Resistance Biology and Combination Rationale in Second-Line GIST

This segment covers the panelists' discussion of why efficacy drops after imatinib in KIT-mutant gastrointestinal stromal tumor (GIST). They review sunitinib's longstanding role as the second-line standard, established in a placebo-controlled trial, and explain that patients progress with heterogeneous secondary mutations affecting either the ATP binding pocket or the activation loop, with separate lesions in a single patient sometimes carrying different drivers. Because sunitinib covers one of those domains well and later agents cover the other, the panelists describe a field that cycles drugs rather than suppressing resistance broadly. They note that single agents have repeatedly failed to outperform sunitinib in this setting, including ripretinib in the INTRIGUE trial, and then talk through the rationale for pairing sunitinib with the type I inhibitor bezuclastinib, a combination intended to broaden mutation coverage without the overlapping toxicity that has discouraged pairing tyrosine kinase inhibitors previously.