1. Zanzalintinib Plus Pembrolizumab Versus Pembrolizumab Alone In Patients with PD-L1 Positive Metastatic Head And Neck Squamous Cell Carcinoma (STELLAR-305): A Double-Blind, Randomized, Placebo-Controlled, Phase 2/3 Study.
- Author
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Saba, N.F., Harrington, K., Licitra, L., Machiels, J.P., Huang, M., Xu, F., Patel, P., and Haddad, R.I.
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SQUAMOUS cell carcinoma , *PROGRAMMED death-ligand 1 , *IMMUNOTHERAPY , *IMMUNE checkpoint inhibitors , *PEMBROLIZUMAB , *CANCER chemotherapy - Abstract
Pembrolizumab as monotherapy or in combination with chemotherapy is a standard of care in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) and PD-L1 CPS ≥1. While pembrolizumab monotherapy results in low response rates, the addition of 5FU/cisplatin adds significant toxicity for pts. Rational combinations which improve outcomes while avoiding cytotoxic chemotherapy are needed. HNSCC is associated with overexpression of VEGFR, MET, and AXL, and there are preclinical data supporting the antitumor effect of inhibition of these kinases through suppressing tumor growth and angiogenesis, and promoting an immune-permissive tumor microenvironment. In a phase 2 study, pembrolizumab plus the multi-kinase inhibitor cabozantinib demonstrated encouraging clinical activity and safety in pts with R/M HNSCC (Saba et al. Nat Med 2023), suggesting that targeting kinases including VEGFR, MET, and AXL has antitumor effect in this population and may enhance responses to immune checkpoint inhibitor (ICIs). Zanzalintinib (XL092) is a novel, multi-targeted kinase inhibitor that inhibits VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). STELLAR-305 (NCT06082167) is a randomized, double-blind, phase 2/3 study that will evaluate the efficacy and safety of zanzalintinib plus pembrolizumab vs pembrolizumab plus placebo in pts with previously untreated, PD-L1-positive, R/M HNSCC. Eligible pts are aged ≥18 years and have histologically or cytologically confirmed R/M HNSCC that is incurable with local therapy and has not been treated with systemic therapy, unless completed >6 months before randomization and given as part of multimodal treatment for locally advanced disease. Pts must have a primary tumor location of the oropharynx (HPV testing required), oral cavity, hypopharynx, or larynx; pts 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. Prior treatment with ICIs or zanzalintinib is not allowed. Patients will be randomized 1:1 to either zanzalintinib plus pembrolizumab or placebo plus 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. In total, approximately 500 pts will be enrolled across phase 2 and 3. The study is ongoing with enrollment planned across sites in US, Europe, and the Asia-Pacific region. TBD TBD [ABSTRACT FROM AUTHOR]
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- 2024
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