Early-Phase Trial of IAP Antagonist Tolinapant and Definitive Radiation in Cisplatin-Ineligible Patients with Advanced Head and Neck Cancer

Abstract Purpose: Tolinapant is an inhibitor of apoptosis protein antagonist that enhances apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) enhances antitumor immunity. We conducted an open-label, single-arm trial to evaluate the safety and feasibility of concurrent tolinapant and RT in cisplatin-ineligible patients with head and neck squamous cell carcinoma. Patients and Methods: Eligible patients had locally/locoregionally advanced head and neck squamous cell carcinoma, were human papillomavirus positive or negative, and were cisplatin ineligible. RT was delivered via intensity-modulated RT or proton therapy to a total of 70 Gy (35 fractions). Tolinapant was given every other week during RT at 180 mg/day with option to de-escalate to 90 mg for toxicity. Blood samples for research were collected at baseline and during RT. Results: Ten patients were enrolled. Treatment was well tolerated, with the most common adverse events similar to standard chemoRT (radiodermatitis, fatigue, dysphagia, pain, dysgeusia, and dry mouth). All patients completed treatment, and tolinapant dose de-escalation was not required. One patient experienced brief treatment interruptions due to severe dysphagia. Two patients developed distant metastases after treatment. Another patient developed second and third tumors outside the radiation field after treatment and was treated surgically. At a median follow-up of 13.8 months, the remaining 7 (70%) patients remained free of disease. Blood samples showed a burst of activated (CD38+HLA-DR+) CD8+ T lymphocytes in 40% of patients. Conclusions: Tolinapant + RT is well tolerated and induced proliferation of activated T cells in a subset of patients. Larger prospective studies are needed to better assess efficacy.