KEY TAKEAWAYS
- The STELLAR-303 trial is a phase 3 study evaluating the efficacy and safety of XL092, a novel multi-kinase inhibitor, in combination with atezolizumab in patients with previously treated RASwt or RASmut mCRC.
- The trial is open-label, global, and randomized, and plans to enroll 600 patients stratified by geographic region, RAS status, and liver metastases.
- 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 evaluated by RECIST v1.1 by the investigator.
- XL092 targets MET, VEGFR2, and TAM kinases AXL and MER, and has a favorable half-life of ~21 hours, allowing for once-daily dosing and dose modification for tolerability management.
- Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed in the trial, and patients must have progressed during/after or be intolerant to standard-of-care treatments for mCRC. The trial also assesses safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization.
With only a 14% 5-year survival rate, patients with mCRC face a dismal outlook (American Cancer Society 2020). After initial chemotherapy, patients with advanced disease have few therapeutic alternatives. Although regorafenib and trifluridine-tipiracil have been approved for patients in the third or later-line scenario, the benefits to survival are modest at best. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC patients are eligible for immune checkpoint inhibitor (ICI) therapy (nivolumab, ipilimumab, and pembrolizumab), however only about 5 percent of mCRC patients have this profile.
Atezolizumab and durvalumab (ICIs) in conjunction with the MKI cabozantinib have shown promising clinical activity in phase 1/2 trials for mCRC, with results suggesting a larger benefit in RAS wild-type (wt) than mutant (mut) illness (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a new MKI that inhibits the activities of MET, VEGFR2, and the TAM kinases AXL and MER. Its short half-life (21 hours) makes it well-suited for once-daily (QD) dosing and dose adjustment to regulate tolerance. Patients with previously treated RASwt or RASmut mCRC will participate in STELLAR-303, a phase 3 research comparing XL092 + atezolizumab to regorafenib for effectiveness and safety.
The STELLAR-303 trial (NCT05425940; XL092-303) is a multinational, randomised, open-label, phase 3 investigation. Patients must be 18 years old, have demonstrable mCRC as defined by RECIST v1.1, have no evidence of MSI-H or dMMR illness, have an ECOG performance level of 0-1 and acceptable organ function, and be ineligible for any other treatment. Tissue analysis is required to ascertain RAS and MSI/dMMR status. Patients cannot have received regorafenib, trifluridine, tipiracil, or PD-L1/PD-1 ICIs previously, and must have progressed during or after standard-of-care treatment for mCRC. Patients are assigned to receive either XL092 (100 mg PO QD + atezolizumab 1200 mg IV Q3W) or regorafenib (160 mg PO QD; 21 days of 28-day cycle) in a 1:1 ratio, with allocation stratified by Asia/Other, RAS status (wt vs mut), and liver metastases (yes/no).
Around 600 people are expected to take part in the study (400 RASwt and 200 RASmut). Survival in the RASwt population is the primary endpoint, with progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator as secondary efficacy endpoints; efficacy endpoints will also be evaluated in the overall study population and in patients with RASmut mCRC. Further evaluations will evaluate atezolizumab’s immunogenicity, pharmacokinetics, and healthcare use alongside safety and quality of life assessments, biomarker alterations, and pharmacodynamic analyses. Membership signups are continuing.
Source: https://meetings.asco.org/abstracts-presentations/216064
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT05425940/
Hecht, J.R., Tabernero, J., Parikh, A.R., Wang, Y., Wang, Z., Schwickart, M., Curran, D. and Saeed, A. (2023). STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer (mCRC). Journal of Clinical Oncology, 41(4_suppl), pp.TPS267–TPS267. doi:https://doi.org/10.1200/jco.2023.41.4_suppl.tps267.
