FDA Grants Priority Review to Bezuclastinib Plus Sunitinib for Patients With Advanced GIST

The FDA has accepted the new drug application (NDA) for bezuclastinib (Cogent Biosciences) in combination with sunitinib (Sutent; Pfizer) for the treatment of patients with advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib (Gleevec; Novartis), granting the application Priority Review and assigning a Prescription Drug User Fee Act target action date of November 30, 2026. The regulatory milestone follows positive findings from the phase 3 PEAK trial (NCT05208047), which demonstrated statistically significant improvements in progression-free survival (PFS) and objective response rate (ORR) with the investigational combination compared with standard second-line sunitinib monotherapy.¹

GIST is the most common mesenchymal malignancy of the gastrointestinal tract and is frequently driven by activating KIT mutations. Although tyrosine kinase inhibitors (TKIs) such as imatinib and sunitinib have transformed management of the disease, resistance mutations remain a major therapeutic challenge, particularly in advanced disease settings.²

Phase 3 PEAK Trial Demonstrates Significant PFS Benefit

The global, randomized phase 3 PEAK study evaluated bezuclastinib plus sunitinib against sunitinib monotherapy in patients with imatinib-resistant or imatinib-intolerant advanced GIST. The study enrolled 413 patients who were randomly assigned 1:1 to receive either bezuclastinib 600 mg once daily combined with sunitinib 37.5 mg daily or sunitinib alone.³

According to results presented during an oral abstract session at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO), the combination therapy reduced the risk of disease progression or death by 50% compared with sunitinib monotherapy (HR, 0.50; 95% CI, 0.39-0.65; P < .0001). Median PFS was 16.5 months in the combination arm compared with 9.2 months in the monotherapy arm.^1-3

Investigators also reported a substantial improvement in ORR. Patients treated with bezuclastinib plus sunitinib achieved an ORR of 46% compared with 26% among those receiving sunitinib alone. Overall survival data remain immature at this time.^1-3

“These findings represent the first time a treatment has demonstrated a statistically significant advantage against an active comparator in GIST patients,” Cogent Biosciences stated in its announcement regarding the FDA acceptance.¹

Dual KIT Inhibition Strategy Targets Resistance Mutations

Bezuclastinib is an oral, selective type 1 KIT inhibitor designed to target primary and secondary KIT resistance mutations commonly observed in advanced GIST.³ The rationale behind the combination approach centers on pairing bezuclastinib with sunitinib, a type 2 TKI, to broaden inhibition across heterogeneous resistance mutations that frequently develop after frontline therapy.^2,3

Approximately 60% of patients enrolled in the PEAK trial had activating KIT exon 11 mutations only, while 14% had exon 9 mutations only.³ Resistance mutations emerging during treatment have historically limited the durability of currently available TKIs, contributing to disease progression and reduced treatment options.^2,3

Safety Profile Appears Manageable

Investigators reported that the combination regimen was generally well tolerated, with no new safety signals identified compared with the known safety profile of sunitinib. Rates of grade 3 or higher adverse events were largely comparable between treatment groups.^1,3

The most common grade 3 or higher treatment-emergent adverse events in the combination arm included hypertension, neutropenia, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), anemia, and diarrhea. Elevated hepatic laboratory values were primarily transient, asymptomatic, and manageable with dose modification.^1,3

ALT/AST elevations led to bezuclastinib dose reductions in approximately 13% of patients and treatment discontinuation in 1.5% of patients receiving the combination therapy. Importantly, all grade 3 hepatic adverse events resolved, and no grade 4 hepatic events were observed. No treatment-related adverse events resulted in death in the combination arm.^1,3

If approved, bezuclastinib plus sunitinib could represent a new second-line standard of care for patients with advanced GIST following imatinib treatment, offering improved disease control in a setting where resistance mutations continue to drive unmet clinical need.

REFERENCES

1. Cogent Biosciences Announces FDA Acceptance of New Drug Application (NDA) with Priority Review for Bezuclastinib in Combination with Sunitinib for Patients with GIST. Cogent Biosciences. Published May 28, 2026. Accessed June 3, 2026. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-fda-acceptance-new-drug-0

2. National Cancer Institute: Gastrointestinal Stromal Tumors Treatment (PDQ)–Health Professional Version. Accessed June 3, 2026. https://www.cancer.gov/types/soft-tissue-sarcoma/hp/gist-treatment-pdq

3. Wagner AJ, Trent JC, Tap WD, et al. Primary results of the phase 3 Peak study of bezuclastinib + sunitinib vs sunitinib monotherapy in advanced gastrointestinal stromal tumors (GIST). J Clin Oncol. 2026;44(suppl 16):11500. doi:10.1200/JCO.2026.44.16_suppl.11500