Zanzalintinib (multi-kinase TAM/MET/VEGFR inhibitor) + atezolizumab (PD-L1) shows OS/PFS benefit—and atezo exposure appears to matter—in refractory mCRC

Zanzalintinib (zanza) is an oral multi-kinase inhibitor (TYRO3/AXL/MER, MET, VEGFRs) combined with atezolizumab (atezo), an anti–PD-L1 antibody, in the Phase 3 STELLAR-303 trial in previously treated metastatic CRC (largely MSS/pMMR). In this immunogenicity/exposure analysis among 451 pts on zanza+atezo (394 TEADA-evaluable), both TEADA-positive (n=143) and TEADA-negative (n=251) subgroups retained benefit vs regorafenib (n=450): PFS HR 0.81 (95% CI 0.67–0.99) and 0.59 (0.51–0.71), respectively; OS HR 0.79 (0.63–0.98) and 0.72 (0.60–0.86), respectively, with the strongest efficacy in TEADA-negative pts. Exposure–response modeling (n=376) linked higher time-varying atezo trough concentrations with better outcomes (95th vs 5th percentile HR 0.82 [0.80–0.83] for PFS; 0.73 [0.70–0.75] for OS; p<0.001), while safety appeared comparable by TEADA status; in the parent STELLAR-303 readout, the combo improved OS vs regorafenib (median OS 10.9 vs 9.4 months; stratified HR 0.80, p=0.0045), an incremental gain over an established late-line SOC with modest survival expectations (regorafenib historically mOS ~6.4 months vs placebo in CORRECT).