Abstract CT213: A phase 2 study of first-line domvanalimab, zimberelimab, and chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma: Substudy-01 of the VELOCITY-HNSCC platform trial

Abstract Background: Pembrolizumab (anti-PD-1 monoclonal antibody [mAb]) ± chemotherapy (chemo) is a recommended first-line (1L) treatment strategy for patients (pts) with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Despite improvement in overall survival (OS) with this regimen, the prognosis of R/M HNSCC is generally poor, with a median OS of 6 to 18 months depending on patient- and disease-related factors. The combination of domvanalimab (dom; anti-T-cell immunoglobulin and ITM domain [TIGIT] mAb) and zimberelimab (zim; anti-PD-1 mAb) with chemo has shown promising antitumor activity with manageable safety in advanced gastroesophageal adenocarcinomas (Janjigian, J Clin Oncol, 2023). Substudy-01 of the open-label, phase 2 VELOCITY-HNSCC platform study is evaluating the efficacy and safety of 1L treatment with dom + zim + chemo versus zim + chemo in pts with R/M HNSCC. Methods: Key eligibility criteria for substudy-01 of the VELOCITY-HNSCC platform study include age ≥ 18 years; confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; no prior systemic therapy or immune checkpoint inhibitor treatment for R/M disease; measurable disease; ECOG PS 0-1; and any PD-L1 status. Substudy-01 consists of Cohort 1 (randomization group), with a planned enrollment of ∼100 pts globally, and a possible Cohort 2 (biomarker group), along with the potential for future experimental groups. In Cohort 1, pts will be randomized (1:1) to dom + zim + platinum-doublet chemo or zim + platinum-doublet chemo. Randomization will be stratified by PD-L1 expression (tumor area positivity < 20% vs ≥ 20%) and HPV p16 status for oropharyngeal cancer (positive vs negative). In Cohort 2, pts will receive 2 cycles of dom + zim followed by dom + zim + chemo, and tumor tissue samples will be collected at baseline (fresh samples only) and on-treatment for analysis of predictive, prognostic, or pharmacodynamic biomarkers that may be associated with disease status, mechanisms of response, and/or treatment resistance. Pts will receive dom 1200 mg and zim 360 mg intravenously (IV) once every 3 weeks (Q3W) for up to a total of 35 cycles. Chemo will consist of paclitaxel 175 mg/m2 + carboplatin AUC 5 administered IV Q3W for up to 6 cycles. Treatment will be continued until progressive disease, unacceptable toxicity, death, patient decision to withdraw or if other prespecified criteria are met. The primary endpoints are objective response rate (ORR) and progression-free survival (Cohort 1 only). The secondary endpoints include duration of response, OS, disease control rate, time to progression, and safety/tolerability. Two-sided 90% and/or 95% confidence intervals will be calculated for ORR, and the Kaplan-Meier method will be used for survival estimates. Safety data will be summarized descriptively. Citation Format: Kevin Harrington, Myung-Ju Ahn, Lisa Licitra, Douglas Adkins, Amaury Daste, Irene Brana, Muh-Hwa Yang, Riddhi Patel, Jin You, Kun Xu, Manish Monga, Ye Guo. A phase 2 study of first-line domvanalimab, zimberelimab, and chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma: Substudy-01 of the VELOCITY-HNSCC platform trial [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 CT213.