Bezuclastinib Plus Sunitinib Shows Encouraging Safety and Efficacy Profile in R/R Second-Line GIST

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William D. Tap, MD

The combination of bezuclastinib (CGT9486, formerly PLX9486) and sunitinib (Sutent) had a tolerable safety profile and demonstrated early signals of clinical activity in patients with gastrointestinal stromal tumor (GIST), according to early findings from part 1 of the phase 3 Peak trial (NCT05208047), which were presented at the 2023 ASCO Annual Meeting.¹

Most treatment-emergent adverse effects (TEAEs) seen with the combination were low grade and reversible, and there was a low rate of adverse effects (AEs) of grade 3 or higher.

“The combination does not appear to be adding to the overall frequencies or severity of risk known to be associated with single-agent sunitinib,” William D. Tap, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, stated in a poster presentation.

Activating KIT mutations are found in approximately 80% of patients with GIST at diagnosis, most frequently in exons 11 and 9. Although the TKI imatinib (Gleevec) inhibits the primaryKIT mutations, 60% of GIST tumors develop resistance to imatinib within 2 years of treatment.²

The investigational TKI bezuclastinib inhibits KIT mutations in exons 9, 11, 17, and 18.³ Sunitinib, another TKI approved for the management of GIST, targets KIT mutations in exons 9, 11, 13, and 14. Thus, the combination of bezuclastinib and sunitinib targets the full spectrum of primary and secondary mutations in GIST.¹

Furthermore, in a phase 1/2 trial (NCT02401815), patients with relapsed/refractory GIST who had received a median of 3 prior lines of therapy who received the combination of bezuclastinib and sunitinib experienced clinical benefit, and the combination had an acceptable safety profile.³

The objective of part 1a, which has completed enrollment, was to identify the dose for the optimized formulation of bezuclastinib in combination with sunitinib that achieved target drug exposures defined based on previous Phase 1/2 clinical data with bezuclastinib and sunitinib in patients with GIST. The primary end point of part 1a was to determine the pharmacokinetics of bezuclastinib. The objective of part 1b, which has completed enrollment, was to characterize the potential interactions between bezuclastinib and sunitinib, with primary end points of determining the pharmacokinetics of bezuclastinib and sunitinib, and the primary active metabolite of sunitinib. The objective of part 2, which is open for enrollment, is to determine the efficacy of bezuclastinib plus sunitinib vs sunitinib alone, with a primary end point of progression-free survival per mRECIST v1.1 criteria.

Part 1a of Peak was an optimized formulation lead-in with 19 patients. Cohort 1 (n = 5) received bezuclastinib at 300 mg once daily plus sunitinib at 37.5 mg once daily. Cohort 2 received bezuclastinib at 600 mg once daily plus sunitinib at 37.5 mg once daily. The expansion cohort (n = 9) also received bezuclastinib at 600 mg once daily plus sunitinib at 37.5 mg once daily, which was selected as the dose for parts 1b and 2, which will be conducted in parallel. In all part 1a cohorts, sunitinib treatment began on day 2. Part 1b, which enrolled approximately 20 patients, investigated bezuclastinib or sunitinib as monotherapy for 2 weeks followed by bezuclastinib plus sunitinib. Part 2, which aims to enroll 388 patients, is randomly assigning patients 1:1 to receive either bezuclastinib plus sunitinib at the selected dose or sunitinib monotherapy at 37.5 mg daily.

Patients with histologically confirmed GIST with at least 1 measurable lesion per mRECIST v1.1 criteria are eligible to enroll in Peak. Patients are required to have locally advanced, unresectable, or metastatic disease; documented disease progression on or intolerance to imatinib, and an ECOG performance score of 0 to 2. Part 1a enrolled patients who had received at least 1 prior line of therapy. Part 1b enrolled patients who had received at least 2 prior TKIs. Part 2 is enrolling patients who have received imatinib as their only prior therapy for GIST.

At a data cutoff date of March 29, 2023, 39 total patients had been treated in part 1: 19 patients in part 1a and 20 patients in part 1b. In part 1a, 5 patients received a starting dose of bezuclastinib at 300 mg daily, 3 of whom elected to increase their dose to 600 mg daily, and 14 patients received bezuclastinib at 600 mg daily. In part 1b, patients were randomly assigned to receive bezuclastinib at 600 mg daily or sunitinib at 37.5 mg daily for 2 weeks, followed by combination therapy with bezuclastinib plus sunitinib. Of the patients treated in part 1, 25 remained on the study treatment as of the data cutoff date.

