Bezuclastinib/Sunitinib Improves Efficacy Vs Sunitinib Alone in GIST

Positive efficacy responses were observed with bezuclastinib plus sunitinib (Sutent) in patients with imatinib (Gleevec)-resistant or intolerant gastrointestinal stromal tumors (GIST) in the phase 3 PEAK trial (NCT05208047), according to a press release from Cogent Biosciences.¹

At the data cutoff of September 30, 2025, the combination arm experienced a median progression-free survival (PFS) of 16.5 months vs 9.2 month for sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65; P <.0001). Additionally, the objective response rate was 46% in the combination arm vs 26% in the monotherapy arm (P <.0001).

The press release also highlighted that based on the results, the estimated median duration of treatment for the bezuclastinib arm would exceed 19 months.

As of the safety cutoff, the combination was well tolerated with no unique risks observed. The most common grade 3 or higher treatment-emergent adverse effects (AEs) in either the combination or monotherapy arms included hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), alanine transaminase/aspartate transaminase increases (10.8% vs 1.4%), anemia (9.3% vs 4.8%), and diarrhea (7.8% vs 7.2%). Due to treatment-related AEs, 7.4% of patients in the bezuclastinib combination arm and 3.8% in the monotherapy arm discontinued treatment early.

Hepatic AEs were observed but were transient and manageable. Dose reduction in 12.7% of patients in the combination arm were due to alanine transaminase/aspartate transaminase increases, and 1.5% of patients discontinued treatment. All grade 3 alanine transaminase/aspartate transaminase increases resolved, and no grade 4 instances were reported.

A full analysis of the data will be reported in the first half of 2026. The drug’s developer plans to submit a new drug application to the FDA in the first half of 2026, as well.

“The results from the PEAK trial are truly transformative and practice changing,” Neeta Somaiah, MD, professor and department chair in the Department of Sarcoma Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in the press release.¹ “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.”

A total of 442 patients is expected to be enrolled in the study.² Sunitinib will be given at 37.5 mg every day with or without bezuclastinib. The primary end point was PFS. Secondary end points included overall survival, ORR, disease control rate, time to response, duration of response, and safety.

Key inclusion criteria were having confirmed, locally advanced, metastatic, and/or unresectable GIST; documented disease progression on or intolerance of imatinib; at least 1 measurable lesion by mRECIST criteria; an ECOG performance status of 0 to 2; and having clinically acceptable local laboratory screening results.

Exclusion criteria were having PDGFR-driving mutations, clinically significant cardiac disease, major surgeries within 4 weeks of the first dose of study drug, gastrointestinal abnormalities, active bleeding, or having received sunitinib within 3 weeks.

“It is a historic day for Cogent Biosciences and the GIST patient community,” Andrew Robbins, Cogent’s president and chief executive officer, said in the press release.¹ “We are extremely excited to announce positive results from the phase 3 PEAK trial of bezuclastinib plus sunitinib, which have far surpassed our expectations for the activity of this combination in patients with imatinib-resistant or intolerant GIST. With these incredible results, including a greater than 7-month improvement on median PFS—reducing the rate of progression or death by half—the bezuclastinib combination is poised to become the new standard of care for treatment in the second-line for patients with GIST. We are pleased to have an existing Expanded Access Program available to patients with GIST who have an urgency to access this novel treatment immediately and look forward to partnering with regulatory agencies to make this combination broadly available to patients as soon as possible.”

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 11, 2025. https://tinyurl.com/4cv8hwvf
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 11, 2025. https://tinyurl.com/d34wd45w