Schmitt Nicole C, Stokes William A, Bates James E, Kinney Brendan L C, Remick Jill, McDonald Mark W, Rudra Soumon, Steininger Madison, Oyewole Mosope, Patel Mihir R, Kaka Azeem S, Gross Jennifer H, Switchenko Jeffrey, Steuer Conor E, Shin Dong M, Saba Nabil F
Department of Otolaryngology - Head and Neck Surgery, Emory University, Atlanta, Georgia.
Winship Cancer Institute, Emory University, Atlanta, Georgia.
Clin Cancer Res. 2025 Jul 15;31(14):2910-2918. doi: 10.1158/1078-0432.CCR-25-0429.
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.
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.
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.
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.
托利那潘是一种凋亡蛋白拮抗剂抑制剂，可增强凋亡途径。在临床前研究中，托利那潘+放疗（RT）可增强抗肿瘤免疫力。我们进行了一项开放标签、单臂试验，以评估在不符合顺铂治疗条件的头颈部鳞状细胞癌患者中，托利那潘与放疗同时使用的安全性和可行性。
符合条件的患者患有局部/区域晚期头颈部鳞状细胞癌，人乳头瘤病毒呈阳性或阴性，且不符合顺铂治疗条件。放疗通过调强放疗或质子治疗进行，总剂量为70 Gy（35次分割）。在放疗期间，托利那潘每隔一周给药一次，剂量为180 mg/天，如有毒性反应可减至90 mg。在基线和放疗期间采集用于研究的血样。
招募了10名患者。治疗耐受性良好，最常见的不良事件与标准放化疗（放射性皮炎、疲劳、吞咽困难、疼痛、味觉障碍和口干）相似。所有患者均完成治疗，无需降低托利那潘剂量。1名患者因严重吞咽困难经历了短暂的治疗中断。2名患者在治疗后发生远处转移。另1名患者在治疗后在放射野外发生第二和第三种肿瘤，并接受了手术治疗。在中位随访13.8个月时，其余7名（70%）患者仍无疾病。血样显示40%的患者中有一群活化的（CD38+HLA-DR+）CD8+T淋巴细胞。
托利那潘+放疗耐受性良好，并在一部分患者中诱导活化T细胞增殖。需要进行更大规模的前瞻性研究以更好地评估疗效。
