Bezuclastinib Plus Sunitinib Shows PFS Benefit in Second-Line GIST

Addition of the selective TKI bezuclastinib (CGT9486) to sunitinib (Sutent) led to a significant improvement in progression-free survival (PFS) vs sunitinib alone in patients with imatinib (Gleevec)–resistant or intolerant gastrointestinal stromal tumors (GISTs), meeting the primary end point of the phase 3 PEAK trial (NCT05208047).1

At the September 30, 2025, data cutoff, patients treated with the bezuclastinib combination experienced a 50% reduction in the risk of disease progression or death vs the current standard-of-care (SOC) sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65; P < .0001). The median PFS was 16.5 months with the combination vs 9.2 months with sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65; P < .0001). Moreover, bezuclastinib plus sunitinib produced an objective response rate (ORR) of 46% vs 26% with sunitinib monotherapy (P < .0001). At the time of this analysis, overall survival (OS) data remain immature.

Based on these data and the number of ongoing patients receiving treatment on the bezuclastinib arm, the estimated mean duration of treatment for the bezuclastinib combination is projected to exceed 19 months.

“It is a historic day for Cogent Biosciences and the GIST patient community,” Andrew Robbins, president and chief executive officer of Cogent, stated in a news release. “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 SOC for treatment of second-line GIST patients. We are pleased to have an existing Expanded Access Program available to GIST patients 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.”

Comprehensive analysis of the PEAK trial is ongoing, with full data expected to be presented at a major medical conference in the first half of 2026. Cogent Biosciences, the drug’s developer, plans to submit a new drug application with these data to the FDA for bezuclastinib in GIST during the same period.

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

What was the design of the PEAK trial?

PEAK is a global, randomized, multi-part phase 3 study evaluating bezuclastinib plus sunitinib compared with sunitinib monotherapy in adult patients with histologically confirmed locally advanced, metastatic, or unresectable GIST and documented disease progression on or intolerance to imatinib.2

Part 1 included 2 components: confirmation of the optimal dose of the updated bezuclastinib (CGT9486) formulation in approximately 20 patients who received at least 1 prior line of therapy for GIST, and evaluation of potential drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who received at least 2 prior TKIs.

Part 2 enrolled approximately 388 patients who were intolerant to, or had progressed on, imatinib alone. Eligible patients were required to have a molecular pathology report, at least 1 measurable lesion per mRECIST 1.1 criteria, and an ECOG performance status of 0 to 2. Participants were randomly assigned 1:1 to receive 37.5 mg of sunitinib daily with or without CGT9486. CGT9486 monotherapy was continued until steady state was achieved, after which both agents were administered orally until protocol-defined stopping rules were met.

A separate drug-drug interaction substudy was designed to assess whether CGT9486 acts as a CYP3A4 inducer in approximately 16 patients who had received at least 1 prior line of GIST therapy.

Primary end points were pharmacokinetics in part 1 and PFS in part 2. Secondary end points across both parts included OS, ORR, time to response, duration of response, and safety.

What is the safety profile of beclistamab plus sunitinib?

At the data cutoff, the combination of bezuclastinib and sunitinib was generally well tolerated, and toxicities were in line with the established profile of sunitinib monotherapy.1 No new safety signals were observed.

The most frequent grade 3 or higher treatment-emergent adverse effects (AEs) with the bezuclastinib combination vs sunitinib monotherapy were hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), increased alanine/aspartate aminotransferase levels (ALT/AST; 10.8% vs 1.4%), anemia (9.3% vs 4.8%), and diarrhea (7.8% vs 7.2%). Treatment discontinuation due to treatment-related AEs occurred in 7.4% of patients receiving the combination and 3.8% receiving sunitinib alone.

Hepatic AEs were largely transient, manageable, and reversible laboratory abnormalities. In the combination arm, elevated ALT/AST levels led to bezuclastinib dose reductions in 12.7% of patients, with only 3 patients (1.5%) discontinuing treatment for ALT/AST elevations. All grade 3 elevations resolved, and no grade 4 ALT/AST elevations were observed.

“Imatinib-resistant or intolerant GIST patients have waited nearly 20 years for a new second-line treatment option. The remarkable results of the PEAK study suggest that [this] wait has come to an end,” Sara Rothschild, executive director of The Life Raft Group, concluded in the press release. “Like so many in the GIST community, we’ve actively followed this trial with real anticipation. On behalf of [patients with] GIST around the world, we share our excitement for the hope that the bezuclastinib combination may bring these patients and their families.”

References

1. Cogent Biosciences reports positive results from bezuclastinib PEAK phase 3 trial in gastrointestinal stromal tumors (GIST). News release. Cogent. November 10, 2025. Accessed November 10, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-reports-positive-results-bezuclastinib-peak
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://classic.clinicaltrials.gov/ct2/show/NCT05208047