Abstract CT037: Early-phase trial of IAP antagonist tolinapant and definitive radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer
Authors: Nicole C. Schmitt, William A. Stokes, James E. Bates, Jill Remick, Mark McDonald, Soumon Rudra, Brendan L. Kinney, Madison Steininger, Mosope Oyewole, Azeem S. Kaka, Jennifer H. Gross, Mihir R. Patel, Dong M. Shin, Conor Steuer, Nabil F. Saba
Journal: Cancer Research (2025)

Abstract Background: Tolinapant is an orally bioavailable inhibitor of apoptosis ( IAP) antagonist that enhances intrinsic and extrinsic apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) also enhances multiple facets of the anti-tumor immune response. Methods: This is an early phase, open-label, single-arm trial to evaluate the safety and feasibility of concurrent tolinapant and definitive radiation in cisplatin-ineligible patients with head and neck squamous cell carcinoma (HNSCC). Eligible patients had locally/locoregionally advanced HNSCC, HPV positive or negative, and were cisplatin ineligible according to hearing loss, renal insufficiency, or age &amp;gt;70 with comorbidities. RT was delivered via intensity-modulated radiation therapy (IMRT) or proton therapy (IMPT) to a total of 70 Gy in 35 fractions. Tolinapant was given every other week 7 days at a time during 7 weeks of RT at the recommended phase II monotherapy dose (180 mg) with option to de-escalate to 90 mg for toxicity. Blood samples for research were collected at baseline and during weeks 2 and 7 of RT. Results: A total of 19 patients were screened, including 10 enrolled and 9 screen failures for prolonged QTc interval or elevated amylase/lipase. Patients enrolled had cancers of the oropharynx (5/10, one HPV-negative), larynx (4/10), and nasopharynx (1/10). Mean age was 68.6 years (range, 53-81). The most common adverse events were radiation dermatitis (100%), fatigue (90%), anorexia (90%), dysphagia (80%), dysgeusia (70%), nausea (50%), and maculopapular rash (30%). All patients completed treatment, and no patients required dose de-escalation of tolinapant. One patient (an 81-year-old with locoregionally-advanced disease) experienced brief interruptions due to severe dysphagia requiring admission for gastrostomy placement. There were no documented locoregional failures. Two patients developed distant metastatic disease after completing treatment; one patient enrolled in hospice, and the other patient remains enrolled on another clinical trial. Another patient developed second and third primary tumors outside the radiation field months after treatment, both treated surgically. At a median follow-up of 12.4 months, 7 patients (70%) remain free of disease. Flow cytometric analysis of blood samples showed increases (up to 30-fold) in circulating activated (CD38+HLA-DR+) CD8+ T lymphocytes by week 7 in 50% of patients, which was associated with maculopapular rash. Conclusions: Tolinapant + RT is safe and feasible in cisplatin-ineligible HNSCC patients. In the absence of platinum chemotherapy, the combination of IAP-antagonizing drugs with RT may induce proliferation and circulation of activated T cells. The study was supported by a grant from Astex Pharmaceuticals/Taiho Oncology to NCS and NFS. Clinical trial information: NCT05245682. Citation Format: Nicole C. Schmitt, William A. Stokes, James E. Bates, Jill Remick, Mark McDonald, Soumon Rudra, Brendan L. Kinney, Madison Steininger, Mosope Oyewole, Azeem S. Kaka, Jennifer H. Gross, Mihir R. Patel, Dong M. Shin, Conor Steuer, Nabil F. Saba. Early-phase trial of IAP antagonist tolinapant and definitive radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT037.