Bezuclastinib With Sunitinib Improves Safety, Efficacy in Patients With GIST
Bezuclastinib plus sunitinib showed favorable safety and efficacy in GIST, outperforming sunitinib alone in phase 3 Peak study results.
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Phase 3 Peak study (NCT05208047) data presented at the 2025 ASCO Gastrointestinal Cancers Symposium demonstrated that bezuclastinib (CGT9486) combined with sunitinib (Sutent) showed acceptable efficacy and favorable long-term safety and tolerability compared with sunitinib alone in patients with gastrointestinal stromal tumors (GIST).
In the randomized, open-label, multicenter trial, the median progression-free survival (PFS) in all patients (n = 42) was 10.2 months (95% CI, 7.4-19.4), with a 2.5 (range, 1-6) median number of prior tyrosine kinase inhibitors (TKI). The median PFS in patients receiving the combination in the second-line following imatinib (Gleevec) was 19.4 months (95% CI, 1.0–not estimable). Notably, 3 of 7 patients treated with 1 prior TKI remain on the treatment beyond 19 months.
“Efficacy compares favorably to historical data in previously treated GIST,” Jonathan C. Trent, MD, PhD, and study co-authors wrote in a poster presentation of the data. “Encouraging long-term safety and tolerability [was seen] with combination bezuclastinib and sunitinib therapy in part 1, with a median treatment duration of 32 weeks.”
Trent [RS1] currently serves as the Associate Director of Clinical Research and the Director of the Sarcoma Medical Research Program, Department of medicine, Division of Medical Oncology, at the University of Miami, Miller School of Medicine, in Florida.
Understanding the Methods of the Trial
In 80% of GIST cases, primary activating mutations are found in KIT, mostly in exon 11 or exon 9, the study authors wrote in the post. And though the TKI imatinib may be used to inhibit the mutation, resistance to the drug increases to 60% within 2 years. This is driven by additional mutation in KIT exons 13/14 or exons 17/18.
The investigational combination allows for broad activity across a spectrum of mutations and aims to target the full spectrum of primary and secondary resistance. This approach was also examined in the phase 1/2 PLX121-01 trial, in which, bezuclastinib plus sunitinib was well tolerated and demonstrated clinical activity in patients with relapsed/refractory disease.
At the meeting, investigators presented parts 1a—the optimized formulation lead-in (n = 19)—and 1b—the investigational drug-drug interaction portion (n = 23)—of the phase 3 study. In part 1a, bezuclastinib was given at a 300 mg dose or 600 mg dose daily plus sunitinib at a 37.5 mg dose daily; the selected dose was then used in part 1b.
Notably, in part 2, the randomized study, patients who had received prior imatinib are randomly assigned 1:1 to 600 mg of bezuclastinib plus 37.5 mg of sunitinib daily or sunitinib alone at 37.5 mg daily, though sunitinib begins on day 2. Also in part 2, mutational ctDNA are being collected at baseline and disease progression. In the sunitinib monotherapy arm, patients who progress may be eligible to cross-over to the investigational treatment arm.
Patients were eligible for enrollment so long as they have histologically confirmed GIST with at least one measurable lesion per RECIST v1.1 criteria; locally advanced, unresectable or metastatic disease; documented disease progression or intolerance to imatinib; an ECOG performance status of 0, 1, or 2; and at least 1 prior line of therapy (to be eligible for part 1a), at least 2 prior TKIs (for part 1b), and prior imatinib treatment only (for part 2).
The primary end point of part 1a is the pharmacokinetics of bezuclastinib; the primary end point of part 1b is the pharmacokinetics of bezuclastinib, sunitinib, and the primary active metabolite of sunitinib; and the primary end point of 2 is PFS per RECIST v1.1 criteria. Notably, the current enrollment status of all 3 study parts is complete.
In patients enrolled across both part 1a and 1b (n = 42), 81.0% of patients were men; the median age was 59.5 years (range, 33-77); and patients had a baseline ECOG performance status of 0 (57.1%), 1 (40.5%), or 2 (2.4%). The median number of prior therapies patients received was 2.5 (1-6) and patients had received a total of either 1 (16.7%) or 2 (83.3%) and more prior TKI therapies. These prior therapies consisted of imatinib (100%), sunitinib (66.7%), ripretinib (Qinlock; 50.0%), and regorafenib (Stivarga; 35.7%). Additionally, patients received prior treatment with radiotherapy (23.8%) as well as prior anti-cancer surgery (90.5%).
The primary tumor location at diagnosis for patients ranged from the stomach (16.7%), small intestine (54.8%), and other abdominal locations (28.6%). The primary mutations consisted of exon 9 (19%), exon 11 (47.6%), and others (33.3%). The median weeks patients had on treatment was 32.1 (range, 1.9-102.7). Patients on the study treatment as of the April 1, 2024, data cut-off was 11 (26.2%), though 31 patients discontinued treatment (73.8%). This was due to disease progression (52.4%), withdrawn consent (7.1%), clinical progression (7.1%), adverse effect (AE; 4.8%), or enrollment onto another therapeutic study (2.4%).
Additional Data and Safety Outcomes
Looking to responses observed per investigator assessment, treatment with bezuclastinib plus sunitinib resulted in an objective response rate of 27.5% in all patients and 33% in patients with prior imatinib. In all patients, 27.5% had a partial response, 57.5% had stable disease, and 15.0% had progressive disease. Additionally, the disease control rate was 80%.
Regarding safety, the majority of treatment-emergent AEs (TEAEs) were of low CTCAE grade and reversible. In total three patients experienced serious AEs, including grade 2 neutrophil count decrease and pyrexia and grade 3 platelet count decrease; grade 2 bacterial peritonitis and grade 3 febrile neutropenia; and grade 3 anemia, asthenia, and edema peripheral. All 3 patients’ serious AEs were suspected to possibly be associated with study medications.
Moreover, dose reductions of study medications due to TEAEs occurred in 29% of patients, and 2 patients in total discontinued treatment due to TEAEs, including grade 2 rash and grade 1 abdominal pain as well as grade 3 diarrhea.
“The combination of bezuclastinib and sunitinib does not appear to add to the severity of AEs associated with sunitinib monotherapy and is well-tolerated, [with a] median treatment duration of 32 weeks,” Trent and co-authors wrote in the poster.
Patients on both part 1a and part 1b of the study experienced grade 3 or higher diarrhea (5%), hypertension (17%), neutropenia (7%), ALT/AST increase (5%), anemia (7%), and hypokalemia (2%). Common all grade AEs included diarrhea (69%), fatigue (55%), hypertension (45%), nausea (40%), hair color changes (36%), gastroesophageal reflux disease (31%), taste disorder (31%), decreased appetite (29%), rash (26%), and neutropenia (21%).
“[The] combination was well tolerated with infrequent discontinuations due to AEs,” the study authors concluded in the poster.
