Lessons from Early Phase TKI-Immunotherapy Combinations and the Development of Zanzalintinib

Dr. Saeed and Dr. Ahn review what has been learned from early phase trials examining multi-kinase inhibitors combined with immune checkpoint inhibitors in MSS metastatic colorectal cancer, including LEAP-017 and COSMIC-021. Dr. Saeed notes that while each study demonstrated responses and long-term survivors in early phase cohorts, translating these findings to positive phase 3 results proved challenging, with LEAP-017 illustrating the risk of an unselected study population diluting benefit. Subgroup analyses across studies consistently identified patients without liver metastasis as deriving the greatest benefit, informing subsequent trial design. Dr. Ahn then asks Dr. Saeed to characterize zanzalintinib and how its target profile differs from cabozantinib. Dr. Saeed highlights the shorter half-life of zanzalintinib as a tolerability advantage and reviews early phase expansion cohort data supporting its combination with atezolizumab in colorectal cancer.