Bezuclastinib Plus Sunitinib Elicits Preliminary Activity, Is Safe in Pretreated GIST

The combination of bezuclastinib (CGT9486) and sunitinib (Sutent) generated favorable efficacy outcomes compared with historical data, as well as long-term tolerability, in patients with previously treated gastrointestinal stromal tumors (GIST), according to findings from part 1 of the phase 3 Peak study (NCT05208047) that were presented at the 2025 Gastrointestinal Cancers Symposium.

In the 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), and patients had received a median of 2.5 (range, 1-6) prior TKIs. The median PFS in patients receiving the combination in the second-line setting following treatment with 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 currently serves as the associate director of Clinical Research and the director of the Sarcoma Medical Research Program in the Department of Medicine in the 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 poster. Although 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 mutations in KIT exons 13/14 or exons 17/18.

The investigational combination of bezuclastinib plus sunitinib allows for broad activity across a spectrum of mutations and may target the full spectrum of primary and secondary resistance. This approach was also examined in the phase 1/2 PLX121-01 trial (NCT02401815), in which bezuclastinib plus sunitinib was well tolerated and demonstrated clinical activity in patients with relapsed/refractory advanced solid tumors.

At the meeting, investigators presented findings from parts 1a—the optimized formulation lead-in portion (n = 19)—and 1b—the investigational drug-drug interaction portion (n = 23)—of the Peak study. In part 1a, bezuclastinib was given at a 300-mg dose or a 600-mg dose daily in combination with sunitinib at a 37.5-mg dose daily; the selected dose was then used in part 1b.

Notably, in part 2, the randomized portion of the study, patients who had received prior imatinib were randomly assigned 1:1 to receive 600 mg of bezuclastinib plus 37.5 mg of sunitinib daily or sunitinib alone at 37.5 mg daily, though sunitinib treatment begins on day 2. Also in part 2, mutational circulating tumor DNA is being collected at baseline and at 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 had histologically confirmed GIST with at least 1 measurable lesion per RECIST 1.1 criteria; locally advanced, unresectable or metastatic disease; documented disease progression on 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), or prior imatinib treatment only (for part 2).

The primary end point of part 1a was the pharmacokinetics of bezuclastinib; the primary end point of part 1b was the pharmacokinetics of bezuclastinib, sunitinib, and the primary active metabolite of sunitinib; and the primary end point of part 2 is PFS per RECIST 1.1 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% 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 (range, 1-6), and patients had received a total of either 1 (16.7%) or 2 or more (83.3%) 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 anticancer surgery (90.5%).

The primary tumor location at diagnosis for patients included the stomach (16.7%), small intestine (54.8%), and other abdominal locations (28.6%). The primary mutation locations consisted of exon 9 (19%), exon 11 (47.6%), and others (33.3%). The median number of weeks patients had on treatment was 32.1 (range, 1.9-102.7). As of the April 1, 2024, data cutoff date, 11 (26.2%) patients remained on treatment, and 31 patients had discontinued treatment (73.8%) 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, 3 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 peripheral edema. All 3 patients’ serious AEs were suspected to 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 coauthors wrote in the poster.

Patients on both parts 1a and part 1b of the study experienced grade 3 or higher diarrhea (5%), hypertension (17%), neutropenia (7%), increased alanine aminotransferase/aspartate aminotransferase levels (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.

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