Apex Part 1: Updated Assessment of Bezuclastinib (CGT9486), a Selective KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM)
Authors: DeAngelo Daniel J. , Gotlib Jason , Pullarkat Vinod , Vachhani Pankit , Tashi Tsewang , Lee Stephanie , Schiller Gary J. , Hunter Anthony M. , Piris-Villaespesa Miguel , Pomares Helena , Cridtina Bulai Livideanu , Shoumariyeh Khalid , Lambert Jonathan , George Tracy I. , Patel Jay , Papayannidis Cristina , Jain Tania , Deininger Michael W. , Reiter Andreas , Hobbs Gabriela S. , Sun Lei , Nagendra Deepak , Zhang Jenna , Pilla Amanda , Dishman Kim , Carden Marcus , Radia Deepti H. 
Published: December 2024

Background: Systemic mastocytosis (SM) is a rare disease characterized by the abnormal accumulation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V that spares closely related kinases and has minimal brain penetration. Initial results from the Part 1 dose optimization portion of the Apex trial (NCT04996875) in patients with AdvSM demonstrated an encouraging safety profile and signs of clinical activity as well as deep reductions across biomarkers of mast cell burden including the proportion of bone marrow mast cells, serum tryptase levels, and KIT D816V variant allele fraction (VAF). Herein we report updated safety and efficacy results from the fully enrolled Part 1 of the Apex trial.

Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per WHO criteria. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Part 2 evaluated an optimized formulation of bezuclastinib at doses of 150mg and 300 mg. TKI-naïve patients and those with a history of prior TKI therapy (e.g., avapritinib, midostaurin) or other treatments were permitted in the trial after appropriate washout. The primary efficacy endpoint for this trial is ORR [complete response [CR] + CR with incomplete hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) as assessed by the central response review committee (CRRC) based on mIWG-MRT-ECNM response criteria]. Responses require 12-week confirmation.

Results: In Part 1, a total of 32 patients were enrolled with AdvSM (ASM, n=7; SM-AHN, n=23; MCL, n=2) by central adjudication and were randomized and dosed with 50mg BID (n=8), 100mg BID (n=7), 200mg BID (n=8), or 400mg QD (n=9). Median age was 68 years (range, 33-87), 66% were male, and 84% had ECOG PS 0-1. Median KIT D816V VAF was 6.1% (range, 0-47.2%) and 91% of patients were positive for KIT D816V in peripheral blood at baseline. At baseline, 69% of patients had never received midostaurin and/or avapritinib, while 31% had prior midostaurin only and 16% had both prior avapritinib and midostaurin. Of those enrolled, 27 (84%) patients were mIWG-MRT-ECNM-evaluable, exhibiting 1 or more mIWG organ damage finding(s). As of 18Jun2024, median treatment duration was 60 (range, 0.3 - 124.1) weeks. In all Part 1 patients across dose levels, 94%, 93%, and 100% of patients achieved at least 50% reduction in serum tryptase, KIT D816V VAF, and bone marrow mast cell burden, respectively. Treatment-related adverse events (TRAEs) were reported in 91% of patients; 44% had TRAEs of at least grade 3. The most common TRAEs reported in &gt;10% patients (% all grades, % grade ≥3) were hair color changes (34%, 0%), neutropenia (25%, 9%), thrombocytopenia (25%, 6%), ALT/AST increased (28%, 6%), fatigue (16%, 0%), periorbital edema (13%, 3%), peripheral edema (13%, 0%), and dysgeusia (13%, 0%). No treatment-related cognitive impairment or intracranial bleeding events were reported. Overall, 11 (34%) patients dose reduced and 2 (6%) discontinued due to TRAEs [1 Gr3 drug induced liver injury (DILI); 1 Gr3 ALT/AST increased]. No treatment-related deaths occurred. In the 27 mIWG-MRT-ECNM evaluable patients enrolled in the study, the ORR is 52% (14/27). Median time to the start of confirmed response was 2.1 (range 1.9-4.8) months. Median duration of response was not yet reached in response-evaluable patients (range 2.8 to 19.4 months). The rate of pure pathologic response (CR/CRh+PR) was 88% (28/32).

Conclusion: In Part 1 of the Apex trial, bezuclastinib is well tolerated and exhibits durable signs of clinical activity, with marked reductions in objective measures of mast cell burden. Based on a composite of safety/tolerability, efficacy, and pharmacokinetics, 150 mg daily has been chosen as the recommended dose.