Safety Profile, Dose Management, and Treatment Positioning of Zanzalintinib Plus Atezolizumab

Dr. Saeed and Dr. Ahn examine the safety data from STELLAR 303 and discuss practical strategies for managing toxicity in clinical practice. Dr. Ahn notes that grade 3 or higher treatment-related adverse events were more frequent with zanzalintinib plus atezolizumab than with regorafenib, with hypertension, diarrhea, fatigue, and proteinuria among the most common. Dr. Saeed emphasizes that despite high rates of grade 3 toxicity, discontinuation due to treatment-related adverse events occurred in fewer than 20% of participants in the investigational arm, comparable to the regorafenib arm, indicating that dose modification was feasible and effective. Dr. Saeed proposes that a step-up dosing strategy starting as low as 40 mg may reduce early toxicity burden, consistent with the approach now being explored in ongoing studies using a 16 mg starting dose. The discussants also address treatment positioning, with Dr. Saeed arguing that the non-chemotherapy mechanism of action makes zanzalintinib plus atezolizumab a compelling third-line option, particularly for patients already heavily exposed to cytotoxic agents.