Bezuclastinib Demonstrates Early Promise in Advanced Systemic Mastocytosis

Bezuclastinib showcased early signs of clinical activity in that it resulted in a meaningful reduction in serum tryptase levels, as well as reductions in mast cell burden and KIT D816V variant allele frequency, in adult patients with advanced systemic mastocytosis.

Bezuclastinib (formerly PLX 9486) showcased early signs of clinical activity in that it resulted in a meaningful reduction in serum tryptase levels, as well as reductions in mast cell (MC) burden and KIT D816V variant allele frequency (VAF), in adult patients with advanced systemic mastocytosis, according to data from the phase 2 APEX trial (NCT04996875).1

The findings, which were presented during the 2022 EHA Congress, showed that all 11 patients who received treatment with the selective KIT D816V inhibitor experienced more than a 50% reduction in serum tryptase level, with 6 patients achieving a level of less than 20 ng/mL.

Moreover, all 8 patients who received 2 or more cycles of treatment and who had data available up to day 1 of cycle 3 of treatment achieved a 50% or higher reduction in bone marrow MC. Notably, 6 of these 8 patients achieved complete clearance of MC aggregates per central review. All 8 patients also experienced decreases in KIT D816V VAF per ddPCR.

“Advanced systemic mastocytosis is a severe, debilitating hematologic disorder and physicians and patients remain in search of more effective and better tolerated treatment options to fight this disease,” Daniel DeAngelo, MD, PhD, clinical study investigator and chief of the Division of Leukemia at the Dana-Farber Cancer Institute, stated in a press release.2 “I am very impressed with the early, encouraging results presented today from the APEX study. If results like these can be shown in a larger set of patients with advanced systemic mastocytosis, I believe bezuclastinib has the potential to help us take a big step forward in treating [patients with this disease].”

Systemic mastocytosis is primarily driven by mutations in KIT D816V and is known to result in uncontrolled proliferation of MCs. Depending on the subtype of the disease, the median overall survival of patients can range from less than 6 months to 3-4 years. Moreover, the limited therapeutic options that are available for these patients are known to come with significant toxicity, such as nausea, vomiting, diarrhea, edema, intracranial bleeding, and cognitive effects.

Bezuclastinib is an oral, selective, potent, type I TKI that has been shown to have strong activity against KIT D816V. Preclinical evidence suggests that the agent is very active in that it has specificity for mutations in KIT exons 9, 11, 17, and 18, as well as D816V. The TKI has also been shown to spare closely related kinases, have minimal brain penetration, and have acceptable pharmacokinetic (PK) properties.

The multicenter, open-label, 2-part APEX trial enrolled patients with advanced systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), or mast cell leukemia (MCL) per World Health Organization 2016 criteria. Patients were required to have measurable disease, an ECOG performance status of 0 to 3, and acceptable laboratory results.

Patients were allowed to have received prior TKIs such as avapritinib (Ayvakit) or midostaurin (Rydapt), but systemic corticosteroids were not permitted.

Study participants (n = 60) were randomized 1:1:1:1 to receive oral bezuclastinib at the following doses: 50 mg twice daily (n = 3), 100 mg twice daily (n = 3), 200 mg twice daily (n = 3), and 400 mg once daily (n = 2).

The primary objective of part 1 is to determine the optimal dose for the agent, and the primary end points include evaluating the safety, PK, and pharmacodynamic assessments; changes in laboratory results and dose modifications from baseline; and overall response rate (ORR) based on the mIWG response criteria.

Once the optimal dose is selected from part 1 data, it will be utilized for the expansion phase of the research. The primary objective of part 2 is to identify the efficacy of bezuclastinib in the selected optimal dose, and ORR per mIWG and as assessed by a CRCC will serve as the primary end point.

As of May 24, 2022, a total of 11 patients determined to be evaluable per mIWG response criteria were enrolled to the trial, and the median age of these patients was 70 years (range, 48-87).

