J. Randolph (Randy) Hecht, MD
The protection and efficacy of a mix routine comprised of XL092 and atezolizumab (Tecentriq) is being in contrast with that of regorafenib (Stivarga) monotherapy in sufferers with microsatellite secure (MSS) or microsatellite instability–low (MSI-L) metastatic colorectal most cancers (mCRC) who’ve progressed on or are illiberal to standard-of-care (SOC) remedy, as a part of the section 3 STELLAR-303 trial (NCT05425940).1
Though a number of immune checkpoint inhibitors are accredited for the therapy of sufferers with microsatellite instability–excessive (MSI-H)/mismatch restore–poor (dMMR) mCRC, solely roughly 5% of these identified with mCRC have MSI-H standing underscoring an unmet want. Information from earlier section 1/2 trials have proven that when immune checkpoint inhibitors have been paired with VEGFR2 TKIs, they’d exercise in sufferers with mCRC who didn’t have MSI-H or dMMR tumors.
“The query has been whether or not we are able to get immunotherapy to work in sufferers who wouldn’t have a genetic marker that makes them delicate to immunotherapy,” lead examine creator J. Randolph (Randy) Hecht, MD, defined in an interview with OncLive®. Hecht is a professor of Scientific Medication on the David Geffen Faculty of Medication of College 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, that are concerned in tumor development, metastasis, angiogenesis, and immunosuppression. The agent has a comparatively brief half-life of roughly 16 to 22 hours, which could make this a positive once-daily dosing routine that may be modified to make sure tolerability.
Beforehand reported knowledge from a section 1 dose-escalation trial (NCT03845166) recognized the really useful section 2 dose of XL092 as 100 mg when utilized together with atezolizumab.2 The mix displayed a manageable security profile and generated responses in sufferers with strong tumors.
“STELLAR-303 is a worldwide examine that’s simply getting ramped up. It’s [being done] in the US, Europe, and [several] different nations,” Hecht mentioned. “Sufferers who’ve had prior therapies with cytotoxic chemotherapy are eligible. Nevertheless, they can not have had regorafenib or [trifluridine/tipiracil (TAS-102; Lonsurf)]. It’s [being done] within the salvage setting, and it’s a randomized trial.”
Different inclusion standards to the section 3 examine embody being at the very least 18 years of age, having histologically confirmed RAS-mutated or RAS wild-type adenocarcinoma of the colon or rectum, and measurable illness per RECIST v1.1 standards. Sufferers have been additionally required to have an ECOG efficiency standing of 0 or 1, have progressed on or be refractory to SOC therapies, and have progressed throughout therapy with or inside 3 months of finishing their most up-to-date SOC remedy.
Sufferers have been excluded if they’d MSI-H or dMMR mCRC; acquired prior therapy with XL092, regorafenib, TAS-102, or PD-1/PD-L1 immune checkpoint inhibitors; therapy with a TKI inside 2 weeks of randomization; therapy with any anticancer antibody remedy, systemic chemotherapy, or hormonal anticancer remedy inside 3 weeks previous to randomization; therapy with bevacizumab (Avastin) inside 3 weeks of randomization; or radiation remedy inside 4 weeks or radiation for bone metastasis inside 2 weeks of randomization. Sufferers additionally couldn’t have uncontrolled, vital intercurrent or latest sickness.
The worldwide, open-label, randomized trial is estimated to enroll roughly 600 sufferers, which can embody 400 sufferers with RAS wild-type illness and 200 sufferers with RAS-mutated illness. Individuals will probably be randomly assigned in a 1:1 vogue to obtain 100 mg of oral XL092 per day plus 1200 mg of intravenous atezolizumab each 3 weeks, or 160 mg of oral regorafenib per day for the primary 21 days of each 28-day cycle. Sufferers will probably be stratified by geographical area (Asia vs different), liver metastases (sure vs no), and RAS standing (mutated vs wild-type).
The trial’s major finish level will probably be general survival (OS) within the all-randomized RAS wild-type inhabitants. Secondary finish factors embody investigator-assessed progression-free survival, general response charge, and period of response per RECIST v1.1 standards, in addition to OS and alter in tumor markers within the all-randomized, RAS wild-type, and RAS-mutant populations. Extra finish factors will consider security, high quality of life (QOL), change in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization.
Sufferers will obtain a CT scan and MRI at baseline, then each 8 weeks for the primary 49 weeks, adopted by each 12 weeks thereafter. Security evaluations will embody assessments of adversarial results (AEs), outlined by the Nationwide Most cancers Institute Frequent Know-how Standards for Opposed Occasions v5.0.
Biomarker and tumor marker assessments will probably be derived from recent tumor tissue samples. Circulating tumor DNA plasma samples will probably be collected at week 9, then each 8 weeks via week 49, and each 12 weeks thereafter. Blood samples will probably be collected to additional inform pharmacokinetic and immunogenicity assessments. QOL will probably be assessed previous to the examine, at weeks 4 and seven, then on the identical schedule as radiographic assessments.
The continuing trial is being performed at roughly 136 websites globally and commenced enrolling sufferers in September 2022.
“Though we have no idea if it will work, my hope is twofold. Most significantly, as a clinician, I hope that this helps my sufferers,” Hecht concluded. “That is [potentially] another possibility for us to assist this group of sufferers who’re sorely in want. Furthermore, [ this could break the paradigm for sufferers who’ve MSS illness.”