Bezuclastinib Plus Sutent May Be Safe and Effective in GIST

Among patients with gastrointestinal stromal tumors (GIST), the most common mesenchymal tumor of the GI tract, treatment with bezuclastinib (CGT9486) and Sutent (sunitinib) demonstrated acceptable efficacy and favorable long-term safety versus Sutent alone, according to data from the phase 3 Peak study presented at the 2025 ASCO Gastrointestinal Cancers Symposium.

In this trial, the median progression-free survival (PFS) in all patients (42 patients) was 10.2 months. The median PFS in patients who received the combination following treatment with Gleevec (imatinib) was 19.4 months. Notably, three of seven patients who were treated with one prior tyrosine kinase inhibitor (TKI) remained on the treatment after 19 months.

“Efficacy compares favorably to historical data in previously treated GIST,” Dr. Jonathan C. Trent, and study co-authors wrote in a poster presentation of the data. “Encouraging long-term safety and tolerability [was seen] with combination bezuclastinib and [Sutent] therapy in part 1 [of the study], with a median treatment duration of 32 weeks.”

Trent currently serves as the associate director of clinical research and the director of the sarcoma medical research program at the University of Miami Miller School of Medicine in Florida.

Understanding the Methods of the Trial

Approximately 4,000 to 6,000 new cases of GIST are reported each year in the United States, the study authors wrote in the poster. And in 80% of these tumors, primary activating mutations in KIT are found, mostly in exon 11 or exon 9. Although Gleevec may be used to inhibit the mutation, resistance to the drug increases to 60% within 2 years. This resistance is driven by additional mutations in KIT exons 13/14 or exons 17/18.

The investigational combination allows for broad activity against several KIT mutations, particularly those related to primary and secondary resistance. This approach was also examined in the phase 1/2 PLX121-01 trial, in which, bezuclastinib plus Sutent 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 with 19 patients) and 1b (the investigational drug-drug interaction portion with 23 patients) of the phase 3 study. In part 1a, bezuclastinib was given at a 300-milligram dose or 600-milligram dose daily plus Sutent at a 37.5-milligram dose daily; the selected dose was then used in part 1b.

Notably, in part 2, the randomized study, patients who had received prior Gleevec were randomly assigned to 600 milligrams of bezuclastinib plus 37.5 milligrams of Sutent daily or Sutent alone at 37.5 milligrams daily. In the Sutent monotherapy arm, patients whose disease progressed may be eligible to crossover to the investigational treatment arm.

Patients were eligible for enrollment so long as they have histologically confirmed GIST with at least one measurable lesion; locally advanced, unresectable or metastatic disease; documented disease progression or intolerance to Gleevec; an ECOG performance status of 0, 1 or 2; and at least one prior line of therapy (to be eligible for part 1a), at least two prior TKIs (for part 1b) and prior Gleevec 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, Sutent, and the primary active metabolite of Sutent; and the primary end point of 2 is PFS. Notably, the current enrollment status of all three study parts is complete.

Additional Data and Safety Outcomes

Regarding responses, treatment with bezuclastinib plus Sutent resulted in an objective response rate of 27.5% in all patients and 33.3% in patients with prior Gleevec. In all patients, 27.5% had a partial response, 57.5% had stable disease and 15% had progressive disease. Additionally, the disease control rate was 80%.

Most treatment-emergent side effects were low grade and reversible. In total, three patients experienced serious side effects, including grade 2 (moderate) neutrophil count decrease and fever and grade 3 (severe) platelet count decrease; grade 2 bacterial infection of the peritoneum and grade 3 febrile neutropenia; and grade 3 anemia, weakness and peripheral edema. All three patients’ serious side effects were possibly associated with the study medications.

Moreover, dose reductions of any study medications due to treatment-emergent side effects occurred in 29% of patients, and two patients discontinued treatment due to treatment-emergent side effects, including grade 2 rash and grade 1 (mild) abdominal pain, as well as grade 3 diarrhea.

“The combination of bezuclastinib and Sutent does not appear to add to the severity of [side effects] associated with Sutent 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 side effects included diarrhea (69%), fatigue (55%), high blood pressure (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 [side effects],” the study authors concluded in the poster.

Reference:

Trent J, Wagner A, Attia S, et al. Peak part 1 summary: A phase 3, randomized, open-label, multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol. 2025;43(suppl 4):826. doi:10.1200/JCO.2025.43.4_suppl.826.

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