Cogent Biosciences announced that the FDA has accepted its New Drug Application (NDA) for bezuclastinib in combination with sunitinib for patients with gastrointestinal stromal tumors (GIST) who have received prior treatment with imatinib. The application has been granted Priority Review with a PDUFA target action date of November 30, 2026.

Clinical Takeaway

The bezuclastinib-sunitinib combination represents the first treatment to demonstrate statistically significant advantage against an active comparator in GIST patients, achieving a 50% reduction in risk of disease progression or death compared to sunitinib monotherapy (HR=0.50, 95% CI: 0.39-0.65, p<0.0001).

Drug Profile & Mechanism

Bezuclastinib is a selective tyrosine kinase inhibitor designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. These exon 17 mutations are found in patients with advanced GIST, a cancer with strong dependence on oncogenic KIT signaling.

Target Population

The NDA filing is for patients with gastrointestinal stromal tumors (GIST) who have received prior treatment with imatinib, specifically those with imatinib-resistant or intolerant disease.

Study Design

The PEAK trial is a global, randomized Phase 3 clinical trial evaluating bezuclastinib in combination with sunitinib versus sunitinib monotherapy in patients with imatinib-resistant or intolerant GIST. Data cutoff was September 30, 2025.

Efficacy Outcomes

  • Primary Endpoint (Progression-Free Survival):
    • Median PFS: 16.5 months (combination) vs 9.2 months (sunitinib alone)
    • Hazard ratio: 0.50 (95% CI: 0.39-0.65)
    • P-value: <0.0001
  • Objective Response Rate:
    • 46% of patients achieved objective response with combination therapy
    • 26% of patients achieved objective response with sunitinib monotherapy
  • Overall Survival: Data remains immature

Safety Profile

The bezuclastinib combination was generally well tolerated, with no unique risks observed compared to the known safety profile of sunitinib.

  • Most Common Grade 3+ Adverse Events (combination vs sunitinib):
    • Hypertension: 29.4% vs 27.4%
    • Neutropenia: 15.2% vs 15.4%
    • ALT/AST increased: 10.8% vs 1.4%
    • Anemia: 9.3% vs 4.8%
    • Diarrhea: 7.8% vs 7.2%
  • Treatment Discontinuation: 7.4% (combination) vs 3.8% (sunitinib) due to treatment-related adverse events
  • Hepatic Events: Predominantly transient and manageable lab abnormalities; majority were low grade, non-serious, reversible, and asymptomatic
  • ALT/AST Management: Led to dose reductions in 12.7% of patients; only 1.5% discontinued bezuclastinib for ALT/AST elevations

Regulatory Timeline & Status

  • Priority Review Status: Granted by FDA
  • PDUFA Date: November 30, 2026
  • Advisory Committee: FDA indicates no plans to hold an advisory committee at this time
  • Previous Designations: Breakthrough Therapy Designation and Real-Time Oncology Review
  • Expanded Access Program: Active for eligible U.S. patients with GIST

Key Clinical Implications

✔ First combination therapy to demonstrate statistically significant improvement over active comparator in GIST

✔ Substantial clinical benefit with 50% reduction in risk of disease progression or death

✔ Nearly doubled median PFS compared to current standard of care (16.5 vs 9.2 months)

✔ Enhanced objective response rate (46% vs 26%) in imatinib-resistant patients

✔ Manageable safety profile with no unique risks beyond known sunitinib effects

Bottom Line

The FDA acceptance of bezuclastinib plus sunitinib with Priority Review represents a significant milestone for GIST treatment. The groundbreaking PEAK trial results demonstrate unprecedented efficacy in imatinib-resistant GIST patients, with the potential to establish a new standard of care for this challenging patient population. Full trial results will be presented at ASCO 2026 on May 30, with regulatory decision expected by November 30, 2026.

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