Two patients had advanced systemic mastocytosis; 1 received the agent at 50 mg twice daily, and the other received it at 400 mg once daily. Eight patients with SM-AHN were included; 2 patients received the agent at 50 mg twice daily, 2 received it at 100 mg twice daily, 3 received it at 200 mg twice daily, and 1 received it at 400 mg once daily. One patient with MCL was included, and this patient received bezuclastinib at a dose of 100 mg twice daily.

All patients who received the agent at 50 mg twice daily were treatment naïve, along with 2 patients each in the remaining dose cohorts. Two patients on the trial received prior avapritinib and midostaurin; these patients were in the dose cohorts of 100 mg twice daily (n = 1) and 200 mg twice daily (n = 1).

In the 50 mg, 100 mg, 200 mg, and 400 mg dose cohorts, the median bone marrow MC burden was 60% (range, 30%-70%), 70% (range, 30%-80%), 10% (range, 7%-30%), and 55% (range, 30%-80%), respectively. The median serum tryptase in these dose cohorts was 187 ng/mL (range, 169-605), 253 ng/mL (range, 144-1578), 83 ng/mL (range, 67.9-111), and 301 ng/mL (range, 232-370).

In a poster presentation, investigators shared 2 cases of patients who received bezuclastinib on the trial.

The first patient had SM-AHN, previously received midostaurin and experienced disease progression, and also received avapritinib but discontinued due to grade 3 thrombocytopenia and anemia. At baseline, the patient had a serum tryptase of 1578 ng/mL, a MC burden of 80%, and a platelet count of less than 75,000/μL. This patient was randomized to receive bezuclastinib at a twice daily dose of 100 mg and experienced a 93% reduction in serum tryptase, a 63% reduction in bone marrow MC, and a 63% reduction in KIT D816V VAF. The patient experienced grade 3 anemia but remains on study treatment for more than 2 months without requiring a dose interruption or reduction.

The second patient had advanced systemic mastocytosis and had not previously received treatment with a TKI. At baseline, they had serum tryptase of 370 ng/mL, a MC burden of 80%, and a spleen volume of greater than 5 cm below the left costal margin. This patient was randomized to receive bezuclastinib at a once daily dose of 400 mg. Treatment resulted in a reduction of serum tryptase of 94%, a reduction in bone marrow MC of 50%, and a reduction in KIT D816V VAF of 72%.

This patient experienced hypersensitivity on cycle 1 dose 2; investigators reduced the dose of the agent to 200 mg once daily without interruption, and symptoms were noted to resolve within 1 day. The patient continues to be on the study for more than 4 months.

Overall, bezuclastinib was generally well tolerated spanning all dose levels examined. Most of the treatment-emergent adverse effects (TEAEs) experienced with the drug were low grade. Only 1 patient experienced a serious toxicity, and no grade 4 effects occurred. Notably, no periorbital/peripheral edema, cognitive effects, or intracranial bleeding were observed.

The most common TEAEs experienced with the agent included anemia (grade 1/2, 18%; grade 3, 9%), neutropenia (grade 1/2, 9%; grade 3, 9%), thrombocytopenia (grade 1/2, 18%), diarrhea (grade 3, 9%), and hypersensitivity (grade 3, 9%).

No patients have discontinued bezuclastinib, and all remain on study. Two patients required dose reductions because of toxicities, and 1 re-escalated to their randomized dose.


  1. DeAngelo, DJ, Pullarkat V, Pires-Villaespesa M, et al. A phase 2 study of bezuclastinib (CGT9486), a novel, highly selective, potent KITD816V inhibitor in adults with advanced systemic mastocytosis (Apex): methods, baseline data, and early insights. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1049.
  2. Cogent Biosciences announces positive initial clinical data from ongoing phase 2 APEX trial evaluating bezuclastinib in patients with advanced systemic mastocytosis (AdvSM). News release. June 10, 2022. Accessed June 13, 2022.