FDA Grants Breakthrough Designation for Bezuclastinib in GIST

The FDA has granted breakthrough therapy designation (BTD) for bezuclastinib in combination with sunitinib (Sutent) for the treatment of patients with gastrointestinal stromal tumors (GIST), according to a news release from Cogent Biosciences.¹

This designation specifically applies to patients who have previously received treatment with imatinib (Gleevec), marking a significant milestone in the second-line treatment landscape for this disease.

The Unmet Need in GIST

GISTs are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by oncogenic mutations in the KIT receptor tyrosine kinase. Although the introduction of imatinib revolutionized the first-line treatment of advanced GIST, nearly 90% of patients eventually experience disease progression due to the emergence of secondary mutations.²

Secondary resistance typically occurs through mutations in the KIT ATP-binding pocket (exons 13 and 14) or the activation loop (exons 17 and 18). Sunitinib is the current standard of care for second-line therapy; however, its efficacy is often limited because it primarily targets mutations in the ATP-binding pocket while remaining less effective against activation loop mutations. This biological gap leaves a significant number of patients with few effective options once imatinib fails.

Clinical Evidence from the PEAK Trial

The FDA's decision to grant BTD was supported by data from the registration-directed PEAK trial (NCT05208047). In this global, randomized phase 3 study, the combination of bezuclastinib and sunitinib demonstrated a substantial and highly statistically significant clinical benefit over sunitinib monotherapy.^3,4

According to the trial results, the combination therapy led to a median progression-free survival of 16.5 months, compared with 9.2 months for sunitinib alone. This represents a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.39-0.65; P <.0001). Furthermore, the objective response rate was 46% for the combination arm, nearly double the 26% observed in the monotherapy arm. These figures represent some of the highest efficacy metrics reported in a phase 3 trial for imatinib-resistant GIST.

Mechanism of Action and Safety

Bezuclastinib is a highly selective and potent tyrosine kinase inhibitor designed to target KIT exon 17 mutations, including the D816V mutation. By combining bezuclastinib with sunitinib, researchers aimed to create a dual-blockade strategy that covers a broader spectrum of both primary and secondary KIT mutations.

Safety data from the PEAK trial indicated that the combination was generally well tolerated, with no new safety risks identified beyond the known profile of sunitinib. Common grade 3 or higher adverse events included hypertension, neutropenia, and elevated liver enzymes which were described as transient and manageable.³

Impact on the GIST Treatment Landscape

The BTD status is intended to expedite the development and review of drugs for serious conditions where preliminary evidence shows potential for substantial improvement over existing therapies.

Following this announcement, Cogent Biosciences remains on track to complete its new drug application submission for the combination therapy in April 2026 under the previously granted Real-Time Oncology Review (RTOR) designation.¹ If approved, this combination is poised to become the new standard of care for second-line GIST, offering the first significant advancement in this patient population in over 2 decades.

The company plans to present full results from the PEAK trial at a major medical meeting during the first half of 2026. Additionally, it plans to initiate a phase 2 trial of the combination in previously untreated patients with GIST who have exon 9 mutations who are naive to imatinib or have recently initiated treatment with it.

References

1. Cogent Biosciences announces breakthrough therapy designation for bezuclastinib in combination with sunitinib for patients with gastrointestinal stromal tumors (GIST). News release. Cogent Biosciences. January 26, 2026. Accessed January 26, 2026. https://tinyurl.com/y2crmy9e

2. Abudurexiti N, Lou Y, Wu M, et al. The mechanisms of imatinib resistance in gastrointestinal stromal tumours: theoretical basis and therapeutic aspect. J Cell Mol Med. 2025;29(21):e70931. doi:10.1111/jcmm.70931

3. Trent J, Wagner A, Attia S, et al. Peak part 1 summary: A phase 3, randomized, open-label, multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol. 2025;43(suppl 4):826. doi:10.1200/JCO.2025.43.4_suppl.826.

4. Cogent Biosciences reports positive results from bezuclastinib PEAK phase 3 trial in gastrointestinal stromal tumors (GIST). News release. November 10, 2025. Accessed January 26, 2026.