Mutation-Specific Response Data and Treatment Selection for GIST

Dr. Pollack addresses clinicians' desire for mutation-specific response data before adopting combination therapy, emphasizing the transformative insights from the INTRIGUE trial's ctDNA analysis. The INTRIGUE study demonstrated dramatic differences in patients with KIT exon 11 mutations based on secondary resistance patterns: those with exon 13/14 secondary mutations achieved over 12 months progression-free survival with sunitinib versus only months with ripretinib, while the reverse pattern held for exon 17/18 secondary mutations.

These weren't marginal statistical differences but clinically meaningful treatment selection opportunities that sparked the INSIGHT trial design. The INSIGHT trial specifically enrolls patients with KIT exon 11 plus secondary exon 17/18 mutations to test ripretinib's superiority in this molecularly defined population.

In the PEAK study, ctDNA is being collected as an exploratory endpoint to assess molecular correlates of response, with the first Phase 3 look at mutation-specific outcomes presented at ASCO 2026. Early data suggest the bezuclastinib plus sunitinib combination provides benefit regardless of secondary mutation status, potentially simplifying treatment selection for community oncologists.

This creates an interesting decision paradigm: mutation-guided monotherapy selection requiring ctDNA testing and potential delays versus broad-spectrum combination therapy providing immediate treatment initiation. The pending INSIGHT results may influence this balance, particularly if ripretinib monotherapy shows exceptional activity in the exon 17/18 population.

Dr. Heinrich notes the possibility of both approvals occurring simultaneously, creating exciting but complex decision-making scenarios where oncologists must balance mutation-specific approaches against one-size-fits-all combination strategies based on patient factors, institutional resources, and testing turnaround times.