The PEAK Study – Dual KIT Inhibition in Advanced GIST: Bezuclastinib + Sunitinib

The PEAK Study: Bezuclastinib + Sunitinib Significantly Prolonged PFS in Advanced GIST After Imatinib

Why is resistance so important in GIST?

Most GISTs develop with mutations that activate tyrosine kinase pathways such as KIT or PDGFRA. Imatinib has been a highly effective first-line treatment, especially for KIT exon 11 and some other sensitive mutations. However, in advanced disease, different resistant clones may develop over time under treatment pressure.

This resistance often cannot be explained by a single mutation. Different metastatic sites in the same patient may harbor different secondary KIT mutations. This mutational heterogeneity makes it difficult for a single tyrosine kinase inhibitor to suppress all resistant clones. This is precisely the biological rationale of the PEAK study: using two drugs together that target different KIT resistance regions in a complementary way.

The rationale for combining bezuclastinib + sunitinib

Sunitinib is one of the second-line tyrosine kinase inhibitors that has long been used in advanced GIST after imatinib. Bezuclastinib is a next-generation, highly selective KIT inhibitor. It stands out particularly for its activity against certain resistance mutations, such as those in KIT exons 17 and 18. Sunitinib can suppress different KIT resistance regions.

Combining the two drugs therefore rests on the idea of providing broader coverage of mutational heterogeneity that cannot be suppressed with one drug. As summarized by Targeted Oncology, this strategy aims to suppress a broader range of primary and secondary KIT resistance mutations through the complementary use of type 1 and type 2 KIT inhibition.

Study design: how was PEAK conducted?

PEAK is a global, randomized, open-label phase 3 study. It enrolled adult patients with histologically confirmed, locally advanced, unresectable or metastatic GIST whose disease progressed during imatinib treatment or who could not tolerate imatinib. Patients were required to have at least one measurable lesion according to mRECIST criteria.

A total of 413 patients were randomized. Patients received bezuclastinib + sunitinib or sunitinib monotherapy in a 1:1 ratio. In the sunitinib monotherapy arm, switching to the combination was allowed after progression confirmed by BICR.

The baseline population was generally representative of advanced GIST after imatinib. The median age was 63 ; %63,9 of patients were male, %65,9 had ECOG 0 performance status. The primary KIT exon 11 mutation was reported in %75,5 of patients. The study was conducted in North America, Europe, Latin America and Asia-Pacific.

Main efficacy results: PFS increased by almost 7 months

PEAK met its primary endpoint. According to independent central review, median PFS was 16,5 monthsin the bezuclastinib + sunitinib arm and 9,2 months in the sunitinib arm. The reported HR was 0,50, with p<0,0001. This means a %50 relative reduction in the risk of progression or death. The absolute gain in median PFS was approximately 7,3 months .

The objective response rate was also significantly higher in favor of the combination. ORR in the bezuclastinib + sunitinib arm was %45,6, compared with %25,8 in the sunitinib arm. Complete response rates were reported as %6,4 and %1,9 , respectively.

Additional efficacy findings: DCR, DOR and PFS2

The disease control rate was %86,8in the combination arm and %76,1 in the sunitinib arm. Median duration of response was reported as 15,7 monthswith the combination and 12,0 months with sunitinib. Median time to response was similar in the two arms: 3,8 vs 3,7 months.

The PFS2 analysis also favored the combination. PFS2, the time from randomization to progression or death on the next treatment line, had not yet been reached in the combination arm, compared with 21,0 months in the sunitinib arm. The reported HR was 0,57 . This suggests that receiving the combination in the initial treatment line may provide a more durable clinical advantage that also extends to subsequent treatment.

Mutation subgroups: the benefit appears broad

According to Cogent’s ASCO announcement, analyses using available baseline genotyping information showed a PFS advantage for bezuclastinib + sunitinib over sunitinib monotherapy across primary and secondary KIT mutation subgroups. This finding is biologically important because resistance in GIST after imatinib is often associated with heterogeneous secondary KIT mutations.

It was also reported that a new first-line expansion cohort had been initiated for patients with KIT exon 9 mutations. This cohort aims to enroll 40 patients and will evaluate bezuclastinib + sunitinib in GIST patients with a primary KIT exon 9 mutation who have received limited or no imatinib. This decision is based on the finding with the combination in 32 patients with a detectable exon 9 mutation within PEAK of a median PFS of 25,1 months .

Safety: strong efficacy, but ALT/AST monitoring is important

The safety analysis showed that the combination was generally consistent with the known safety profile of sunitinib and that no new safety signal was identified. However, grade 3 or higher treatment-related adverse events were more frequent in the combination arm: %71,6 vs %52,4. The rate of serious adverse reactions was %16,7 vs %11,5 .

The most notable safety difference involved liver enzymes. ALT/AST elevations of any grade occurred in %56,4of the combination arm, and grade 3 or higher elevations in %10,8; in the sunitinib arm, any-grade elevations occurred in %16,8and grade 3 or higher in %1,4 . These elevations were described as generally asymptomatic, reversible and manageable; no grade 4 ALT/AST elevations were reported.

Other grade 3 or higher adverse events were more similar between the two arms: hypertension %29,4 vs %27,4, neutropenia %15,2 vs %15,4, anemia %9,3 vs %4,8, diarrhea %7,8 vs %7,2. In the combination arm, bezuclastinib dose reduction due to ALT/AST elevation was required in %12,7 of patients; only %1,5 patients discontinued bezuclastinib because of ALT/AST.

Regulation: FDA Priority Review and the PDUFA date

The PEAK data have reached an important milestone not only academically but also from a regulatory perspective. The FDA accepted the new drug application for bezuclastinib + sunitinib in GIST patients after imatinib and granted Priority Review . The target PDUFA date was announced as 30 November 2026 .

This application is also supported by processes such as breakthrough therapy designation and real-time oncology review. If approved, bezuclastinib + sunitinib will be one of the strongest candidates to change the second-line treatment standard in GIST after imatinib.

Critical reading: how should these data be interpreted in a balanced way?

Message for clinical practice

The PEAK study provides strong phase 3 evidence that sunitinib, the longstanding second-line standard in advanced GIST after imatinib, may no longer be sufficient on its own. Bezuclastinib + sunitinib significantly prolonged disease control, particularly through the rationale of targeting KIT resistance heterogeneity more broadly.

In clinical practice, these data strengthen the case for closer evaluation of the mutation profile in patients progressing after imatinib, a better understanding of resistance biology, and discussion of moving from sequential single-agent TKI treatment to more rational combination strategies.

Conclusion

The phase 3 PEAK study presented at ASCO 2026 showed that bezuclastinib + sunitinib significantly improved PFS and ORR compared with sunitinib monotherapy in advanced GIST after imatinib. Median PFS was 16,5 months versus 9,2 months, with HR 0,50; ORR was %45,6 versus %25,8 .

OS is not yet mature; however, PFS2 and mutation subgroup signals suggest that the combination may provide more durable disease control. No new risk was identified in the safety profile, but grade ≥3 adverse events, particularly ALT/AST elevations, should be managed carefully.

PEAK should be viewed as one of the strongest examples of moving from sequential single-agent TKI treatment after imatinib in GIST toward rational combinations that target resistance biology more broadly.