Regulatory & Policy

Cogent files KIT-targeted bezuclastinib plus sunitinib for approval in imatinib-pretreated GIST

Cogent Biosciences has submitted a New Drug Application to the US FDA for bezuclastinib, a selective KIT tyrosine kinase inhibitor, seeking approval for use...

Edited by Robert McTiernan··4 min read

Cogent Biosciences (NASDAQ: COGT) has submitted a New Drug Application to the US FDA for bezuclastinib, a selective KIT tyrosine kinase inhibitor, seeking approval for use in combination with sunitinib in patients with gastrointestinal stromal tumors (GIST) who have received prior treatment with imatinib. The filing marks the first NDA submission for bezuclastinib in GIST and positions the drug as the first potential new FDA-approved therapy specifically for second-line post-imatinib GIST since sunitinib’s 2006 approval.

The NDA was submitted under the US FDA's Real-Time Oncology Review program, a pathway designed to allow rolling review of data prior to formal submission completion. Bezuclastinib also holds Breakthrough Therapy Designation for GIST, granted earlier in 2026, the company said. No PDUFA date has been disclosed. The filing seeks approval for bezuclastinib administered in combination with sunitinib, targeting patients who have progressed on or are resistant to imatinib — the established first-line standard of care for KIT-driven GIST.

The submission is supported by data from the PEAK trial, a global, randomized Phase III study evaluating bezuclastinib plus sunitinib against sunitinib monotherapy in imatinib-pretreated GIST patients. Top-line results from PEAK were reported in November 2025. The combination arm met the primary endpoint of progression-free survival, reducing the risk of disease progression or death by 50% relative to sunitinib alone, with a hazard ratio of 0.50 (95% CI: 0.39–0.65). Median PFS, assessed by blinded independent central review, was 16.5 months in the bezuclastinib combination arm versus 9.2 months with sunitinib monotherapy. The objective response rate was 46% in the combination group compared with 26% for sunitinib. Overall survival data remain immature. The company said the combination was generally well tolerated, with no unique risks identified beyond the known safety profile of sunitinib. Full PEAK data are expected to be presented at a major medical meeting in the first half of 2026.

The clinical context

The clinical rationale for bezuclastinib in this setting is grounded in the molecular biology of imatinib resistance. The majority of GIST are driven by activating mutations in the KIT receptor tyrosine kinase, most commonly in exons 9 and 11. Resistance to imatinib typically arises through secondary mutations in the KIT activation loop, particularly in exon 17 — a region that existing approved agents, including sunitinib, cover with limited efficacy. Bezuclastinib is designed to selectively inhibit KIT exon 17 mutations, including KIT D816V, addressing the dominant molecular mechanism underlying acquired imatinib resistance. Adding bezuclastinib to sunitinib is intended to provide complementary kinase coverage across both primary and secondary resistance mutations.

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The GIST treatment landscape has followed a sequential TKI paradigm since imatinib received FDA approval in 2002. Sunitinib was approved in the second-line setting in 2006, and regorafenib followed in the third line in 2013. More recently, avapritinib (Ayvakit) received approval in 2020 for patients with PDGFRA exon 18 mutations, including the D842V variant, while ripretinib (Qinlock) was approved the same year for patients who have received three or more prior kinase inhibitors. Despite this sequential framework, no new therapy has been approved specifically in the second-line post-imatinib setting since sunitinib. An attempt by ripretinib to displace sunitinib in second-line GIST — the INTRIGUE trial — did not demonstrate superiority, leaving sunitinib entrenched as the standard comparator.

The PEAK data represent the first Phase III evidence of a combination strategy outperforming sunitinib monotherapy in this patient population. The 7.3-month improvement in median PFS and the near-doubling of the objective response rate are notable in a disease where responses to second-line therapy have historically been modest. The company reported that the estimated mean treatment duration for patients on the bezuclastinib combination arm is projected to exceed 19 months at the time of data cutoff, though overall survival data are not yet mature and will be required to fully characterise the clinical benefit.

Cogent is also advancing bezuclastinib in additional settings. The company said it is on track to initiate a Phase II trial in Q2 2026 investigating bezuclastinib plus sunitinib in first-line GIST patients with KIT exon 9 mutations who are treatment-naive or have recently initiated imatinib. A separate NDA submission for bezuclastinib in advanced systemic mastocytosis — where the KIT D816V mutation is the primary disease driver — remains on track for the first half of 2026, the company said. Expanded access programs for both GIST and systemic mastocytosis are currently active in the United States.

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