Bezuclastinib Plus Sunitinib Halves Risk of Progression in Second-Line GIST

Adding the next-generation oral KIT inhibitor bezuclastinib (CGT9486) to sunitinib (Sutent) significantly improved progression-free survival (PFS) compared with sunitinib monotherapy in patients with advanced gastrointestinal stromal tumors (GIST) who had received prior imatinib (Gleevec) therapy, according to primary results from the phase 3 Peak trial (NCT05208047).¹

Data presented at the 2026 ASCO Annual Meeting showed that the trial met its primary end point, with a median PFS of 16.5 months (95% CI, 13.8-19.2) observed with the combination vs 9.2 months (95% CI, 7.2-11.0) with sunitinib alone, representing a 50% reduction in the risk of progression or death (HR, 0.50; 95% CI, 0.39-0.65; P <.0001). This PFS benefit was observed across demographic and KIT mutational subgroups.

The objective response rate (ORR) also improved significantly with the combination: 45.6% vs 25.8% with monotherapy, a risk difference of approximately 20 percentage points (95% CI, 10.6-28.6; P <.0001). Overall survival (OS) data remain immature as of the September 30, 2025, data cutoff. These results, drawn from 413 randomized patients, position the dual KIT inhibitor strategy as a potential new standard in the second-line GIST setting.

“This trial represents the first successful combination of 2 kinase inhibitors targeting the same oncogenic driver that delivers both meaningful efficacy and tolerability,” said Andrew J. Wagner, MD, PhD, of Dana-Farber Cancer Institute, during the presentation of data.¹ “Taken together, these findings suggest that mutational heterogeneity in GIST can be effectively addressed through rational combination therapy, and that bezuclastinib plus sunitinib has the potential to become a new standard of care in the second-line setting.”

Peak Trial Design

PEAK was a global, open-label, multipart study comprising a dose confirmation phase (part 1a), 2 drug-drug interaction assessments (part 1b and a drug-drug interaction substudy), and a randomized phase 3 component (part 2), the focus of the ASCO readout.²

In part 2 of the trial, 413 patients with advanced GIST who had documented disease progression on or intolerance to imatinib were randomized 1:1 to continuous daily dosing of bezuclastinib 600 mg plus sunitinib 37.5 mg once daily (n = 204) or sunitinib 37.5 mg once daily monotherapy (n = 209).

The primary end point was median PFS per blinded independent central review (BICR). Key secondary end points included ORR per BICR and OS; additional secondary end points included investigator-assessed PFS, disease control rate, time to response, and duration of response.

Crossover from sunitinib monotherapy to the combination was permitted at BICR-confirmed progression, an important design feature that will affect the interpretation of future OS analyses.

Patient Characteristics

Baseline characteristics were well balanced between arms. The median age of the patient population was 63 years (range, 30-88). The population was geographically diverse: 39% of patients came from North America, 45% from Europe, 7% from Latin America, and 8% from the Asia-Pacific region. Consistent with the broader GIST population, 75% of patients had tumors harboring KIT exon 11 mutations and approximately 16% had KIT exon 9 mutations. Only 3.4% of patients enrolled due to imatinib intolerance; the remainder had imatinib-resistant disease.

Safety and Tolerability

The overall adverse event (AE) profile for the combination was manageable and consistent with the known toxicity profiles of the individual agents. TEAEs occurring at a notably higher frequency in the combination arm included ALT/AST elevations (56.4% vs. 16.8%), taste disorder (47.5% vs. 25.0%), and hair color changes (38.7% vs. 17.8%). Conversely, PPE (28.9% vs. 45.7%), stomatitis (22.5% vs. 32.7%), and thrombocytopenia (19.1% vs. 26.4%) were all reported less frequently with the combination.

At the grade 3 or higher level, the majority of severe TEAEs occurred at similar rates between arms, and no increase in frequency was observed in the combination arm for key sunitinib-associated risks including neutropenia (15.2% vs. 15.4%), diarrhea (7.8% vs. 7.2%), and PPE (2.9% vs. 2.4%).

ALT/AST elevations were more pronounced with the combination at the grade ≥3 level (10.8% vs. 1.4%), as was anemia (9.3% vs. 4.8%). However, ALT/AST elevations led to dose reductions in 12.7% of patients and discontinuation in only 1.5%, all grade 3 events resolved, and no grade 4 elevations were reported, indicating these liver enzyme changes were manageable and reversible.

Clinical Implications and Regulatory Pathway

The PEAK results address a long-standing challenge in the second-line GIST setting: the inability of any single agent to overcome the polyclonal nature of imatinib resistance. By pairing bezuclastinib's activity against activation-loop mutations (exons 17/18) with sunitinib's coverage of ATP-binding pocket mutations (exons 13/14), the combination achieves broad KIT inhibition without additive toxicity to standard sunitinib-associated AEs.

The recent FDA priority review designation for the combination in GIST underscores the potential clinical relevance of this regimen, which already held breakthrough therapy designation in the indication. Pending the November 30, 2026 target action date, bezuclastinib plus sunitinib could represent a new standard of care for patients with imatinib-resistant advanced GIST if approved.

DISCLOSURES: Wagner reported honoraria from AADi and Cogent Biosciences; a consulting or advisory role with AADi, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera, EMD Serono/Merck, InhibRx, Pharmaessentia, and SERVIER; and receipt of institutional research funding from AADi, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera, Foghorn Therapeutics, Rain Therapeutics, Sumitomo Pharma Oncology.

REFERENCES

1. Wagner, AJ. Primary results of the phase 3 peak study of bezuclastinib + sunitinib vs sunitinib monotherapy in advanced gastrointestinal stromal tumors (GIST). Presented at: ASCO Annual Meeting; May 29–June 2, 2026; Chicago Illinois. Abstract 11500.

2. (Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors. ClinicalTrials.gov. Updated May 22, 2026. Accessed May 30, 2026. https://clinicaltrials.gov/study/NCT05208047