STELLAR-305: phase II/III study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with HNSCC

Despite therapeutic advances in the treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), survival outcomes with immune checkpoint inhibitor (ICI) therapy, with or without chemotherapy, remain unsatisfactory, indicating a need for more effective treatments in this setting. The overexpression or hyperactivation of VEGF receptor, MET, and AXL in HNSCC can promote tumor growth, angiogenesis, metastasis, and an immune-suppressive tumor microenvironment. Through the potent, multitargeted inhibition of these tyrosine kinases, zanzalintinib (XL092) has been shown to reduce tumor cell proliferation and survival, suppress angiogenesis, and promote an immune-permissive tumor microenvironment. In vivo, zanzalintinib plus an ICI resulted in enhanced tumor growth inhibition when compared with either agent alone. STELLAR-305 is a randomized, double-blind, phase II/III study to evaluate the efficacy and safety of zanzalintinib plus pembrolizumab versus placebo plus pembrolizumab in adult patients with programmed cell death ligand 1-positive (combined positive score ≥ 1) R/M HNSCC that is not curable by local therapy, who have not received prior systemic therapy for R/M disease. The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) and overall survival. Secondary endpoints include safety, investigator-assessed PFS, and objective response rate and duration of response per BICR and investigator review. Tweetable abstract: STELLAR-305: design of an ongoing phase III #clinicaltrial, assessing the multi-targeted tyrosine kinase inhibitor, zanzalintinib, in combination with pembrolizumab in previously untreated recurrent/metastatic #HNSCC. Clinical trial registration: NCT06082167 (ClinicalTrials.gov).