STELLAR-303: A randomized phase 3 study of zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated metastatic colorectal cancer.

TPS3634

Background: Metastatic colorectal cancer (mCRC) has seen increased rates in overall survival (OS) as novel targeted agents have become available. Unfortunately, the median OS is still less than 2 years, and the 5-year survival rate is only about 16%. This underscores an unmet need in this population that necessitates finding therapeutic options to enhance treatment outcomes. As monotherapy, immune checkpoint inhibitors (ICIs) have shown limited efficacy in non–microsatellite instability-high (non–MSI-H) mCRC, which represents a majority of mCRC cases. However, addition of tyrosine kinase inhibitors (TKIs) to ICIs has demonstrated encouraging efficacy in mCRC, particularly in patients without liver metastases (LM). Clinical data suggest synergy whereby TKIs may increase sensitivity to ICIs by promoting an immune-permissive tumor microenvironment. Zanzalintinib is a novel TKI targeting VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER), which are involved in tumor angiogenesis, metastasis, and immunosuppression. In a phase 1 study, zanzalintinib in combination with atezolizumab (an anti–PD-L1 ICI) showed antitumor activity and a manageable safety profile across multiple tumor types, including mCRC. The present study, STELLAR-303, was designed to evaluate the efficacy and safety of zanzalintinib + atezolizumab in patients with non–MSI-H mCRC. Methods: STELLAR-303 (NCT05425940) is a global, randomized, open-label, phase 3 study. Patients must be aged ≥18 years and have non–MSI-H/non-mismatch repair deficient disease, with documented RAS status by tissue-based analysis, measurable disease per RECIST v1.1, and ECOG performance status of 0–1. Patients must have had intolerance to, or radiographic progression during/after, standard-of-care treatments for mCRC. Patients previously treated with regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are excluded. Patients with or without active LM at baseline are eligible; those with definitively treated LM (including surgical resection, microwave/radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active LM if treated ≥6 months before enrollment with no evidence of radiologic progression on subsequent imaging. Patients are randomized 1:1 to receive either zanzalintinib + atezolizumab, or regorafenib alone. Planned enrollment is 874 patients, and the number of patients with/without LM will be capped to ensure relevance to the real-world mCRC population. The primary endpoint is OS in patients without LM, while OS in all randomized patients is the key secondary endpoint. A hierarchical testing strategy will be employed for primary and key secondary endpoints. Safety will also be assessed. STELLAR-303 enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940 .