NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (Pembrolizumab) in high risk head and neck squamous cell carcinoma (HNSCC).

Julie E. Bauman University of Arizona Cancer Center, Tucson, AZ info_outline Julie E. Bauman, Jonathan Harris, Ravindra Uppaluri, Min Yao, Robert L. Ferris, Josephine Chen, Richard C. Jordan, Nikhil Purushottam Joshi, Srinivas Jujjuvaparu, Dukagjin Blakaj, Mohammad Razaq, Jawad Sheqwara, Loren K. Mell, Neilayan Sen, David Anthony Clump, Madhur Garg, Emrullah Yilmaz, Quynh-Thu Le

Authors Julie E. Bauman University of Arizona Cancer Center, Tucson, AZ info_outline Julie E. Bauman, Jonathan Harris, Ravindra Uppaluri, Min Yao, Robert L. Ferris, Josephine Chen, Richard C. Jordan, Nikhil Purushottam Joshi, Srinivas Jujjuvaparu, Dukagjin Blakaj, Mohammad Razaq, Jawad Sheqwara, Loren K. Mell, Neilayan Sen, David Anthony Clump, Madhur Garg, Emrullah Yilmaz, Quynh-Thu Le Organizations University of Arizona Cancer Center, Tucson, AZ, NRG Oncology Statistics and Data Management Center - ACR, Philadelphia, PA, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA, Case Comprehensive Cancer Center, University Hospital of Cleveland Medical Center, Cleveland, OH, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, Kaiser Permanente Department of Radiation Oncology, Dublin, CA, NRG Oncology Biospecimen Bank, University of California, San Francisco, San Francisco, CA, All India Institute of Medical Sciences, New Delhi, India, Cleveland Clinic Taussig Cancer Center, Cleveland, OH, Einstein-Montefiore Cancer Ctr, Bronx, NY, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Henry Ford Health System, Detroit, MI, University of California San Diego Moores Cancer Center, La Jolla, CA, Rush University Medical Center, Chicago, IL, University of Pittsburgh Cancer Institute, Pittsburgh, PA, Montefiore Medical Center, Bronx, NY, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA Abstract Disclosures Research Funding U.S. National Institutes of Health Pharmaceutical/Biotech Company Background: Pembrolizumab, an anti-PD1 monoclonal antibody, improves survival in advanced HNSCC. Patients with pathologic high risk, HPV-negative HNSCC have a high recurrence rate despite adjuvant cisplatin-IMRT (CRT), the current standard. Immunosuppression is induced by HNSCC and CRT, and may be reversible by targeting PD1. Methods: We conducted a phase I trial with expansion cohort to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to adjuvant CRT (NCT02775812). Eligibility: oral cavity, pharynx, or larynx primary; HPV-negative; pathologic high risk (positive margin or extranodal extension [ENE]); Zubrod 0-1. During phase I, patients enrolled in descending cohorts of 12 (Table). RP2S was declared if ≤ 3 dose-limiting toxicities (DLT) occurred. DLT was defined as ≥ Grade 3 non-hematologic adverse event (AE) related to pembrolizumab, immune-related (ir)AE requiring > 2 weeks of systemic steroids, or unacceptable delay in IMRT. The expansion cohort enrolled 20. Results: From Nov 2016-Oct 2018, 34 eligible patients enrolled at 22 NRG institutions. During the first cohort, 1 DLT was observed (Grade 3 fever). RP2S was declared as Schedule 3 and the expansion cohort triggered. Among all 34 patients, median age was 60 years (26-83); 68% were male; 74% had Zubrod 1; 85% had oral cavity; 88% had ENE; 21% had positive margin. During expansion, 3 additional patients with DLT were observed: wound infection; diverticulitis; nausea. No DLT unacceptably delayed IMRT. Twenty-eight of 34 (82%) received ≥ 5 doses of pembrolizumab; 17 (50%) got all 8 doses. Thirty-one of 32 (97%) DLT-evaluable patients received all adjuvant RT; 1 withdrew consent after starting protocol. Conclusions: The RP2S is pembrolizumab 200 mg IV q 3 weeks for 8 doses, starting the week before adjuvant CRT. This regimen was safe and feasible in a cooperative group setting. irAE were rare in this population. Clinical trial information: NCT02775812 Modality Week of Adjuvant IMRT Loading CRT Maintenance -1 1 2 3 4 5 6 9 12 15 18 21 24 27 IMRT (60 Gy, 2 Gy/Fx/day) – all schedules X X X X X X Cisplatin 40 mg/m 2 /week IV – all schedules X X X X X X Pembrolizumab 200 mg IV Schedule 3 (Starting) X X X X X X X X Schedule 2 (1 st De-escalation) X X X X X X X X Schedule 1 (2 nd De-escalation) X X X X X X X X