Cogent Biosciences (Nasdaq: COGT), based in Waltham, Massachusetts, has submitted a New Drug Application (NDA) to the US FDA for bezuclastinib in combination with sunitinib (Sutent) in patients with gastrointestinal stromal tumors (GIST) who have received prior treatment with imatinib. The FDA has accepted the application and granted Priority Review, with a PDUFA target action date of November 30, 2026.
The NDA seeks approval for bezuclastinib used in combination with sunitinib in the second-line GIST setting, specifically in patients with imatinib-resistant or intolerant disease. The FDA has indicated it does not plan to convene an advisory committee and has not identified any potential review issues at this stage, the company said.
The filing builds on prior regulatory designations, including Breakthrough Therapy Designation and eligibility for Real-Time Oncology Review, both granted following Phase III PEAK trial data. The combination of Priority Review and these earlier designations reflects the FDA’s assessment of the unmet need in this patient population, where sunitinib monotherapy has remained the standard of care since its approval in 2006.
The NDA is supported by data from the Phase III PEAK trial (NCT05208047), a global, randomized, open-label study evaluating bezuclastinib in combination with sunitinib versus sunitinib monotherapy in patients with imatinib-resistant or intolerant advanced GIST.
As of the data cutoff of September 30, 2025, the combination arm met the primary endpoint of progression-free survival (PFS) with a hazard ratio of 0.50 (95% CI: 0.39–0.65; p < 0.0001), corresponding to a 50% reduction in the risk of disease progression or death compared with sunitinib alone. Median PFS, assessed by blinded independent central review, was 16.5 months for the combination versus 9.2 months for sunitinib monotherapy.
In imatinib-resistant patients, the objective response rate (ORR) was 46% in the combination arm compared with 26% in the sunitinib arm. Overall survival data remain immature.
On safety, Grade 3 or higher treatment-emergent adverse events occurring in either arm included hypertension (29.4% combination vs 27.4% sunitinib), neutropenia (15.2% vs 15.4%), elevated 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 adverse events occurred in 7.4% of patients in the combination arm versus 3.8% in the sunitinib arm. Hepatic laboratory abnormalities were predominantly low grade, transient, and reversible; all Grade 3 ALT/AST elevations resolved and no Grade 4 elevations were reported. Bezuclastinib dose reductions due to ALT/AST elevations occurred in 12.7% of patients, with 1.5% discontinuing bezuclastinib for this reason.
Scientific and competitive context
Bezuclastinib is a selective KIT tyrosine kinase inhibitor designed to inhibit KIT exon 17 activation-loop mutations alongside primary KIT mutations — a resistance mechanism that limits the efficacy of earlier-generation TKIs including sunitinib. In the GIST setting, acquired resistance to imatinib is driven predominantly by secondary KIT kinase domain mutations, many of which fall in the activation loop and are poorly covered by sunitinib.
The filing adds to a second-line GIST landscape that has seen no new approved therapy since sunitinib’s approval nearly two decades ago. Approved agents across lines of therapy include regorafenib (Stivarga) in the third-line setting, avapritinib (Ayvakit) for PDGFRA exon 18-mutant disease, and ripretinib (Qinlock) for patients who have received three or more prior kinase inhibitors. None of these approvals addressed the second-line population with a combination approach or demonstrated superiority over an active comparator in a randomized Phase III trial in this setting, according to the available clinical record.
The PEAK data, if reflected in an eventual approval, would position bezuclastinib plus sunitinib as the first regimen to demonstrate a statistically significant PFS advantage over sunitinib monotherapy in a randomized trial in post-imatinib GIST. Full results from PEAK are scheduled for oral presentation at the American Society of Clinical Oncology annual meeting on May 30, 2026.
This article was generated with AI assistance and reviewed and edited by the AllSci editorial team
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