FDA Grants Priority Review for Bezuclastinib Plus Sunitinib in GIST

The FDA has accepted a new drug application (NDA) for bezuclastinib (CGT9486) in combination with sunitinib (Sutent) for patients with gastrointestinal stromal tumors (GIST) who have received prior imatinib (Gleevec) therapy, granting priority review with a PDUFA target action date of November 30, 2026, according to a news release from Cogent Biosciences.¹

The FDA communicated that no advisory committee meeting is currently planned and no potential review issues have been identified. The application is supported by primary results from the phase 3 PEAK trial (NCT05208047), which will be presented in an oral session at the 2026 ASCO Annual Meeting on May 30 in Chicago.²

The NDA acceptance builds on prior designations including breakthrough therapy designation and real-time oncology review, reflecting the FDA's assessment of the unmet need and clinical promise of the regimen in this setting.¹

PEAK Trial Design

PEAK was a global, randomized, multipart study. The phase 3 randomized portion (part 2) enrolled 413 patients with advanced GIST who had received prior imatinib therapy. Patients were randomly assigned 1:1 to bezuclastinib 600 mg once daily plus sunitinib 37.5 mg once daily (n = 204) or sunitinib 37.5 mg once daily monotherapy (n = 209). The primary end point was blinded independent central review (BICR)-assessed median progression-free survival (mPFS). Key secondary end points included objective response rate (ORR) per BICR and overall survival (OS). Crossover from the monotherapy arm to the combination was permitted at BICR-confirmed progression.

The trial enrolled a heavily pretreated population with a median age of 63 years (range, 30–88). At baseline, 59.6% of patients had activating KIT mutations in exon 11 only and 14.0% had mutations in exon 9 only.

Efficacy Results

As of the September 30, 2025 data cutoff, the bezuclastinib combination demonstrated a highly statistically significant improvement in the primary end point.^1,2 Median PFS was 16.5 months (95% CI, 13.8-19.2) for the combination vs 9.2 months (95% CI, 7.2-11.0) for sunitinib monotherapy, representing a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.39-0.65; P <.0001). ORR also improved significantly with the combination vs monotherapy (46% vs 26%; risk difference, 20%; 95% CI, 10.6-28.6; P <.0001). OS data remain immature as of the data cutoff.

According to Cogent Biosciences, the bezuclastinib combination is the first treatment to demonstrate a statistically significant advantage over an active comparator in this patient population.

Safety Profile

The combination was generally well tolerated, with no new safety signals identified beyond the known profile of sunitinib. Overall incidence of adverse events was similar between arms, and grade 3 or higher events were broadly comparable. The most common grade 3 or higher treatment-emergent adverse events in the combination vs monotherapy arms included hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), ALT (alanine aminotransferase)/AST (aspartate aminotransferase) elevation (10.8% vs 1.4%), anemia (9.3% vs 4.8%), and diarrhea (7.8% vs 7.2%).

Hepatic adverse events in the combination arm were predominantly low-grade, transient, non-serious, reversible, and asymptomatic. ALT/AST elevations led to bezuclastinib dose reductions in 12.7% of patients and discontinuation in 1.5%; all grade 3 hepatic events resolved and no grade 4 elevations were reported. No treatment-related adverse events led to death in the combination arm. Treatment discontinuation due to treatment-related adverse events occurred in 7.4% of combination patients vs 3.8% on monotherapy.

Mechanism and Context

Bezuclastinib is an oral, selective type 1 KIT tyrosine kinase inhibitor (TKI) designed to inhibit KIT exon 17 mutations including the D816V mutation, as well as primary and secondary resistance mutations. In combination with sunitinib, a type 2 TKI, the regimen is designed to address the heterogeneous resistance mutations that limit the durability of current approved second-line therapies in KIT-mutant GIST.

The full primary results will be presented by Andrew J. Wagner, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, at the ASCO Sarcoma Oral Abstract Session (Abstract 11500) on May 30, 2026. Cogent Biosciences has also established an expanded access program for eligible US patients with GIST pending regulatory action.

REFERENCES

1. Cogent Biosciences announces FDA acceptance of new drug application (NDA) with priority review for bezuclastinib in combination with sunitinib for patients with GIST. News release. Cogent Biosciences. May 28, 2026. Accessed May 28, 2026. https://tinyurl.com/ye7hhrhy

2. Wagner AJ, Trent JC, Tap WD, et al. Primary results of the phase 3 Peak study of bezuclastinib + sunitinib vs sunitinib monotherapy in advanced gastrointestinal stromal tumors (GIST). J Clin Oncol. 2026;44(suppl 16):11500. doi:10.1200/JCO.2026.44.16_suppl.11500