Dr Saeed on the Rationale for Evaluating the Combination of Zanzalintinib Plus Atezolizumab vs Regorafenib in mCRC

“The STELLAR-303 trial is the first immunotherapy-based phase 3 trial that showed a significant survival advantage [with a multi-kinase inhibitor plus checkpoint inhibitor vs the standard of care] in patients with chemorefractory, metastatic, or advanced-stage colorectal cancer that are not MSI-high and not mismatch repair deficient, which represents [approximately] 95% of cases.”

Anwar Saeed, MD, an associate professor of medicine and chief of Gastrointestinal Medical Oncology at the University of Pittsburgh Medical Center (UPMC) and UPMC Hillman Cancer Center, discussed the biological and clinical rationale supporting the phase 3 STELLAR-303 trial NCT05425940), which evaluated the combination of zanzalintinib, a next-generation multi–TKI plus atezolizumab (Tecentriq) vs regorafenib (Stivarga) in patients with previously treated metastatic colorectal cancer (mCRC).

Saeed explained that STELLAR-303 was the first immunotherapy-based phase 3 trial to demonstrate a survival advantage with a differentiated TKI plus checkpoint inhibition vs a standard-of-care (SOC) TKI in patients with mCRC that is not microsatellite instability (MSI)–high or mismatch repair–deficient—a population that comprises approximately 95% of mCRC cases and has historically shown minimal responsiveness to checkpoint inhibition. The trial builds on the concept that targeted pathway inhibition can modulate the tumor microenvironment to enhance susceptibility to immunotherapy.

Zanzalintinib is a differentiated inhibitor of TAM kinases (TYRO3, AXL, MER), MET, and VEGF receptors. These pathways contribute to angiogenesis, tumor proliferation, and immune evasion. Preclinical and early clinical data suggested that inhibiting these signaling networks could decrease myeloid-derived suppressor cell infiltration, improve cytotoxic T-cell trafficking, and reduce immunosuppressive signaling, thereby creating conditions more favorable for PD-L1 blockade.

Saeed noted that earlier work with cabozantinib, a multi-kinase inhibitor that shares targets with zanzalintinib, provided foundational evidence for the STELLAR-303 design. In the phase 2 CAMILLA trial (NCT03539822), cabozantinib combined with checkpoint inhibition demonstrated encouraging antitumor activity in chemorefractory microsatellite–stable and mismatch repair–proficient mCRC. Subsequently, the phase 1 STELLAR-001 study (NCT03845166) evaluating zanzalintinib plus atezolizumab showed greater antitumor activity than zanzalintinib alone. These findings supported moving the combination into phase 3 evaluation.

STELLAR-303 was designed to determine whether zanzalintinib plus atezolizumab could meaningfully improve outcomes compared with regorafenib, an established SOC in this setting. Overall survival was selected as the primary end point to directly assess clinical benefit in a population with limited available therapy options.