JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer
Abstract
Chemoradiotherapy (CRT) is the standard of care for locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). The immune checkpoint inhibitors nivolumab and pembrolizumab were recently approved by the US FDA for treatment of recurrent or metastatic HNSCC that are refractory to platinum chemotherapy. However, prospective studies incorporating immune checkpoint inhibitors in the definitive management of poor prognosis, nonmetastatic, locoregionally advanced HNSCC are lacking. The JAVELIN Head and Neck 100 study is a multinational, Phase III, double-blind, placebo-controlled, randomized clinical trial assessing the efficacy of avelumab, a PD-L1 inhibitor, in combination with CRT compared with placebo in combination with CRT for high-risk HNSCC.
Trial registration: Javelin Head and Neck 100; NCT 02952586.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), e359–e386 (2015).
- 2 Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 21(Suppl. 5), 184–186 (2010).
- 3 Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363(1), 24–35 (2010).
- 4 Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 17(4), 440–451 (2016).
- 5 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. 32(27), 2940–2950 (2014).
- 6 Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised Phase III trial. Lancet Oncol. 14(3), 257–264 (2013).
- 7 Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J. Clin. Oncol. 32(25), 2735–2743 (2014).
- 8 Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359(11), 1116–1127 (2008).
- 9 Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J. Clin. Oncol. 26(21), 3582–3589 (2008).
- 10 Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, Phase II trial. Lancet Oncol. 17(10), 1374–1385 (2016).
- 11 Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN solid tumor): pooled results from two expansion cohorts of an open-label, Phase I trial. Lancet Oncol. 19(1), 51–64 (2017).
- 12 Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN solid tumor): a Phase Ia, multicohort, dose-escalation trial. Lancet Oncol. 18(5), 587–598 (2017). • Phase Ia clinical trial demonstrates the safety of avelumab in previously treated solid tumors.
- 13 Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN solid tumor): dose-expansion cohort of a multicentre, open-label, Phase Ib trial. Lancet Oncol. 18(5), 599–610 (2017).
- 14 . The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252–264 (2012).
- 15 . Immunology and immunotherapy of head and neck cancer. J. Clin. Oncol. 33(29), 3293–3304 (2015).
- 16 Pembrolizumab for platinum- and cetuximab- refractory head and neck cancer: results from a single-arm, Phase II study. J. Clin. Oncol. 35(14), 1542–1549 (2017).
- 17 Durvalumab for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): preliminary results from a single-arm, Phase II study. Ann. Oncol. 28(Suppl. 5), mdx374 (2017).
- 18 Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375(19), 1856–1867 (2016).
- 19 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 Ib trial. Lancet Oncol. 17(7), 956–965 (2016).
- 20 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. J. Clin. Oncol. 34(32), 3838–3845 (2016).
- 21 Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) Phase III KEYNOTE-040 trial. Ann. Oncol. 28(Suppl. 5), mdx440.040 (2017).
- 22 . Amidst the excitement: a cautionary tale of immunotherapy, pseudoprogression and head and neck squamous cell carcinoma. Oral Oncol. 62, 147–148 (2016).
- 23 Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res. 27(1), 151–153 (2017).
- 24 . PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19(7), 813–824 (2007).
- 25 Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol. Res. 3(10), 1148–1157 (2015).
- 26 Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab. J. Thorac. Oncol. 11(11), 1993–2005 (2016).
- 27 Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget 7(23), 33498–33511 (2016).
- 28 Avelumab (Msb0010718c; Anti-Pd-L1) in patients with advanced cancer: safety data from 1300 patients enrolled in the Phase Ib Javelin solid tumor trial. J. Clin. Oncol. 34(Suppl. 15), 3055 (2017). • Safety data from 1300 patients enrolled on Phases I and II clinical trials of avelumab in advanced solid tumors.
- 29 . The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol. Res. 3(5), 436–443 (2015).
- 30 Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6(226), 226ra32 (2014).
- 31 . Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin. Oncol. 8(3), 151–160 (2011).
- 32 Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39(1), 74–88 (2013).
- 33 . Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin. Cancer Res. 20(21), 5384–5391 (2014).
- 34 . The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci. Immunol. 1(3), eaag1266 (2016).
- 35 Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114(3), 589–595 (2009).
- 36 Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 74(19), 5458–5468 (2014).
- 37 Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase II study. J. Clin. Oncol. 30(17), 2046–2054 (2012).
- 38 Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase II trial. Ann. Oncol. 24(1), 75–83 (2013).
- 39 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364(26), 2517–2526 (2011).
- 40 Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379(24), 2342–2350 (2018).
- 41 Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027), 1540–1550 (2015).
- 42 Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377(20), 1919–1929 (2017). •• In this landmark clinical trial, the addition of a PD-L1 inhibitor improved progression-free survival in locoregionally advanced lung cancer.
- 43 PET-CT surveillance versus neck dissection in advanced head and neck cancer. N. Engl. J. Med. 374(15), 1444–1454 (2016).
- 44 The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy – head and neck scale. A study of utility and validity. Cancer 77(11), 2294–2301 (1996).
- 45 Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual. Life Res. 22(7), 1717–1727 (2013).