STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.

TPS3630 Background: Metastatic colorectal cancer (mCRC) is associated with poor prognosis and limited treatment options for patients who have progressed on first- and second-line chemotherapy. Regorafenib and trifluridine-tipiracil are approved in third- or later-line setting, but survival benefit is limited. Immune checkpoint inhibitor (ICI) therapy with nivolumab ± ipilimumab or single-agent pembrolizumab is approved in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC; however, MSI-H mCRC is present in only ~5% patients. Phase 1/2 studies have evaluated the tyrosine kinase inhibitor (TKI) cabozantinib in combination with the ICIs atezolizumab and durvalumab and have demonstrated encouraging clinical activity, with data suggesting greater benefit in RAS wild-type (wt) versus RAS mutant (mut) mCRC (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a TKI that targets MET, VEGFR2, and the TAM kinases AXL and MER, which are implicated in tumor growth, metastasis, angiogenesis, and immunosuppression of the tumor microenvironment. XL092 displays immunomodulatory properties that may promote an immunopermissive tumor microenvironment and its half-life of 16–22 hours is supportive of once daily (QD) dosing. The phase 3 STELLAR-303 study (NCT05425940) is evaluating the efficacy and safety of XL092 in combination with atezolizumab versus regorafenib in patients with microsatellite stable or microsatellite instability-low mCRC who have progressed after or are intolerant to standard of care (SOC) therapy. Methods: STELLAR-303 is a global, randomized, open-label, phase 3 study. Eligible patients are aged ≥18 years with non-MSI-H/dMMR mCRC (determined by tissue-based analysis) that is measurable per RECIST v1.1 and have an ECOG performance status of 0–1 and adequate organ function. Patients must have progressed during/after or be intolerant to SOC therapies for mCRC; prior regorafenib, trifluridine-tipiracil, or anti–PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to XL092 100 mg PO QD + atezolizumab 1200 mg IV Q3W or to regorafenib 160 mg PO QD (21 days/28-day cycle); randomization is stratified by geographic region (Asia, other), RAS status (wt, mut), and liver metastases (yes, no). Enrollment of 600 patients is planned (400 RASwt, 200 RASmut). The primary endpoint is duration of overall survival (OS) in the RASwt population, with other efficacy endpoints (progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator and change in tumor markers) assessed in the RASwt population and, with OS, in the RASmut populations and in all randomized patients. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .