rischin D, Harrington KJ, Greil R, . Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 6000.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Hirsch FR, McElhinny A, Stanforth D, . PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017;12:208222.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Baitsch L, Baumgaertner P, Devêvre E, . Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest 2011;121:23502360.

  • 33.

    Tivol EA, Borriello F, Schweitzer AN, . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541547.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Waterhouse P, Penninger JM, Timms E, . Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995;270:985988.

  • 35.

    Wolchok JD, Chiarion-Sileni V, Gonzalez R, . Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:13451356.

  • 36.

    Wolchok JD, Rollin L, Larkin J. Nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:25032504.

  • 37.

    Hellmann MD, Ciuleanu TE, Pluzanski A, . Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:20932104.

  • 38.

    Hellmann MD, Paz-Ares L, Bernabe Caro R, . Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:20202031.

  • 39.

    Siu LL, Even C, Mesía R, . Safety and efficacy of durvalumab with or without tremelimumab in patients with PD-L1-low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical trial. JAMA Oncol 2019;5:195203.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Licitra LF, Haddad RI, Even C, . EAGLE: a phase 3, randomized, open-label study of durvalumab (D) with or without tremelimumab (T) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 6012.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Komiya T, Huang CH. Updates in the clinical development of epacadostat and other indoleamine 2,3-dioxygenase 1 inhibitors (IDO1) for human cancers. Front Oncol 2018;8:423.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Mitchell TC, Hamid O, Smith DC, . Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol 2018;36:32233230.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Long GV, Dummer R, Hamid O, . Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol 2019;20:10831097.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Sporn MB, Roberts AB. TGF-beta: problems and prospects. Cell Regul 1990;1:875882.

  • 45.

    Lan Y, Zhang D, Xu C, . Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med 2018;10:eaan5488.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Strauss J, Gatti-Mays ME, Tedman J, . Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 3007.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Strauss J, Gatti-Mays ME, Cho B, . Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies [abstract]. Cancer Res 2019;79(13 Suppl):Abstract CT075.

    • Search Google Scholar
    • Export Citation
  • 48.

    Taylor MH, Rasco DW, Brose MS, . A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 6016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Glisson B, Massarelli E, William WN, . Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer [abstract]. Ann Oncol 2017;28(Suppl):Abstract 2757.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50.

    Massarelli E, William W, Johnson F, . Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol 2019;5:6773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Park JH, Rivière I, Gonen M, . Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018;378:449459.

  • 52.

    Maude SL, Laetsch TW, Buechner J, . Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439448.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med 2018;379:6473.

  • 54.

    Nagarsheth N, Norberg S, Doran SL, . Regression of epithelial cancers in humans following T-cell receptor gene therapy targeting human papillomavirus-16 E7 [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 3043.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Blumenschein GR, Bourgogne A, Reinhardt C, . Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC [abstract]. J Clin Oncol 2018;36(Suppl):Abstract TPS78.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56.

    Pfister DG, Spencer S, Adelstein D, . NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 1.2020. Accessed May 20, 2020. To view the most recent version, visit NCCN.org

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