Contribution of atezolizumab (atezo) to the efficacy of the zanzalintinib (zanza) + atezo combination in patients (pts) with previously treated metastatic colorectal cancer (mCRC): Evidence from the phase 3 STELLAR-303 trial.

3574 Background: Outcomes remain poor for pts with previously treated mCRC, the vast majority of whom have tumors that are not microsatellite instability-high or mismatch repair deficient. Zanza is a novel, small molecule inhibitor of multiple kinases, including TAM kinases (TYRO3, AXL, and MER), MET, and VEGF receptors, which play important roles in oncogenic processes, including immune suppression in the tumor microenvironment. In STELLAR-303, zanza + atezo significantly improved overall survival (OS) versus regorafenib (rego) in pts with previously treated mCRC. The objective here was to assess the contribution of atezo to the efficacy of the zanza + atezo combination. Methods: The effect of atezo immunogenicity on efficacy was evaluated by comparing progression-free survival (PFS) and OS between atezo treatment-emergent anti-drug antibody (TEADA)-positive and TEADA-negative pts. Unstratified Cox proportional hazards regression models were used to estimate HRs for TEADA subgroups relative to the rego arm. Exposure-response (ER) analyses examined the relationship between atezo serum trough concentrations and efficacy endpoints using Cox proportional hazards models. Results: Of 451 pts randomized to zanza + atezo, 394 were evaluable for atezo TEADAs (TEADA-positive at any post-baseline visit, n = 143; TEADA-negative, n = 251). Baseline clinical characteristics and key prognostic factors (eg, RAS status, geographic region, presence of liver metastasis, location of primary tumor) were well balanced between TEADA subgroups, minimizing potential confounding due to subpopulation differences. Relative to the rego arm (n = 450), HRs (95% CI) favored zanza + atezo for PFS across both TEADA-positive (0.81 [0.67–0.99]) and TEADA-negative (0.59 [0.51–0.71]) subgroups. Similar results were observed for OS in the TEADA-positive (0.79 [0.63–0.98]) and TEADA-negative (0.72 [0.60–0.86]) subgroups. The greatest benefit for both PFS and OS was in the TEADA-negative subgroup. Based on ER analyses (n = 376), there was a statistically significant (p < 0.001) relationship between time-varying atezo trough concentrations and efficacy endpoints—estimated HRs (95% CI) comparing the 95 th with the 5 th percentiles of atezo trough concentrations were 0.82 (0.80–0.83) for PFS and 0.73 (0.70–0.75) for OS. Safety profiles were comparable between TEADA-positive and TEADA-negative pts. Conclusions: Zanza + atezo demonstrated PFS and OS benefit regardless of atezo TEADA status, with greater efficacy observed in TEADA-negative pts. ER analyses showed that higher atezo serum trough concentrations were associated with longer PFS and OS. These results support the contribution of atezo to the survival benefits observed with the zanza + atezo combination in pts with mCRC in the STELLAR-303 trial. Clinical trial information: NCT05425940 .