TPS6114 Background: VEGFR, MET, and the TAM kinase AXL are overexpressed in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC); their activation contributes to increased tumor aggressiveness and poor prognosis. The immune checkpoint inhibitor (ICI) pembrolizumab, as monotherapy or in combination with chemotherapy, is a standard of care in patients with PD-L1 expressing R/M HNSCC. However, the response rate and survival benefit with pembrolizumab monotherapy are unsatisfactory, and addition of chemotherapy results in unfavorable toxicity. Zanzalintinib is a novel, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). Preclinical data suggest zanzalintinib-mediated inhibition of these kinases may suppress tumor growth and angiogenesis, while simultaneously promoting an immune-permissive tumor microenvironment that may enhance response to ICIs. Zanzalintinib + ICI combination has shown promising antitumor activity and manageable safety in a phase 1 study in solid tumors. To further support the TKI-ICI combination, phase 2 clinical activity was observed in R/M HNSCC with the multi-targeted TKI cabozantinib (inhibits VEGFR, MET, and TAM kinases) in combination with pembrolizumab. The present study, STELLAR-305, will evaluate the efficacy and safety of zanzalintinib + pembrolizumab vs pembrolizumab alone in previously untreated, PD-L1-positive, R/M HNSCC. Methods: STELLAR-305 (NCT06082167) is a randomized, double-blind, phase 2/3 study. Eligible patients are adults (≥18 years) with histologically or cytologically confirmed R/M HNSCC that is incurable with local therapy. Patients may not have been treated with systemic therapy, unless given as part of multimodal treatment for locally advanced disease and completed >6 months before randomization. Patients must have a primary tumor location of the oropharynx (HPV testing required), oral cavity, hypopharynx, or larynx; those with nasopharynx, salivary gland, or occult primary sites are excluded. Other eligibility criteria include a PD-L1 CPS ≥1, measurable disease per RECIST v1.1, and an ECOG performance status of 0–1. Patients with prior treatment with ICIs or zanzalintinib are not eligible. Patients will be randomized 1:1 to zanzalintinib + pembrolizumab, or placebo + pembrolizumab. The dual primary endpoints are PFS per RECIST v1.1 by blinded independent radiology committee and overall survival. Secondary endpoints include safety, PFS per RECIST v1.1 by investigator, objective response rate, and duration of response. If minimum efficacy requirements are met in phase 2, the study will proceed to phase 3 with approximately 500 patients enrolled across both phases. STELLAR-305 is currently enrolling, with 200 sites estimated for global expansion. Clinical trial information: NCT06082167 .