Bezuclastinib Plus Sunitinib Meets PFS End Point in KIT-Mutant GIST

Disease control was demonstrated with bezuclastinib plus sunitinib (Sutent) vs sunitinib monotherapy in patients with advanced, KIT-mutant gastrointestinal stromal tumors (GIST) who had progressed on or were intolerant to prior imatinib (Gleevec), according to results from the phase 3 PEAK trial (NCT05208047) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

The trial met its primary end point. Bezuclastinib plus sunitinib produced a median progression-free survival (PFS) of 16.5 months (95% CI, 13.8–19.2) compared with 9.2 months (95% CI, 7.2–11.0) for sunitinib alone, representing a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.39–0.65; P <.0001). The PFS benefit was consistent across all pre-specified subgroups, including age, sex, race, and all evaluated baseline KIT mutation profiles, including patients with exon 11 mutations (HR, 0.51), exon 13/14 mutations (HR, 0.44), and exon 17/18 mutations (HR, 0.40).

The combination also demonstrated a significantly superior objective response rate (ORR) of 45.6% (95% CI, 38.6%–52.7%) vs 25.8% (95% CI, 20.0%–32.3%) for sunitinib monotherapy (P <.0001), with complete responses in 6.4% vs 1.9% of patients. The disease control rate was 86.8% vs 76.1%, and the median duration of response was 15.7 months (95% CI, 12.2–not estimable) in the combination arm compared with 12.0 months (95% CI, 7.6–14.9) with sunitinib. PFS2, time from randomization to progression on the next line of therapy or death, was not yet reached in the bezuclastinib plus sunitinib arm vs a median of 21.0 months with sunitinib (HR, 0.57), underscoring the durability of the combination's benefit.

“The PEAK study met its primary end point: bezuclastinib plus sunitinib demonstrated significantly superior efficacy to sunitnib monotherapy,” Andrew J. Wagner, MD, PhD, chief medical officer and the medical director of Adult Ambulatory Oncology of the Dana-Farber Cancer Institute, said during the presentation. “No new safety risks were identified with the combination of bezuclastinib plus sunitinib.”

GIST is driven predominantly by activating KIT mutations in exons 9 and 11, which occur in up to 85% of patients. Despite imatinib's effectiveness against primary KIT mutations, approximately 60% of patients develop resistance within 2 years owing to the emergence of heterogeneous secondary KIT mutations, particularly in exons 13, 14, 17, and 18. Sequential tyrosine kinase inhibitor (TKI) monotherapies each inhibit only a subset of these resistance mutations, and combining approved KIT inhibitors has historically been constrained by overlapping toxicities. Bezuclastinib is a next-generation, highly selective oral KIT inhibitor with potent activity against resistance mutations in KIT exons 17 and 18; its selectivity, including the lack of activity against VEGFR2 and PDGFR, enables combination with sunitinib without additive toxicity concerns.

The PEAK trial enrolled 413 patients and randomly assigned them 1:1 to bezuclastinib 600 mg once daily plus sunitinib 37.5 mg once daily (n = 204) or sunitinib 37.5 mg once daily alone (n = 209), with crossover from the monotherapy arm permitted following blinded independent central review (BICR)–confirmed disease progression. The primary end point was PFS per BICR; key secondary end points included ORR per BICR and overall survival. The enrolled population was representative of patients with imatinib-treated GIST, with a median age of 63 years (range, 30–88), KIT exon 11 mutations present in 75.5% of patients, and exon 9 mutations in 15.7%.

The safety profile of bezuclastinib plus sunitinib was generally consistent with the known safety profile of sunitinib, and no new safety risks were identified with the combination. The overall incidence of treatment-emergent adverse events (TEAEs) was 100% in the combination arm vs 99.5% with sunitinib, and no treatment-related adverse events (TRAEs) leading to death were reported in the bezuclastinib plus sunitinib arm. Grade 3 or higher TRAEs occurred in 71.6% of patients in the combination arm vs 52.4% in the monotherapy arm. The most common grade 3 or higher TEAEs in the combination vs monotherapy arms, respectively, included hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), ALT/AST elevation (10.8% vs 1.4%), and anemia (9.3% vs 4.8%). Notably, rates of palmar-plantar erythrodysesthesia, stomatitis, and thrombocytopenia were lower in the combination arm.

Transaminase elevations were generally asymptomatic and reversible and did not result in more serious hepatic outcomes; all grade 3 ALT/AST events resolved, and no grade 4 elevations were reported. ALT/AST elevations led to bezuclastinib dose reductions in 12.7% of patients, and only 1.5% discontinued due to liver enzyme abnormalities. Overall, treatment discontinuation due to TRAEs occurred in 7.4% of patients in the combination arm vs 3.8% with sunitinib. The FDA has accepted a new drug application for the bezuclastinib and sunitinib combination and granted priority review, with a target action date of November 30, 2026.²

Overall health and quality of life, assessed via the EORTC-QLQ-C30, were not significantly different between the combination and monotherapy arms (least-squares mean improvement of 9.1 vs 7.7, respectively). Wagner and investigators concluded that the PEAK study represents the first time a combination of inhibitors targeting the same kinase in KIT-mutant GIST has delivered a significant efficacy benefit balanced with a manageable safety profile, and that mutational heterogeneity of resistant GIST is more effectively treated with dual kinase inhibition using bezuclastinib plus sunitinib.

References

1. 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
2. Cogent Biosciences announces FDA acceptance of new drug application (NDA) with priority review for bezuclastinib in combination with sunitinib for patients with GIST. News release. Cogent Biosciences. May 28, 2026. Accessed May 39, 2026. https://tinyurl.com/3krxakc9