XL092 Plus Atezolizumab Vs Regorafenib Under Investigation in MSS/MSI-Low mCRC

The safety and efficacy of a combination regimen comprised of XL092 and atezolizumab (Tecentriq) is being compared with that of regorafenib (Stivarga) monotherapy in patients with microsatellite stable (MSS) or microsatellite instability–low (MSI-L) metastatic colorectal cancer (mCRC) who have progressed on or are intolerant to standard-of-care (SOC) therapy, as part of the phase 3 STELLAR-303 trial (NCT05425940).¹

Although multiple immune checkpoint inhibitors are approved for the treatment of patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) mCRC, only approximately 5% of those diagnosed with mCRC have MSI-H status underscoring an unmet need. Data from previous phase 1/2 trials have shown that when immune checkpoint inhibitors were paired with VEGFR2 TKIs, they had activity in patients with mCRC who did not have MSI-H or dMMR tumors.

“The question has been whether we can get immunotherapy to work in patients who do not have a genetic marker that makes them sensitive to immunotherapy,” lead study author J. Randolph (Randy) Hecht, MD, explained in an interview with OncLive^®. Hecht is a professor of Clinical Medicine at the David Geffen School of Medicine of University of California, Los Angeles (UCLA), and the director of the UCLA Gastrointestinal Oncology Program.

The novel TKI, XL092, targets MET, VEGFR2, and the TAM kinases AXL and MER, which are involved in tumor growth, metastasis, angiogenesis, and immunosuppression. The agent has a relatively short half-life of approximately 16 to 22 hours, which might make this a favorable once-daily dosing regimen that can be modified to ensure tolerability.

Previously reported data from a phase 1 dose-escalation trial (NCT03845166) identified the recommended phase 2 dose of XL092 as 100 mg when utilized in combination with atezolizumab.² The combination displayed a manageable safety profile and generated responses in patients with solid tumors.

“STELLAR-303 is a global study that’s just getting ramped up. It’s [being done] in the United States, Europe, and [several] other countries,” Hecht said. “Patients who have had prior therapies with cytotoxic chemotherapy are eligible. However, they cannot have had regorafenib or [trifluridine/tipiracil (TAS-102; Lonsurf)]. It’s [being done] in the salvage setting, and it’s a randomized trial.”

Other inclusion criteria to the phase 3 study include being at least 18 years of age, having histologically confirmed RAS-mutated or RAS wild-type adenocarcinoma of the colon or rectum, and measurable disease per RECIST v1.1 criteria. Patients were also required to have an ECOG performance status of 0 or 1, have progressed on or be refractory to SOC therapies, and have progressed during treatment with or within 3 months of completing their most recent SOC therapy.

Patients were excluded if they had MSI-H or dMMR mCRC; received prior treatment with XL092, regorafenib, TAS-102, or PD-1/PD-L1 immune checkpoint inhibitors; treatment with a TKI within 2 weeks of randomization; treatment with any anticancer antibody therapy, systemic chemotherapy, or hormonal anticancer therapy within 3 weeks prior to randomization; treatment with bevacizumab (Avastin) within 3 weeks of randomization; or radiation therapy within 4 weeks or radiation for bone metastasis within 2 weeks of randomization. Patients also could not have uncontrolled, significant intercurrent or recent illness.

The global, open-label, randomized trial is estimated to enroll approximately 600 patients, which will include 400 patients with RAS wild-type disease and 200 patients with RAS-mutated disease. Participants will be randomly assigned in a 1:1 fashion to receive 100 mg of oral XL092 per day plus 1200 mg of intravenous atezolizumab every 3 weeks, or 160 mg of oral regorafenib per day for the first 21 days of every 28-day cycle. Patients will be stratified by geographical region (Asia vs other), liver metastases (yes vs no), and RAS status (mutated vs wild-type).

The trial’s primary end point will be overall survival (OS) in the all-randomized RAS wild-type population. Secondary end points include investigator-assessed progression-free survival, overall response rate, and duration of response per RECIST v1.1 criteria, as well as OS and change in tumor markers in the all-randomized, RAS wild-type, and RAS-mutant populations. Additional end points will evaluate safety, quality of life (QOL), change in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization.

Patients will receive a CT scan and MRI at baseline, then every 8 weeks for the first 49 weeks, followed by every 12 weeks thereafter. Safety evaluations will include assessments of adverse effects (AEs), defined by the National Cancer Institute Common Technology Criteria for Adverse Events v5.0.

Biomarker and tumor marker assessments will be derived from fresh tumor tissue samples. Circulating tumor DNA plasma samples will be collected at week 9, then every 8 weeks through week 49, and every 12 weeks thereafter. Blood samples will be collected to further inform pharmacokinetic and immunogenicity assessments. QOL will be assessed prior to the study, at weeks 4 and 7, then on the same schedule as radiographic assessments.

The ongoing trial is being conducted at approximately 136 sites globally and began enrolling patients in September 2022.

“Although we do not know if this will work, my hope is twofold. Most importantly, as a clinician, I hope that this helps my patients,” Hecht concluded. “This is [potentially] one more option for us to help this group of patients who are sorely in need. Moreover, [ this would break the paradigm for patients who have MSS disease.”

References

1. Hecht JR, Tabernero J, Parikh A, et al. STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(suppl 4):198. doi:10.1200/JCO.2023.41.3_suppl.TPS267
2. Sharma MR, Subbiah V, Shapiro G, et al. A phase I first-in-human study of XL092 in patients (pts) with locally advanced or metastatic solid tumors: Results from dose-escalation of XL092 alone and in combination with atezolizumab. Ann Oncol. 2022;33(suppl 7):S760. doi:10.1016/j.annonc.2022.07.609