Dual Inhibition With Bezuclastinib/Sunitinib Aims to Fill an Unmet Need in GIST

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Combination therapy targeting multiple exons where mutations commonly develop in gastrointestinal stromal tumor may represent a promising treatment approach to increase efficacy when patients develop resistance to therapies such as imatinib.

Neeta Somaiah, MD

Neeta Somaiah, MD

Combination therapy targeting multiple exons where mutations commonly develop in gastrointestinal stromal tumor (GIST) may represent a promising treatment approach to increase efficacy when patients develop resistance to therapies such as imatinib (Gleevec).

Treatments for KIT mutations, which are present in approximately 70% of patients with GIST,1 encompass imatinib in the first line, sunitinib (Sutent) in the second line, regorafenib (Stivarga) in the third line, and ripretinib (Qinlock) in the fourth line. Despite having several therapies available including the KIT inhibitor imatinib, approximately 50% of patients will develop resistance following 2 years of imatinib treatment.2 Because activating KIT mutations are most frequently found in exons 9 or 11 of tumors, resistance to imatinib which is driven by additional mutations involving the ATP binding domain exons 13/14 or activation loop exons 17/18, requires agents to target several mutations.3

“Approximately 60% to 70% [of patients with GIST] have exon 11 mutations in KIT. [Most of these patients], once they develop resistance to imatinib, [tend to develop] clones with additional mutations, usually in exons 13 or 17, but [clones are] also seen in exons 14 and 18,” Neeta Somaiah, MD, explained in an interview with OncologyLive®. Somaiah is an associate professor and the deputy department chair of the Department of Sarcoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

“[Of] the subsequent treatments that we currently have as standard of care, some, such as sunitinib, target exon 13 secondary mutations well, but don’t target exon 17 as well,” she noted. “Then, we have subsequent lines [of therapy, such as] regorafenib and ripretinib, that have shown that they might have a predilection for targeting exon 17 mutations.”

As secondary mutations can occur for many patients, combination treatment regimens targeting a variety of mutations remain key areas of research. The investigational tyrosine kinase inhibitor (TKI) bezuclastinib (CGT9486) targets KIT exons 9, 11, 17, and 18 and sunitinib inhibits KIT exons 9, 11, 13, and 14, ensuring all primary and secondary mutations are targeted.3 The phase 3 Peak trial (NCT05208047) aims to evaluate this combination in the second line, with part 1a and part 1b already complete, and part 2 currently enrolling patients.4

“It has become feasible to [investigate the combination] because targeted inhibitors don’t have as many overlapping toxicities, hence, they can be combined more easily. That’s what we’re seeing, and that’s what led to the Peak study,” Somaiah said, adding that the phase 1b/2a portion of the trial included “a small number of patients, but showed that [bezuclastinib], a more specific inhibitor of exon 17, can be combined safely with sunitinib. That was a big step forward, [indicating that] we can [administer] this combination and maybe get broader coverage.”

Robin Jones, MD, MRCP, added in an interview with OncologyLive that because “advanced GIST becomes increasingly heterogeneous and complex in its mutational profile, this trial is a starting point for combination therapy and trying to get that broad coverage of mutational heterogeneity.”

Jones is a consultant medical oncologist, a professor of medical oncology, and the head of the Sarcoma Unit at The Royal Marsden NHS Foundation Trust in London, United Kingdom.

Early Data Sets the Stage for Peak Part 2

Findings from part 1 of the Peak trial presented at the 2023 American Society of Clinical Oncology Annual Meeting demonstrated the clinical activity and tolerable safety profile of the bezuclastinib plus sunitinib combination in patients with GIST.3

Data from part 1a and part 1b revealed that patients who received prior TKI therapy with imatinib only (n = 6) experienced a disease control rate (DCR) of 100.0% and patients who previously received 2 or more prior TKI therapies (n = 25) achieved a DCR of 44.0%; the total DCR was 54.8%. As of the March 29, 2023, data cutoff, in the imatinib only group 1 patient had an unconfirmed partial response (PR), the stable disease (SD) rate was 83.3%, and no patients experienced progressive (PD). Of those who received 2 or more prior therapies, 12.0% had a PR, 68.0% had SD, and 20.0% experienced PD.

