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

TPS267 Background: The prognosis of patients with mCRC is poor, with a 5-year survival rate of 14% (American Cancer Society 2020). Patients who have progressed after front-line chemotherapy have limited treatment options. Regorafenib or trifluridine-tipiracil are approved for patients in the third- or later-line setting, but survival benefit is limited. While immune checkpoint inhibitor (ICI) therapy is approved (nivolumab ± ipilimumab, and pembrolizumab) in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC, the MSI-H phenotype is limited to ~5% of mCRC patients. In phase 1/2 trials, ICIs in combination with VEGFR2 multi-kinase inhibitors (MKIs) have demonstrated encouraging clinical activity in mCRC, including atezolizumab and durvalumab (ICIs) in combination with the MKI cabozantinib, with data suggesting a greater benefit in RAS wild-type (wt) vs mutant (mut) disease (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a novel MKI, targeting MET, VEGFR2, and the TAM kinases AXL and MER; the relatively short half-life (~21 hours) of XL092 is favorable for once-daily (QD) dosing and dose modification to manage tolerability. STELLAR-303 is a phase 3 study evaluating the efficacy and safety of XL092 + atezolizumab versus regorafenib in patients with previously treated RASwt or RASmut mCRC. Methods: STELLAR-303 (XL092-303; NCT05425940) is a global, open-label, randomized phase 3 study. Eligible patients are ≥18 years old and have mCRC that is measurable per RECIST v1.1, are documented not to have MSI-H or dMMR disease, and have an ECOG performance status of 0–1 and adequate organ function. RAS and MSI/dMMR status must be determined by a tissue-based analysis. Patients must have progressed during/after or be intolerant to standard-of-care treatments for mCRC; prior regorafenib, trifluridine/tipiracil, or 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 of 28-day cycle); randomization is stratified by geographic region (Asia vs other), RAS status (wt vs mut), and liver metastases (yes/no). The study plans to enroll 600 patients (400 RASwt and 200 RASmut). The primary endpoint is overall survival in the RASwt population, with additional efficacy endpoints of progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator; efficacy endpoints will also be assessed in the overall study population and in patients with RASmut mCRC. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .