Bezuclastinib Combo Yields Promising Efficacy in Second-Line GIST, Is Poised for NDA Submission

The investigational combination of bezuclastinib (CGT9486) and sunitinib (Sutent) yielded clinically meaningful benefits with favorable tolerability in patients with gastrointestinal stromal tumors (GIST) who are resistant or intolerant to imatinib (Gleevec), according to topline data from the phase 3 PEAK trial (NCT05208047).¹

As of the September 30, 2025, cutoff date, patients who were treated with the combination experienced significantly prolonged median progression-free survival (mPFS) compared with those treated with sunitinib monotherapy, the current standard of care (16.5 months vs 9.2 months; HR, 0.50; 95% CI, 0.39-0.65; P <.0001). The HR of 0.50 amounts to a 50% reduction in the risk of disease progression or death by the combination, indicating strong performance in the study’s primary end point. Data for overall survival were immature at the time of analysis.

Further, responses increased by 20% with the combination compared with sunitinib alone, with objective response rates (ORRs) of 46% and 26%, respectively (P <.0001).

Regarding safety, the combination was well tolerated by patients. The most common grade 3 or higher treatment-emergent adverse events (AEs) included hypertension (29.4%), neutropenia (15.2%), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level elevations (10.8%), anemia (9.3%), and diarrhea (7.8%). ALT/AST level elevations specifically resulted in dose reductions in 12.7% of patients; all grade 3 events were resolved by the cutoff date. Treatment discontinuation due to treatment-related AEs occurred in 7.8% of patients receiving the combination vs 3.8% of patients receiving standard of care.

These positive data continue a promising trend following a previous readout at the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Based on the new data, Cogent Biosciences, the sponsor, has announced plans for submission of a new drug application of the combination in this indication to the FDA in early 2026.² With data collection still ongoing, the sponsor has also announced plans to present full data at a medical conference next year.

“With these incredible results, including a greater than [7]-month improvement on mPFS—reducing the rate of progression or death by half—the bezuclastinib combination is poised to become the new standard of care for treatment of second-line patients [with GIST],” said Andrew Robbins, president and CEO of Cogent Biosciences, in a news release.¹

In addition, the sponsor announced the availability of an expanded access program (EAP) for the combination,³ which will provide the combination to patients with GIST who have no comparable or satisfactory alternative therapy options across 4 US sites.

“We are pleased to have an existing [EAP] 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,” Robbins added.¹

The Unmet Need in GIST

GIST is a rare disease for which the tyrosine kinase inhibitor (TKI) imatinib is widely used as first-line treatment; however, those with more uncommon KIT exon mutations often exhibit poorer responses and develop resistance to the drug.⁴ The TKI sunitinib has therefore been the standard option for second-line treatment. Adding the selective KIT inhibitor bezuclastinib to sunitinib is proposed to increase the potency of second-line treatment by inhibiting key driver mutations in the KIT gene.

If approved, the combination would provide a new, potentially stronger option for patients who have historically lacked treatment options in this setting.

PEAK Trial Design

The phase 3 PEAK trial is a randomized, open-label, multicenter, multipart study of bezuclastinib plus sunitinib that enrolled 442 patients with locally advanced, unresectable, or metastatic GIST who received at least 1 prior line of therapy.⁵ The initial stages of the study, a single-arm optimized formulation lead-in (part 1a) and investigational drug-drug interaction portion (part 1b), involved approximately 48 patients to investigate the pharmacokinetics of the combination.

In the randomized second part of the study, approximately 388 patients who did not respond to imatinib therapy were randomly assigned 1:1 to receive either 600 mg of bezuclastinib plus 37.5 mg of sunitinib daily or 37.5 mg of sunitinib alone.

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/t38vzfuu

2. Cogent hits ‘unprecedented’ efficacy in rare stomach cancer, clearing path to FDA. News release. BioSpace. November 11, 2025. Accessed November 11, 2025. https://tinyurl.com/3s5pyvus

3. Expanded access to bezuclastinib to be coadministered with sunitinib for patients with gastrointestinal stromal tumors. ClinicalTrials.gov. Updated November 5, 2025. Accessed November 11, 2025. https://www.clinicaltrials.gov/study/NCT06948955

4. Jones RL, Golčić M. Recent advances in the systemic treatment of gastrointestinal stromal tumors. Cancer Biol Med. 2023;20(10):701-705. doi:10.20892/j.issn.2095-3941.2023.0302

5. (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://www.clinicaltrials.gov/study/NCT05208047