Bezuclastinib plus sunitinib decreased the risk of progression or death by 50% compared with sunitinib monotherapy in GIST.
Bezuclastinib plus sunitinib (Sutent) significantly improved progression-free survival (PFS) and overall response rate (ORR) compared with sunitinib monotherapy in patients with advanced gastrointestinal stromal tumors (GIST) who had progressed on or were intolerant to imatinib (Gleevec), according to primary results from the phase 3 Peak study (NCT05208047) presented at the
The combination (n = 204) reduced the risk of disease progression or death by 50% vs sunitinib alone (n = 209; HR, 0.50; 95% CI, 0.39-0.65; P < .0001), with a median PFS of 16.5 months (95% CI, 13.8-19.2) vs 9.2 months (95% CI, 7.2-11.0). An ORR of 45.6% (95% CI, 38.6%-52.7%) was achieved with the combination vs 25.8% (95% CI, 20.0%-32.3%) with sunitinib monotherapy (P < .0001). The respective complete response rates were 6.4% and 1.9%.
"The study met its primary end point with the combination of bezuclastinib and sunitinib showing a 50% reduction in the risk of progression or death compared with sunitinib monotherapy,” Andrew J. Wagner, MD, PhD, the deputy chief medical officer, medical director of Adult Ambulatory Oncology, and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine, both in Boston, Massachusetts, said during the presentation.
Peak was a global, randomized, open-label, phase 3 study evaluating bezuclastinib plus sunitinib vs sunitinib monotherapy as second-line treatment in adult patients with advanced GIST. Eligible patients had histologically confirmed locally advanced, unresectable, or metastatic GIST with at least 1 measurable lesion per mRECIST criteria, and documented disease progression on or intolerance to imatinib.
Patients were randomly assigned 1:1 to receive bezuclastinib at 600 mg once daily plus sunitinib at 37.5 mg once daily or sunitinib 37.5 mg once daily alone, with crossover from sunitinib monotherapy to the combination permitted following blinded independent central review (BICR)–confirmed progressive disease. The primary end point was PFS per BICR; key secondary end points were ORR per BICR and overall survival (OS).
At baseline, the overall population (n = 413) was broadly representative of imatinib-treated advanced GIST, with a median age of 63.0 years (range, 30-89). Most patients were male (63.9%), had an ECOG performance status 0 (65.9%), and had KIT exon 11 primary mutations (75.5%). The trial enrolled patients across North America (39.0%), Europe (45.5%), Latin America (7.5%), and Asia-Pacific (8.0%).
The disease control rate was 86.8% (95% CI, 81.3%-91.1%) in the investigational arm vs 76.1% (95% CI, 69.7%-81.7%) in the control arm. The median duration of response was 15.7 months (95% CI, 12.2-not estimable) vs 12.0 months (95% CI, 7.6-14.9). Median time to response was similar between arms at 3.8 months (range, 1.6-26.6) vs 3.7 months (range, 1.5-19.5). The median time to second progression was not yet reached in the bezuclastinib plus sunitinib arm vs 21.0 months in the sunitinib arm (HR, 0.57). OS was immature at the time of data cutoff, with an event rate of less than 20%.
The safety profile of bezuclastinib plus sunitinib was generally consistent with the known profile of sunitinib alone, with no new safety signals identified. Treatment-emergent adverse effects (TEAEs) of any grade occurred in 100% of patients in the combination arm vs 99.5% in the sunitinib arm. Grade 3 or higher treatment-related adverse effects (TRAEs) were observed in 71.6% vs 52.4% of patients, respectively. Serious adverse reactions occurred in 16.7% vs 11.5% of patients. No TRAEs leading to death were observed in the combination arm, compared with 1 patient (0.5%) in the sunitinib arm. TEAEs led to discontinuation in 7.4% vs 3.8% of patients, and dose reductions occurred in 55.9% vs 44.2%.
The most clinically notable difference between arms was in ALT/AST elevations, which occurred in 56.4% (any grade) and 10.8% (grade 3+) of patients in the combination arm vs 16.8% and 1.4% in the sunitinib arm. Grade 3 or higher rates of hypertension (29.4% vs 27.4%), neutropenia (15.2% vs 15.4%), and diarrhea (7.8% vs 7.2%) were broadly comparable between arms.
“There were no new safety risks identified with the combination. This study supports a combinatorial approach to overcoming mutational heterogeneity in imatinib-resistant GIST,” Wagner said in his conclusion.
Disclosures: Wagner received honoraria from AADi and Cogent Biosciences. He holds consulting or advisory roles with AADi; Boehringer Ingelheim; Cogent Biosciences; Daiichi Sankyo; Deciphera; EMD Serono/Merck; InhibRx; Pharmaessentia; and SERVIER. He received research funding from AADi (Inst); Boehringer Ingelheim (Inst); Cogent Biosciences (Inst); Daiichi Sankyo (Inst); Deciphera (Inst); Foghorn Therapeutics (Inst); and Rain Therapeutics (Inst); Sumitomo Pharma Oncology (Inst).
