Bezuclastinib Plus Sunitinib Achieves Strong PFS Benefit in Phase III PEAK Trial for Imatinib-Resistant GIST

Cogent Biosciences has announced positive results from its Phase III PEAK clinical trial (NCT05208047) evaluating bezuclastinib plus sunitinib in participants with imatinib-resistant or intolerant gastrointestinal stromal tumors (GIST).¹

Bezuclastinib shows strong PFS benefit

The bezuclastinib-sunitinib combination demonstrated a statistically significant benefit in the PEAK trial’s primary endpoint of progression free survival (PFS), reducing the risk of disease progression or death by 50% compared to standard of care.

Further results from the trial showed:

• Median PFS was 16.5 months for the bezuclastinib combination versus 9.2 months for sunitinib monotherapy.
• The combination achieved a 46% objective response rate (ORR) in imatinib-resistant patients, versus 26% with sunitinib.
• Overall survival data are still immature and not yet conclusive.
• Estimated mean duration of treatment with the bezuclastinib combination is projected to exceed 19 months.

In a press release, Neeta Somaiah, MD, professor and department chair, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, said: “The results from the PEAK trial are truly transformative and practice changing. Following regulatory approval, I expect the bezuclastinib combination to be rapidly adopted as the new standard of care treatment for the majority of patients in the second-line GIST setting.”

Safety and adverse events

In terms of safety, the bezuclastinib combination was generally well tolerated, with no new safety risks compared to sunitinib.

• Most common Grade 3+ adverse events included hypertension (29.4% vs. 27.4%), neutropenia (15.2% vs. 15.4%), ALT/AST increases (10.8% vs. 1.4%), anemia (9.3% vs. 4.8%), and diarrhea (7.8% vs. 7.2%).
• Treatment discontinuation due to adverse events occurred in 7.4% of patients on the combination versus 3.8% on sunitinib.
• Hepatic lab abnormalities were mostly transient, reversible, low grade, and asymptomatic; only 1.5% discontinued due to ALT/AST elevations.
• ALT/AST elevations led to dose reductions in 12.7% of combination-treated patients; all Grade 3 elevations resolved, and no Grade 4 events were reported.

Based on these positive findings, Cogent plans to submit a New Drug Application (NDA) to the FDA for bezuclastinib in GIST in the first half of 2026.

PEAK trial design

PEAK is an open-label, international, multicenter study:²

• Total planned enrollment of ~442 patients across multiple parts.
  • Part 1: Dose confirmation of the updated bezuclastinib formulation (~20 patients) and evaluation of drug-drug interactions with sunitinib (~18 patients) in patients with ≥1 prior line of therapy.
  • Part 2: Randomized comparison of bezuclastinib plus sunitinib versus sunitinib alone in ~388 patients who are imatinib-intolerant or resistant; patients randomized 1:1.
• Additional substudy (~16 patients) assessing CGT9486 as a potential CYP3A4 inducer.

Research in non-advanced systemic mastocytosis

Earlier in July, Cogent released positive Phase II data from bezuclastinib in non-advanced systemic mastocytosis (NonAdvSM). Part 2 of the SUMMIT trial (NCT05186753) demonstrated a significant difference in the mean change in total symptom score at 24 weeks for those treated with bezuclastinib, meeting its primary endpoint.³

• The mean total symptom score change with treatment was –24.3, versus –15.4 for placebo (placebo-adjusted difference –8.91; p=0.0002).
• The treatment markedly reduced mast cell burden: 87.4% of patients on bezuclastinib achieved ≥50% reduction in serum tryptase, compared to 0% with placebo.
• Bezuclastinib demonstrated a favorable safety and tolerability profile, supporting chronic use for those with NonAdvSM.

According to Cogent, these results set new benchmarks for both absolute and placebo-adjusted symptom improvement in this patient population.

As of the announcement, Cogent was on track to submit an NDA for bezuclastinib in NonAdvSM by the end of 2025.

References

1. Cogent Biosciences Reports Positive Results from Bezuclastinib PEAK Phase 3 Trial in Gastrointestinal Stromal Tumors (GIST). News release. Cogent Biosciences. November 10, 2025. Accessed November 10, 2025. https://www.globenewswire.com/news-release/2025/11/10/3184357/0/en/Cogent-Biosciences-Reports-Positive-Results-from-Bezuclastinib-PEAK-Phase-3-Trial-in-Gastrointestinal-Stromal-Tumors-GIST.html

2. (Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors. ClinicalTrials.gov. Updated May 9, 2025. Accessed November 10, 2025. https://clinicaltrials.gov/study/NCT05208047

3. Cogent Biosciences Announces Positive Top-line Results Achieving Statistical Significance Across All Primary and Key Secondary Endpoints from the SUMMIT Trial of Bezuclastinib in Patients with Non-Advanced Systemic Mastocytosis. News release. Cogent Biosciences. July 7, 2025. Accessed November 10, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-positive-top-line-results-achieving