Preliminary results from an early-phase, open-label study of tolinapant and radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer

Abstract Background: Genomic alterations in NF-kB and inhibitor of apoptosis protein (IAP) pathways are common in head and neck cancer (HNC). IAP antagonists have shown activity in HNC, especially when paired with radiation therapy (RT), in both preclinical and early clinical studies. Our preclinical studies suggest that the combination of tolinapant and RT works in part by enhancing T cell activation, dendritic cell maturation, immunogenic cell death, and other aspects of the anti-tumor immune response. However, the safety and efficacy of IAPi combined with definitive RT, without platinum chemotherapy, has not been explored clinically. Methods: This is an open-label, early-phase study to determine the safety of the IAPi tolinapant combined with definitive or adjuvant RT. Eligible patients have previously untreated, locally advanced HNC, ECOG ≤1, with plan for definitive or adjuvant RT but are ineligible for treatment with cisplatin. Patients are treated with intensity-modulated radiation therapy (IMRT) or proton therapy (IMPT) to 60-70 Gy with tolinapant 180 mg (the single-agent recommended phase 2 dose) daily by mouth or feeding tube for 7 days during weeks 1, 3, 5, and 7 of RT, with the option of tolinapant dose reduction to 90 mg daily for toxicity. In the adjuvant setting, patients are treated for 6 weeks with 3 cycles of tolinapant. Blood is collected for research at baseline and during weeks 2 and 7. Tissue biopsies at baseline and during week 2 are optional. Results: Eight patients have been consented, including 3 screen failures and 5 enrolled (accrual target = 10 enrolled). All enrolled patients to date received definitive RT; four patients were treated with IMPT. Tumor sites included nasopharynx (1), oropharynx (one HPV+, one HPV-), and larynx (2). The most common reason for cisplatin ineligibility was hearing loss. The median age was 70 (range, 64-81). One patient had a grade 2 rash with pruritis that persisted for several weeks after treatment; other AEs included one treatment interruption during week 1, attributed to RT. Dose reduction of tolinapant was not required for any patients. Three patients have been evaluated by imaging and clinical exam 3 months after treatment, with no evidence of residual disease. Flow cytometry of peripheral blood samples showed a decrease in the proportion of CD4+CD25+ T cells (3/5 patients) and increase of differentiation markers on CD8+ T cells (4/5 patients) from baseline to week 2; these trends were more pronounced at week 7. The one patient who experienced a persistent grade 2 rash with pruritis had a >10-fold increase in activated (HLA-DR+CD38+) CD8+ T cells by week 7. Conclusions: Based on preliminary safety and tolerability data reviewed at this interim analysis, tolinapant at 180 mg appears to be a safe dose for combination with definitive RT. Additional studies will further characterize the dynamics of the peripheral immune response and provide longer follow up on a larger cohort of patients. This study was supported by Astex Pharmaceuticals, Inc. with a research grant to NCS and NFS. Citation Format: Nicole C. Schmitt, William A. Stokes, James E. Bates, Madison Stallings, Brendan L. C. Kinney, Mark W. McDonald, Soumon Rudra, Jill Remick, Zachary S. Buchwald, Dong M. Shin, Azeem S. Kaka, Mihir R. Patel, Nabil F. Saba. Preliminary results from an early-phase, open-label study of tolinapant and radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-050.