Crossover to Bezuclastinib Plus Sunitinib Improves Disease Control in Pretreated GIST

Patients with advanced gastrointestinal stromal tumor (GIST) whose disease progressed on second-line sunitinib (Sutent) achieved longer progression-free survival (PFS) and higher response rates after crossing over to bezuclastinib plus sunitinib, with no new safety signals, according to results from part 2 of the phase 3 PEAK trial (NCT05208047) presented by Robin Jones, MD, head of the Sarcoma Unit at The Royal Marsden Hospital in Sutton, United Kingdom, at the 2026 European Society for Medical Oncology Congress.¹

Of the 209 patients randomly assigned to sunitinib monotherapy, 71% (n = 148) had experienced disease progression as of the data cutoff of September 30, 2025, and 128 crossed over to the combination.

Among these crossover patients, median PFS on second-line sunitinib was 5.7 months (95% CI, 3.8-7.3). After crossing over, median PFS on bezuclastinib plus sunitinib was 7.4 months (95% CI, 5.6-11.0).

Responses also improved. The objective response rate (ORR) with second-line sunitinib was 20.3% (95% CI, 13.7%-28.3%; n = 26), compared with 29.7% (95% CI, 21.9%-38.4%; n = 38) with the subsequent combination. Notably, 80% (n = 102) of patients entering crossover had not achieved an objective response on sunitinib, with a best response of stable or progressive disease. In patients whose best response to sunitinib was disease progression, the ORR with the combination was 56%, and 2 of these patients achieved a complete response.

According to Jones, these results compared favorably with approved third-line agents. In prior phase 3 studies, median PFS was 4.8 months with regorafenib (Stivarga)² and 4.2 months with avapritinib (Ayvakit).³

The crossover data build on the pivotal portion of PEAK, in which second-line bezuclastinib plus sunitinib produced a median PFS of 16.5 months vs 9.2 months with sunitinib alone (HR, 0.50; 95% CI, 0.39-0.65; P < .0001) and an ORR of 46% vs 26%. Median PFS2 was not reached with the combination vs 21.0 months with sunitinib (HR, 0.57). Based on these data, the FDA accepted a new drug application for bezuclastinib plus sunitinib in patients with GIST previously treated with imatinib, granting it priority review with a target action date of November 30, 2026.⁴

"Following imatinib treatment, the majority of patients would derive improved disease control with earlier combination therapy," Jones said.

Safety of Bezuclastinib Regimen

Median treatment duration in the crossover cohort was 23.9 weeks (range, 1.0-114.7). Treatment-emergent adverse events (TEAEs) occurred in 97.7% of crossover patients, and treatment-related adverse events (TRAEs) occurred in 94.5%. Grade 3 or higher TRAEs were reported in 39.1% of crossover patients, compared with 71.6% of patients in the pivotal combination arm and 52.4% of those in the sunitinib arm.

Serious adverse reactions occurred in 11.7% of crossover patients. No TRAEs led to death with the combination in either the pivotal or crossover setting. TRAEs led to dose reductions of either drug in 25.8% of crossover patients and to treatment discontinuation in 2.3%. Diarrhea (1.6%) was the only TRAE leading to discontinuation in more than 1 crossover patient.

The most common TEAEs in the crossover cohort were diarrhea (50.8%), increased ALT/AST (46.9%), nausea (28.1%), fatigue (27.3%), anemia (27.3%), and neutropenia (25.8%). Grade 3 or higher TEAEs occurred in 50.0% of patients (n = 64), most often anemia (10.2%), fatigue (7.8%), neutropenia (7.8%), increased ALT/AST (7.0%), and diarrhea (5.5%).

"Safety observations in combination crossover patients were consistent with bezuclastinib + sunitinib combination in the pivotal portion of the trial," Jones said.

PEAK Trial Design

PEAK is a global, randomized, open-label phase 3 trial.⁵ Patients with GIST were randomly assigned 1:1 to bezuclastinib 600 mg once daily plus sunitinib 37.5 mg once daily (n = 204) or sunitinib 37.5 mg once daily (n = 209). Patients in the sunitinib arm who had disease progression confirmed by blinded independent central review could cross over to the combination at the same doses. The crossover analysis evaluated PFS, ORR, and safety.

Rationale for Bezuclastinib Regimen

GIST is commonly driven by activating KIT mutations, typically in exons 9 and 11. Imatinib (Gleevec) is active against these primary mutations, but approximately 50% of patients develop resistance within 2 years, largely because of heterogeneous secondary KIT mutations. Sunitinib is the standard second-line option after imatinib failure,⁶ with a median PFS of approximately 6 to 8 months. Efforts to combine KIT inhibitors have been limited by overlapping toxicities.

Bezuclastinib is a next-generation, highly selective oral KIT inhibitor. Its lack of off-target effects allows it to be combined with sunitinib, and together the 2 agents are designed to cover the broad spectrum of primary and secondary KIT mutations. An earlier phase 1b/2a study supported the clinical activity of this approach in patients with refractory GIST.⁷

REFERENCES

1. Jones R, Somaiah N, Wagner AJ, et al. Phase 3 PEAK crossover: bezuclastinib + sunitinib combination following sunitinib monotherapy in patients with GIST. Presented at: ESMO Congress 2026; October 23-27, 2026. Abstract 3717RO.

2. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1.

3. Kang YK, George S, Jones RL, et al. Avapritinib versus regorafenib in locally advanced unresectable or metastatic GI stromal tumor: a randomized, open-label phase III study. J Clin Oncol. 2021;39(28):3128-3139. doi:10.1200/JCO.21.00217.

4. Cogent Biosciences announces FDA acceptance of new drug application (NDA) with priority review for bezuclastinib in combination with sunitinib for patients with GIST. News release. Cogent Biosciences, Inc. May 28, 2026. Accessed November 13, 2026. https://tinyurl.com/mrhsvw4m

5. (PEAK) A phase 3 randomized trial of CGT9486+sunitinib vs. sunitinib in subjects with gastrointestinal stromal tumors. ClinicalTrials.gov identifier: NCT05208047. Updated May 22, 2026. Accessed November 13, 2026. https://clinicaltrials.gov/study/NCT05208047

6. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338. doi:10.1016/S0140-6736(06)69446-4.

7. 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.