Data from the phase 3 Peak study, presented at the 2025 ASCO Gastrointestinal Cancers Symposium, reveal that the combination of bezuclastinib (CGT9486) and sunitinib (Sutent) offers enhanced safety and efficacy compared to sunitinib alone in patients with gastrointestinal stromal tumors (GIST). This combination shows promise in overcoming resistance to prior tyrosine kinase inhibitors (TKIs).
The randomized, open-label, multicenter trial included 42 patients and reported a median progression-free survival (PFS) of 10.2 months (95% CI, 7.4-19.4) across all patients, who had received a median of 2.5 prior TKIs. Notably, in patients who had previously been treated with imatinib (Gleevec) as a second-line therapy, the median PFS was 19.4 months (95% CI, 1.0–not estimable). Three of seven patients treated with only one prior TKI remained on the treatment for over 19 months.
Study Design and Patient Population
The Peak study comprised multiple parts. Parts 1a and 1b focused on optimizing the formulation and assessing drug-drug interactions, while part 2 was a randomized study comparing bezuclastinib plus sunitinib to sunitinib alone in patients who had progressed on imatinib. Patients were eligible if they had histologically confirmed GIST, measurable lesions, locally advanced or metastatic disease, documented progression or intolerance to imatinib, an ECOG performance status of 0-2, and at least one prior line of therapy.
The primary endpoint for part 2 of the study was PFS per RECIST v1.1 criteria. Enrollment across all three parts of the study is now complete.
Efficacy Outcomes
According to investigator assessments, the combination of bezuclastinib and sunitinib resulted in an objective response rate (ORR) of 27.5% in all patients and 33% in those previously treated with imatinib. The disease control rate was 80%, with 27.5% of patients achieving a partial response and 57.5% experiencing stable disease.
Safety and Tolerability
The combination therapy demonstrated a favorable safety profile. Most treatment-emergent adverse events (TEAEs) were of low CTCAE grade and reversible. Serious adverse events, potentially associated with the study medications, were reported in three patients. Dose reductions due to TEAEs occurred in 29% of patients, and only two patients discontinued treatment due to adverse events.
Common adverse events of any grade included diarrhea (69%), fatigue (55%), hypertension (45%), and nausea (40%). Grade 3 or higher adverse events included hypertension (17%), neutropenia (7%), and anemia (7%).
Expert Commentary
"Efficacy compares favorably to historical data in previously treated GIST," noted Dr. Jonathan C. Trent, Associate Director of Clinical Research and Director of the Sarcoma Medical Research Program at the University of Miami, Miller School of Medicine, and his co-authors. They also highlighted the "encouraging long-term safety and tolerability" observed with the combination therapy, with a median treatment duration of 32 weeks.
Mechanism of Action and Rationale
In approximately 80% of GIST cases, primary activating mutations occur in KIT, particularly in exons 11 or 9. While imatinib can initially inhibit these mutations, resistance often develops within two years due to additional mutations in KIT exons 13/14 or 17/18. Bezuclastinib, in combination with sunitinib, aims to provide broad activity against a spectrum of KIT mutations, addressing both primary and secondary resistance mechanisms. This approach was previously explored in the phase 1/2 PLX121-01 trial, which also demonstrated promising clinical activity and tolerability in patients with relapsed or refractory GIST.
