ASCO 2026: Next-Generation KIT Inhibitors Spark a Paradigm Shift in Rare Gut Cancer
For over two decades, the standard of care for gastrointestinal stromal tumors (GIST)—a rare cancer arising in the gut wall driven by mutations in the tyrosine kinase c-KIT—has remained largely stagnant. Since the landmark FDA approvals of Novartis' Gleevec (imatinib) in 2002 and Pfizer's Sutent (sunitinib) in 2006, patients have faced a steep drop-off in options once tumors inevitably evolve resistance to early-line therapies.
At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, clinical readouts for two next-generation c-KIT inhibitors, GSK's velzatinib and Cogent Biosciences' bezuclastinib, signaled an impending "paradigm shift" in GIST treatment.
Velzatinib Targets the Broad Spectrum of Resistance Mutations
GSK's velzatinib (originally developed as IDRx-45 by IDRx, which GSK acquired in January 2025) is a small-molecule tyrosine kinase inhibitor (TKI) designed to target both the primary c-KIT mutations that drive GIST formation and the subsequent secondary mutations that tumors develop to evade Gleevec and Sutent. By selectively homing in on c-KIT and avoiding other targets like the signaling protein VEGF, velzatinib aims to deliver superior efficacy with a gentler side-effect profile than broad-spectrum TKIs like Sutent.
In its ASCO 2026 debut, preliminary Phase 1 data demonstrated substantial clinical activity:
- First-Line Efficacy: Velzatinib achieved a 61% tumor shrinkage rate (objective response rate) in a limited cohort of 24 treatment-naive patients.
- Second-Line Efficacy: Among 49 second-line-plus patients who had progressed on Gleevec, velzatinib achieved a 38% response rate—nearly doubling the historical response rates of Sutent, which typically hover in the teens.
- Progression-Free Survival (PFS): Second-line-plus patients on velzatinib demonstrated a median PFS of approximately 14 months.
GSK is leveraging these promising results to launch two Phase 3 trials: the StrateGIST 3 trial, which will pit velzatinib directly against Sutent in the second-line setting, and a separate first-line trial comparing velzatinib against Gleevec.
Bezuclastinib Combination Nears FDA Approval
Cogent Biosciences also presented practice-changing Phase 3 data for its selective KIT inhibitor, bezuclastinib, in patients with Gleevec-resistant GIST. Because bezuclastinib targets a specific subset of c-KIT mutations, it is designed to be used in combination with other TKIs.
When paired with Sutent, the bezuclastinib combination delivered:
- A median PFS of 16.5 months, compared to just 9.2 months for patients receiving Sutent alone.
- A clear clinical benefit demonstrated across all mutational patient subgroups.
Bezuclastinib is currently under active FDA review, with a regulatory decision expected by November 30, 2026. Cogent is preparing for a commercial launch later this year, which could establish a new standard of care in second-line GIST treatment.
Verbatim Quotes
- Dr. Suzanne George (Dana-Farber Cancer Institute): "Imatinib is a very potent inhibitor of KIT... But we've learned over time that the primary mechanism of resistance to imatinib is the development of secondary mutations in KIT that imatinib does not work against."
- Dr. Hesham Abdullah (GSK Head of Oncology R&D): "You would typically expect response rates with Sutent to be in the teens... and we're looking at a median progression-free survival of about 14 months in second-line-plus patients, which is quite impressive."
- Andrew Robbins (Cogent Biosciences CEO): "Importantly, there was a clear benefit across all mutational patient subgroups... We plan to launch bezuclastinib later this year and are well prepared to ensure bezuclastinib combination access for GIST patients in need."