P-35 Zanzalintinib (XL092) in combination with atezolizumab for previously treated metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) is associated with poor prognosis, and patients who have progressed on first- second-line chemotherapy limited treatment options. Regorafenib trifluridine-tipiracil are approved in third- or later-line settings, but survival benefit small. Immune checkpoint inhibitor (ICI) therapy nivolumab ± ipilimumab single-agent pembrolizumab microsatellite instability-high (MSI-H) mismatch repair deficient (dMMR) mCRC, which constitutes a small subgroup (∼5%) of the overall patient population. As vast majority stable proficient and, therefore, unlikely to respond ICI alone, there remains an unmet need for effective options these patients. Phase 1/2 studies evaluating cabozantinib (an MET, AXL, VEGFR2) combination atezolizumab durvalumab demonstrated encouraging clinical activity (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, 135). Zanzalintinib (XL092) tyrosine kinase that targets VEGFR2, TAM kinases AXL MER; proteins implicated tumor growth, metastasis, angiogenesis, immunosuppression microenvironment. also displays immunomodulatory properties may promote immunopermissive microenvironment enhance response ICIs. Results from phase 1 dose-escalation study zanzalintinib alone locally advanced metastatic solid tumors (including mCRC) showed manageable safety profile. has half-life 16–22 hours, supporting once-daily dosing regimen (Sharma MR, ESMO 481P). The 3 STELLAR-303 (NCT05425940) efficacy versus regorafenib instability-low mCRC after intolerant standard care (SOC) therapy. Trial design:STELLAR-303 global, randomized, open-label, study. Eligible aged ≥18 years non-MSI-H/dMMR (determined by tissue-based analysis) measurable per RECIST v1.1 investigator ECOG performance status 0–1 adequate organ function. Patients must during/after be SOC therapies mCRC; prior regorafenib, trifluridine-tipiracil, anti–PD-L1/PD-1 ICIs not allowed. randomized 1:1 + regorafenib. administered orally once day. Enrollment 600 RAS wild-type mutant) planned. primary endpoint duration secondary endpoints include progression-free survival, objective rate, (all investigator), as well tolerability. ongoing 16 countries, located North America, Europe, Asia-Pacific regions. NCT05425940. Editorial assistance was provided Fishawack Communications Inc., part Health, funded Exelixis, Inc.