Cogent Biosciences has submitted an NDA for bezuclastinib for patients with GIST who received prior imatinib.
Cogent Biosciences has completed the submission of a new drug application (NDA) to the FDA seeking the approval of bezuclastinib for the treatment of patients with gastrointestinal stromal tumors (GIST) who were previously treated with imatinib (Gleevec).1
The NDA was supported by data from the phase 3 PEAK trial (NCT05208047) and was submitted under the FDA’s Real-Time Oncology Review program.
Findings from PEAK reported in November 2025 demonstrated that patients who received bezuclastinib in combination with sunitinib (Sutent) achieved a median progression-free survival (PFS) of 16.5 months compared with 9.2 months among patients who were treated with sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65; P < .0001).2 The respective overall response rates (ORRs) were 46% and 26% (P < .0001).
“We are excited to complete our PEAK NDA submission, which marks a significant step toward bringing a new therapy to patients with second-line GIST,” Andrew Robbins, president and CEO of Cogent Biosciences, stated in a news release.1 “Based on the strength of the PEAK data, we believe the bezuclastinib combination has the potential to meaningfully change the treatment landscape for these patients. We are grateful to the patients, investigators, and study teams who made this possible.”
PEAK was an open-label, international, multicenter trial that enrolled adult patients with locally advanced, unresectable, or metastatic GIST.3 Patients were required to have documented disease progression on or intolerance to imatinib, an ECOG performance status of 0 to 2, at least 1 measurable lesion per mRECIST 1.1 criteria, and clinically acceptable laboratory results. Patients in part 1a of the study must have received at least 1 prior line of therapy for GIST, those in part 1b needed to have received at least 2 prior TKIs for GIST, and those in part 2 underwent prior treatment with imatinib only.
In parts 1a, 1b, and 2, patients received oral bezuclastinib in combination with sunitinib at 37.5 mg daily; those in the active comparator arm of part 2 received sunitinib monotherapy. The trial also included an experimental substudy arm, in which patients received a single dose of midazolam on days 1 and 16, oral bezuclastinib starting on day 2, and sunitinib starting on day 16 until study stopping rules were fulfilled.
The primary end points in parts 1a and 1b were pharmacokinetic measures; in part 2, the primary end point was PFS. Secondary end points included safety, overall survival, ORR, disease control rate, and duration of response.
Prior safety findings from PEAK revealed that the combination of bezuclastinib plus sunitinib was generally well tolerated. No unique risks were reported with the combination compared with the known safety profile of sunitinib monotherapy.2
The most common grade 3 or higher treatment-emergent adverse effects (AEs) in the combination and monotherapy arms included hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels (10.8% vs 1.4%), anemia (9.3% vs 4.8%) and diarrhea (7.8% vs 7.2%). Patients discontinued treatment due to treatment-related AEs at respective rates of 7.4% and 3.8%.
Hepatic AEs were mostly transient and manageable; a majority of these events were low-grade, non-serious, reversible, and asymptomatic. Dose reductions of bezuclastinib due to elevated AST/ALT levels occurred at a rate of 12.7% and 1.5% of patients discontinued treatment with the agent due to this event. Each instance of grade 3 increased ALT/AST levels were resolved, and no grade 4 elevations occurred.
Full data from PEAK are planned to be presented at a major medical meeting during the first half of 2026.1 Moreover, a phase 2 trial will be initiated this quarter to elucidate the benefit of the bezuclastinib plus sunitinib for the frontline treatment of patients with GIST with exon 9 mutations who are naive to, or recently initiated treatment with, imatinib.