In total, 17.9% (n = 7), 28.2% (n = 11), and 53.8% (n = 21) of patients in part 1 had received 1, 2, and at least 3 prior TKIs. Additionally, 23.1% (n = 9) and 87.2% (n = 34) of patients had received prior radiotherapy and prior anticancer surgery, respectively. The primary tumor locations at diagnosis included the stomach (20.5%; n = 8), small intestine (56.4%; n = 22), and other abdominal locations (23.1%; n = 9). Patients in part 1 had primary mutations in exon 9 (23.1%; n = 9), exon 11 (69.2%; n = 27), and other or unknown locations (10.3%; n = 4). One patient in part 1b had primary mutations in both exon 9 and exon 11.

The most common any-grade TEAEs of all causalities were diarrhea (44%), fatigue (41%), nausea (33%), hair color changes (23%), hypertension (21%), taste disorder (21%), GERD (18%), abdominal pain, headache, and rash (each in 15%). In part 1a, the most common TEAEs of grade 3 or higher were diarrhea and hypertension (each in 11%). In part 1b, the most common TEAE of grade 3 or higher was hypertension (10%).

The most common any-grade laboratory TEAEs were neutropenia and increased aspartate aminotransferase (AST)(each in 39%), increased alanine transaminase (ALT) and decreased white blood cell (WBC) counts (each in 36%), anemia (21%), hypophosphatemia (18%), increased blood creatinine levels, hyponatremia, and thrombocytopenia (each in 15%). In part 1a, the most common laboratory TEAEs of grade 3 or higher were increased AST, anemia, and thrombocytopenia, occurring in 5% of patients each. In part 1b, the most common laboratory TEAEs of grade 3 or higher were neutropenia (10%), increased ALT and decreased WBC counts (each in 5%).

TEAE-related dose reductions of any study drug occurred in 23% (n = 9) of patients. Treatment discontinuations because of TEAEs occurred in 2 patients, 1 with grade 2 rash and 1 with grade 1 abdominal pain and grade 3 diarrhea.

Two patients experienced serious AEs that were possibly associated with the study drugs. One of these patients had grade 2 decreased neutrophil counts and pyrexia, as well as grade 3 decreased platelet counts, and the other patient had grade 2 bacterial peritonitis and grade 3 febrile neutropenia.

Regarding pharmacokinetics, the steady state exposure of bezuclastinib increased in an approximately dose-proportional manner from 300 mg to 600 mg after once-daily administration of bezuclastinib and 37.5 mg of sunitinib.

“Part 1a data support the selection of 600 mg bezuclastinib and 37.5 mg sunitinib as the dose for part 1b and part 2 of the Peak study,” Tap said.

Of the efficacy evaluable subset of patients in part 1 who had received either prior imatinib only (n = 6) or at least 2 prior TKIs (n = 25), the disease control rate (DCR) was 54.8% (n = 17/31), including a 100.0% DCR in the prior imatinib only group, which is the population being enrolled in part 2 of Peak, and a 44.0% (n = 11) DCR in the 2 or more prior therapies group. In total, 12.9% (n = 4), 71.0% (n = 22), and 16.1% (n = 5) of patients achieved best overall responses of partial response (PR), stable disease (SD), and progressive disease (PD), respectively. In the group of patients with prior imatinib only, the PR, SD, and PD rates were 16.7% (n = 1), 83.3% (n = 5), and 0%, respectively. In the group of patients with at least 2 prior TKIs, the PR, SD, and PD rates were 12.0% (n = 3), 68.0% (n = 17), and 20.0% (n = 5), respectively. The median time to response was 4.2 cycles (range, 2.0-8.0).

“Although not mature enough to estimate median progression-free survival, the efficacy data obtained thus far support potential for durable disease control in imatinib-resistant GIST, including heavily pretreated tumors,” Tap concluded.

Part 2 of Peak is open for enrollment.

References

1. Tap WD, Wagner AJ, Bauer S, et al. Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): results from part 1 of the phase 3 Peak study. J Clin Oncol. 2023;41(suppl 16):11537. doi:10.1200/JCO.2023.41.16_suppl.11537
2. Gramza AW, Corless CL, Heinrich MC, et al. Resistance to tyrosine kinase inhibitors in gastrointestinal stroma tumors. Clin Cancer Res. 2009;15(24):7510-7518. doi:10.1158/1078-0432.CCR-09-0190
3. Wagner AJ, Severson PL, Shields AF, et al. Association of combination of conformation-specific KIT inhibitors with clinical benefit in patients with refractory gastrointestinal stromal tumors: a phase 1b/2a nonrandomized clinical trial. JAMA Oncol. 2021;7(9):1343-1350. doi:10.1001/jamaoncol.2021.2086