FDA Grants BTD to Bezuclastinib Combo in Gastrointestinal Stromal Tumors

The FDA has granted breakthrough therapy designation to bezuclastinib in combination with sunitinib (Sutent) for the treatment of patients with gastrointestinal stromal tumors (GISTs) who have demonstrated resistance or intolerance to imatinib (Gleevec), according to a press release from the developer, Cogent Biosciences.¹ This regulatory milestone aims to expedite the development and review of the combination therapy for a population that has lacked new second-line treatment options for nearly 2 decades.

Recently, the FDA accepted a new drug application (NDA) for bezuclastinib plus sunitinib in the same patient population under its Real-Time Oncology Review program, which allows for the pre-submission of NDA components to streamline the review process. The developer is on track to complete the full NDA submission for this indication in April 2026.²

Both recent FDA decisions were supported by primary efficacy and safety data from the global phase 3 PEAK trial (NCT05208047), which evaluated bezuclastinib, a selective tyrosine kinase inhibitor designed to inhibit the KIT D816V mutation, in combination with sunitinib against the current standard of care.

Clinical Efficacy and Survival Findings

The combination of bezuclastinib and sunitinib demonstrated a substantial and highly statistically significant clinical benefit for the primary end point of progression-free survival (PFS). According to results from the PEAK trial, the combination regimen reduced the risk of disease progression or death by 50% compared with sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65).

As assessed by blinded independent central review, the median PFS was 16.5 months for patients receiving the bezuclastinib combination vs 9.2 months for those treated with sunitinib alone. These findings suggest that the dual inhibition of the full spectrum of KIT mutations, specifically targeting exon 17 mutations that are often associated with resistance to earlier-line treatments, may provide a more robust therapeutic effect than current second-line standards.

“We are excited to announce this breakthrough therapy designation, which recognizes the potential for the bezuclastinib combination to substantially improve upon the currently available treatment options for patients with imatinib-resistant GIST,” stated Andrew Robbins, president and chief executive officer of Cogent Biosciences, in the news release.¹ “We look forward to the continued collaboration with the FDA as we work to bring the first new treatment option in over 20 years to this patient population.”

Trial Breakdown

The PEAK study was a global, randomized phase 3 clinical trial evaluating the safety and efficacy of bezuclastinib plus sunitinib vs sunitinib alone in approximately 442 patients with histologically confirmed locally advanced, unresectable, or metastatic GIST.³ This clinical investigation specifically recruited adult patients who demonstrated resistance or intolerance to prior treatment with imatinib and possessed at least 1 measurable lesion per modified RECIST v1.1 criteria with an ECOG performance status of 0 to 2.

The standardized treatment regimen involved the oral administration of sunitinib at a fixed dose of 37.5 mg daily for both study arms. In the combination arm, patients also received bezuclastinib, which was administered once daily following the optimization phase.

The trial’s primary outcome measure was PFS as determined by a blinded independent central review. Key secondary endpoints included the objective response rate, overall survival, and the duration of response.

Safety and Tolerability

The combination of bezuclastinib and sunitinib was well tolerated by patients in the PEAK trial. Safety results indicated that the addition of bezuclastinib did not produce any new or unexpected safety risks when compared with the known safety profile of sunitinib monotherapy.

The developer reported that full results from PEAK are going to be presented at a major medical conference during the first half of 2026. An additional planned phase 2 trial will investigate bezuclastinib plus sunitinib in first-line GIST among patients with exon 9 who are naïve to, or recently began treatment with, imatinib.

Reference

1. Cogent Biosciences Announces Breakthrough Therapy Designation for Bezuclastinib in Combination with Sunitinib for Patients with Gastrointestinal Stromal Tumors (GIST). News release. Cogent Biosciences, Inc. January 26, 2026. Accessed January 27, 2026. https://tinyurl.com/mrxz9u36
2. Cogent Biosciences to initiate new drug application (NDA) submission for bezuclastinib under real-time oncology review (RTOR). News release. Cogent Biosciences, Inc. January 20, 2026. Accessed January 27, 2026. https://tinyurl.com/34budv6y
3. (Peak) A phase 3 randomized trial of CGT9486+sunitinib vs. sunitinib in subjects with gastrointestinal stromal tumors. ClinicalTrials.gov. Updated November 25, 2025. Accessed January 27, 2026. https://tinyurl.com/b3f93yj6