The most common any grade treatment-emergent adverse effects (AEs) that occurred in the part 1a safety population (n = 19) and part 1b safety population (n = 20) were diarrhea (58% vs 30%), fatigue (53% vs 30%), nausea (47% vs 20%), neutropenia (47% vs 30%), increased aspartate aminotransferase (47% vs 30%), increased alanine transaminase (42% vs 30%), decreased white blood cell count (37% vs 35%), respectively. Grade 3 events occurring in more than 1 patient included diarrhea (11% vs 0%), hypertension (11% vs 10%), and neutropenia (0% vs 10%), respectively.

Importantly, it was noted that the combination therapy did not appear to add to the severity of AEs associated with sunitinib monotherapy; there were limited dose reductions (9/39) due to AEs and only 2 patients discontinued treatment due to AEs which included a patient with grade 2 rash and a patient with grade 1 abdominal pain as well as a grade 3 diarrhea.

“The safety and tolerability of the combination are promising,” Jones said. Somaiah added that “we saw some grade 3 hypertension [which] is why knowing the AE profile and being aggressive at managing it early is important. We saw some cytopenias that we’ve seen with sunitinib alone, but the rate was not high.”

Enrollment and Dosing

The estimated enrollment of the randomized, open-label, part 2 portion of the trial is 388 patients.4 Patients will be assigned 1:1 to receive either combination therapy with bezuclastinib and sunitinib or sunitinib monotherapy. Sunitinib will be given at 37.5 mg once daily with or without bezuclastinib given at the selected starting dose of 600 mg once daily. Bezuclastinib will be administered in its optimized formulation that was used in part 1a and 1b which has improved bioavailability and was developed to reduce pill burden.

“The active ingredient is the same but the formulation—the way it’s made to get a higher dosage—is different,” Somaiah explained.

Part 2 of the trial will include patients with locally advanced, unresectable, or metastatic GIST who are intolerant to or have failed prior treatment with imatinib only. The international, multicenter trial is enrolling patients with at least 1 measurable lesion according to mRECIST 1.1 criteria and an ECOG performance status of 0 to 2. The study will be opening and recruiting at 130 study locations globally.

Those with PDGFR driving mutations or succinate dehydrogenase deficiency; clinically significant cardiac disease; active, uncontrolled, systemic bacterial, fungal, or viral infections at screening; and gastrointestinal abnormalities that would preclude adequate absorption will be excluded from the study. Additionally, patients who are seropositive for HIV 1 or 2 or positive for hepatitis B surface antigen or hepatitis C virus antibody; have active bleeding; received a major surgery within 4 weeks of the first study dose; received strong CYP3A4 inhibitors or inducers; or received prior anti-cancer therapy other than imatinib are ineligible as well.

“Previously, [in the] part 1a and part 1b portion, patients [received multiple prior lines of therapy]. However, we’re now in the randomized phase, which is post-imatinib,” Somaiah said. “Patients should have only had 1 prior line of therapy. It’s a nice design that even the investigators like because [although] it randomizes patients to either get a single agent or a combination, there is a crossover, so if a patient does not end up on the combination [arm with the] new drug initially, if they progress on sunitinib, they can cross over [to receive bezuclastinib plus sunitinib].”

Potential to Impact the Paradigm

“Crossing the finish line with this study will be important,” Somaiah said. “It will change the way we sequence drugs. [If the trial is positive, bezuclastinib plus sunitinib] will probably be the first combination treatment. That would be exciting.”

“The field in general is moving toward recognizing the heterogeneity of secondary mutations,” Somaiah continued. “Those data are also being collected as part of the study because it’s important to [understand which] patients are responding and [which] patients are not responding and see what in their tumor profile we need to work on in future lines. This would open the door for combination [therapies for GIST] and investigating specific mutations.”

Jones added that communication between academic centers and community oncologists is key moving forward. “It’s always good to reach out and contact academic centers regarding clinical trials, [including] this trial and other trials in GIST, because now is an exciting time with several promising novel agents and novel approaches in GIST.”


  1. Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment sequencing in advanced gastrointestinal stromal tumors. Drugs. 2023;83(1):55-73. doi:10.1007/s40265-022-01820-1.
  2. Hu X, Wang Z, Su P, Zhang Q, Kou Y. Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors. Front Oncol. 2022;12:933248. doi:10.3389/fonc.2022.933248.
  3. 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
  4. (Peak) a phase 3 randomized trial of CGT9486+sunitinib vs. sunitinib in subjects with gastrointestinal stromal tumors. ClinicalTrials.gov. Updated August 22, 2023. Accessed September 19, 2023. bit.ly/45XYdBj
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