ESMO 2025 | STELLAR-303 primary OS analysis: zanzalintinib + atezolizumab vs regorafenib in pretreated mCRC

Thank you for having me. I’m thrilled to present the results of the STELLAR-303, study, which I presented at the ESMO Congress, and we published the results simultaneously at The Lancet. The STELLAR-303 trial is the first immunotherapy-based phase 3 trial to show significant survival advantage in patients with chemorefractory, metastatic, or advanced stage colorectal cancer that are not MSI high or mismatch repair deficient, which represents 95% of the cases. Zanzalintinib is a differentiated multi-tyrosine kinase inhibitor that targets multiple kinases, including the TAM kinases, as well as MET and VEGF receptor. In preclinical studies, zanzalintinib has shown synergy when combined with immune checkpoint inhibitors, and that has led to exploration of zanzalintinib in combination with immune checkpoint inhibitors in early phase clinical trials. I have developed an early phase trial exploring the combination of an earlier generation multityrosine kinase inhibitor called cabozantinib, which has an overlapping tyrosine target with zanzalintinib. And we combine it with an immune checkpoint inhibitor in the CAMILLA trial. And in that study, we have shown a promising signal in patients with chemorefractory metastatic colorectal cancer. So that, in addition to the findings from the phase one, STELLAR-001 study that combines zanzalintinib with atezolizumab versus zanzalintinib alone, we have shown also a promising signal favoring the combination as opposed to zanzalintinib alone in patients with chemorefractory colorectal cancer. So this evidence has provided the ground to launch the phase 3 STILAR303 study. In this Phase III trial, the population that enrolled on STELAR303 were metastatic colorectal cancer patients who progressed on two prior lines of chemotherapy and have tumors that are not MSI high and not mismatch repair deficient. Patients were randomized one-to-one to either receive zanzalintinib plus atezolizumab or regorafenib dosed at the regulatory approved labeling. Stratification factors we used in the study were geographic region, presence or absence of RAS mutations, and presence or absence of liver metastases. The study has dual primary endpoints of overall survival in the intention to treat population as well as overall survival in patients who do not have liver metastasis. The results I presented are on a planned overall survival in the intention to treat population. And I also presented interim analysis of overall survival in patients without liver metastasis. The trial continues to the final overall survival in patients without liver metastasis. As far as the efficacy, STELLAR-303, the method’s primary endpoint of overall survival in the intention to treat population. We have shown significant survival advantage with the combination, as opposed to regorafenib, with a stratified hazard ratio of 0.80, which translates into a 20% reduction in the risk of death in patients receiving the combination, as opposed to patients receiving regorafenib. With a p-value of 0.0045, the patients receiving the combination have a median overall survival of 10.9 months, as opposed to 9.4 months with regorafenib. We have seen an early separation of the Kaplan-Meier curves that remain consistently separated favoring the combination thereafter. The 24 months overall survival estimates were 20% with the combination as opposed to 10% with regorafenib. As far as the interim overall survival analysis in the patients without liver metastasis, we have shown a stratified hazard ratio of 0.79, favoring the combination with a median overall survival of 15.9 months for the combination, as opposed to 12.8 months with regorafenib. As far as the running, you know, a forest plot looking at subgroup analysis of key subgroups, we have seen consistent relative benefit favoring the combination in all of those key subgroups. So the benefit seen regardless of presence or absence of liver metastasis, regardless of presence or absence of RAS mutations. And also a key point to highlight is that prior exposure to VEGF-targeted therapy, which represented around 80% of the population of the study, did not diminish the benefit of the combination of atezolizumab plus zanzalintinib. So as far as the safety profile for the combination, most of the treatment-related adverse events seen were grade 1 to 3, and mostly are hypertension, diarrhea, nausea, fatigue, and loss of appetite. Of note, the grade 3 and all grade PPE, or hand-foot syndrome, were much lower with the combination as opposed to regorafenib, and that’s despite longer median duration on treatment with the combination as opposed to regorafenib. And then another point to highlight is that we have not seen any new safety signals. The overall safety profile is consistent with the safety profile of similar combinations of VEGF multi-tyrosine kinase inhibitor in combination with immune checkpoint inhibitor that’s available in other tumor types like renal cell carcinoma. So overall, I would like to highlight that metastatic colorectal cancer is considered a major global disease challenge with 150,000 cases expected to be newly diagnosed every year in the U.S. alone and a five-year overall survival of around 15 to 16 percent. And so the success of the STELLAR-303 study with a synergistic combination combining a novel targeted agent zanzalintinib with immune checkpoint inhibitor is potentially changing this trajectory. We are now looking at data analysis from the ongoing STELLAR-303 study, particularly the final overall survival in the subgroup of patients without liver metastasis. We’re also looking at exploring the next generation of clinical trials that could be developed to capitalize on the results seen with STELLAR-303, including potentially exploring the combination in earlier line settings in patients with metastatic colorectal cancer, and potentially exploring it in earlier stages of the disease as well, the potentially neoadjuvant or adjuvant settings. And then possibly looking at novel immune modulators that could be added to the doublet to capitalize on the results. So overall, as a key take-home message, I would like to say that the STELLAR-303 study results are sending a clear message of progress and possibility. It opens a new era of immunotherapy-based chemotherapy-free combinations in patients with colorectal cancer that are not MSI high and not mismatch repair deficient.

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