NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

Julie E Bauman,Neilayan Sen,Jonathan Harris,Robert L Ferris,Jawad Sheqwara,Quynh-Thu Le,David A Clump,Dukagjin M Blakaj,Nikhil P Joshi,Loren K Mell,Madhur K Garg,Emrullah Yilmaz,Srinivas Jujjuvaparu,Ravindra Uppaluri,Christina Henson,Min Yao,Pedro Torres-Saavedra,Richard C Jordan,Josephine Chen

doi:10.3390/cancers13122882

Abstract

Simple SummaryThe anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma. Patients with locoregional, pathologically high-risk disease recur frequently despite adjuvant cisplatin–radiation therapy. Targeting PD1 may reverse immunosuppression induced by cancer, chemotherapy, or radiation therapy. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule for adding fixed-dose pembrolizumab to standard adjuvant cisplatin–radiation therapy. Eligible patients had resected, human papillomavirus-negative, stage III–IV oral cavity, pharynx, or larynx cancer with extracapsular nodal extension or positive margin. A total of four dose-limiting toxicities were observed in 34 patients (fever, wound infection, diverticulitis, nausea). Three of four were successfully rechallenged with pembrolizumab. The recommended phase II schedule was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before adjuvant CRT. The regimen was safe and feasible in the cooperative group setting. Further development is warranted.The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cancer worldwide
III–IVb based upon the American Joint Commission on Cancer, version 7; in the case of oropharynx cancer, human papillomavirus (HPV)-negative status as determined by p16 immunohistochemistry confirmed by central review; age ≥18; Zubrod performance status 0–1; adequate hematologic function, including absolute neutrophil count ≥1500/mm3 and platelets ≥100,000/mm3 ; creatinine clearance (CrCl) ≥50 mL/min; adequate hepatic function including serum total bilirubin ≤1.5 times the upper limit of normal (ULN), aspartate aminotransferase and alanine transaminase ≤ 2.5 × ULN; coagulation studies ≤ 1.5 × ULN; negative pregnancy test for women of child-bearing potential; no active autoimmune disease requiring a diseasemodifying agent within the prior 2 years
The study re-opened to the expansion cohort from October 2017 and accrual was closed in October 2018 with a total of 37 patients enrolled and 34 analyzable patients, of whom 32 (12 phase I, 20 expansion cohort) were evaluable for dose-limiting toxicities (DLT)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cancer worldwide. Among the nearly 800,000 incident cases of HNSCC estimated annually, approximately 80% are caused by environmental carcinogenesis including direct exposures to tobacco, alcohol, and/or areca nut [1]. HNSCC, outcomes for HPV-negative HNSCC remain poor despite historical intensification approaches including altered radiation therapy (RT) fractionation [2], induction or adjuvant chemotherapy [3], or EGFR-targeted monoclonal antibodies (mAb) [4,5,6]. The adjuvant standard for patients who demonstrate a high-risk pathologic feature, a positive surgical margin or extracapsular nodal extension (ENE), is concurrent cisplatin and RT (CRT), which improved disease-free survival (DFS) and locoregional control (LRC) compared with RT alone in the landmark European Organization for the Research and Treatment of Cancer (EORTC) 22931 and Radiation Therapy Oncology. Despite the advance of CRT, patients with pathologically high-risk, HPV-negative disease have a 3-year DFS of only 30–50% [7,8,11], new intensification approaches represent a major unmet need

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