Zanzalintinib Plus Atezolizumab Misses OS End Point in Liver Metastasis–Free mCRC Subgroup

In the subgroup of patients without active liver metastases (non-liver metastases) (NLM) in the phase 3 STELLAR-303 trial, there was a numerical but non–statistically significant improvement in overall survival (OS) with zanzalintinib plus atezolizumab (Tecentriq) versus regorafenib (Stivarga) in patients with previously treated non-microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC).¹

OS in the NLM population was a coprimary end point of STELLAR-303, with the data showing a median OS of 15.9 months with the combination versus 12.7 months with regorafenib in this subgroup (HR, 0.83; 95% CI, 0.66-1.05; P = .1185), which did not cross the prespecified significance threshold. These final results follow a prespecified interim analysis reported at the 2025 ESMO Congress, at which the same subgroup showed a median OS of 15.9 months versus 12.7 months (HR, 0.79; 95% CI, 0.61-1.03; P = .087), also non-significant.²

The NLM result contrasts with findings in the intention-to-treat (ITT) population, which comprises all randomized patients regardless of liver metastasis status. In the ITT population, at a median follow-up of 18.0 months, the combination produced a median OS of 10.9 months (95% CI, 9.9-12.1) versus 9.4 months (95% CI, 8.5-10.2) with regorafenib, representing a 20% reduction in the risk of death (stratified HR, 0.80; 95% CI, 0.69-0.93; P = .0045).^2,3

Safety of Zanzalintinib Plus Atezolizumab

The safety profile of zanzalintinib plus atezolizumab in the NLM subgroup was consistent with what was previously observed in the ITT population, with no new signals identified.¹ In the ITT population, any-grade treatment-related adverse events (TRAEs) occurred in 95% of patients in the combination arm and 92% of those in the regorafenib arm.³ Grade 3 or worse TRAEs occurred in 60% of patients receiving zanzalintinib plus atezolizumab and 37% of patients receiving regorafenib, with AEs leading to discontinuation of all study treatment in 18% and 15% of patients, respectively.^2,3

The most common grade 3/4 TRAEs with the combination versus regorafenib were hypertension (15% vs 9%), fatigue (6% vs 2%), diarrhea (6% vs 2%), and proteinuria (6% vs 2%).^2,3 There were 5 treatment-related deaths in the combination arm and 1 in the regorafenib arm.³

Study Design and Patient Characteristics

STELLAR-303 (NCT05425940) is a global, multicenter, randomized, open-label phase 3 trial enrolling patients with confirmed metastatic adenocarcinoma of the colon or rectum whose tumors were not MSI-high or mismatch repair deficient and who had radiographically progressed on, were refractory to, or showed intolerance to prior standard-of-care therapy including fluoropyrimidine-, irinotecan-, and oxaliplatin-based chemotherapy. Patients with RAS wild-type disease were also required to have received prior anti-EGFR therapy.^1,3

Between September 2022 and July 2024, 901 patients were enrolled across 121 centers in 16 countries and randomized 1:1 to receive oral zanzalintinib at 100 mg daily plus intravenous atezolizumab at 1200 mg every 3 weeks (n = 451) or oral regorafenib at 160 mg daily on days 1 to 21 of each 28-day cycle (n = 450). Among enrolled patients, 59% were male and 41% were female; 54% were White and 38% were Asian.3 The dual primary endpoints were OS in the ITT population and OS in the NLM subgroup. Secondary end points included progression-free survival, objective response rate, and duration of response in both populations.¹

Zanzalintinib is a novel oral kinase inhibitor that targets the TAM kinases (TYRO3, AXL, and MER), MET, and VEGF receptors. Detailed findings from the NLM subgroup will be submitted for presentation at an upcoming medical conference, according to zanzalintinib manufacturer Exelixis.¹

In February 2026, the FDA accepted a new drug application for zanzalintinib in combination with atezolizumab for the treatment of previously treated mCRC, with a PDUFA target action date of December 3, 2026.¹

References

1. Exelixis provides update on the phase 3 STELLAR-303 trial evaluating zanzalintinib in combination with an immune checkpoint inhibitor in patients with metastatic colorectal cancer. Exelixis. Accessed June 23, 2026. https://ir.exelixis.com/news-releases/news-release-details/exelixis-provides-update-phase-3-stellar-303-trial-evaluating

2. Saeed A, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab vs regorafenib in patients with previously treated metastatic colorectal cancer: primary overall survival analysis from the randomized, open-label, phase III STELLAR-303 study. Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA30.

3. Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. Published online October 20, 2025. doi:10.1016/S0140-6736(25)02025-2

4. Exelixis announces U.S. FDA accepted the new drug application for zanzalintinib in combination with an immune checkpoint inhibitor for patients with metastatic colorectal cancer. News release. Exelixis. February 2, 2026. Accessed June 23, 2026. https://tinyurl.com/y6py4m4m