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Early-Phase Trial of IAP Antagonist Tolinapant and Definitive Radiation in Cisplatin-Ineligible Patients with
Nicole C Schmitt1,2, William A Stokes2,3, James E Bates2,3
1Department of Otolaryngology - Head and Neck Surgery, Emory University, Atlanta, Georgia.
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.
Insights
Tolinapant combined with radiotherapy was safe and well-tolerated in head and neck cancer patients. This combination therapy activated T cells, suggesting potential for enhanced anti-tumor immunity in HNSCC treatment.
Area of Science:
- Oncology
- Immunology
- Radiation Oncology
Background:
- Inhibitors of apoptosis (IAP) antagonists, like tolinapant, enhance apoptotic pathways.
- Preclinical data suggest tolinapant combined with radiotherapy (RT) can boost anti-tumor immunity.
Purpose of the Study:
- To evaluate the safety and feasibility of concurrent tolinapant and RT.
- To assess this combination in cisplatin-ineligible patients with head and neck squamous cell carcinoma (HNSCC).
Main Methods:
- An open-label, single-arm trial enrolled 10 patients with locally/locoregionally advanced HNSCC.
- Patients received intensity-modulated radiation therapy (IMRT) or proton therapy (70 Gy) concurrently with tolinapant (180 mg/day, every other week), with dose de-escalation option.
- Blood samples were collected at baseline and during RT to analyze immune responses.
Main Results:
- The combination therapy was well-tolerated, with adverse events comparable to standard chemoradiotherapy.
- All patients completed treatment without requiring tolinapant dose de-escalation.
- A subset of patients (40%) showed a burst of activated CD8+ T lymphocytes post-treatment.
- At a median follow-up of 13.8 months, 70% of patients remained disease-free.
Conclusions:
- Concurrent tolinapant and RT is a safe and feasible treatment option for cisplatin-ineligible HNSCC patients.
- The combination induced T-cell activation in a portion of the patient cohort.
- Larger prospective studies are warranted to confirm efficacy.
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