Bezuclastinib Improves Mast Cell Burden, TSS Vs Placebo in Nonadvanced Systemic Mastocytosis

Frank Siebenhaar, MD

Treatment with bezuclastinib (CGT9486, formerly PLX9486) plus best supportive care (BSC) led to an improvement in mast cell burden and total symptom score (TSS) compared with placebo plus BSC in adult patients with nonadvanced systemic mastocytosis, according to data from part 1b of the phase 2 SUMMIT trial (NCT05186753) presented at the 2024 AAAAI Annual Meeting.^1,2

Findings showed that in evaluable patients with a baseline serum tryptase of at least 20 ng/mL, a reduction below 20 ng/mL was observed in 100% of patients treated with 100 mg of bezuclastinib (n = 11), 89% of those given 150 mg of bezuclastinib (n = 11), and 0% of patients who received placebo (n = 12). The mean time to reduction of serum tryptase to below 20 ng/mL was 4.5 weeks for patients treated with bezuclastinib. Additionally, in patients with a baseline serum tryptase of at least 11.4 ng/mL, the rates of reduction below 11.4 ng/mL were 100%, 90%, and 0% for those given 100 mg of bezuclastinib, 150 mg of bezuclastinib, or placebo, respectively.1

Further, in patients with detectable KIT D816V mutations at baseline, undetectable or at least a 50% reduction in KIT D816V at week 12 occurred in 100% of patients treated with 100 mg of bezuclastinib, 89% of those given 150 mg of bezuclastinib, and 0% of those treated with placebo.

Eighty-six percent of patients with evaluable bone marrow mast cells who were treated with 100 mg of bezuclastinib experienced at least a 50% reduction in bone marrow mast cells at week 12; those rates were 78% and 40% for those given 150 mg of bezuclastinib and placebo, respectively. The mean change in bone marrow mast cells from baseline to week 12 was –70% for the 100-mg cohort and –30% for the placebo cohort.

Additionally, using the novel Mastocytosis Symptom Severity Daily Diary (MS2D2), patients treated with 100 mg of bezuclastinib achieved a 51% mean improvement in MS2D2 TSS at week 12 vs 18% for those given placebo. Seventy percent of patients in the 100-mg arm experienced at least a 50% reduction in MS2D2 TSS at week 12 compared with 8% of those in the placebo arm. Those given 100 mg of bezuclastinib reported a –23.78 reduction in total symptom severity vs –9.03 reduction in the placebo arm (P = .0003).

“The results from SUMMIT part 1b show that bezuclastinib has the potential to provide non-advanced systemic mastocytosis patients with a potent and well-tolerated KIT inhibitor that can drive rapid and clinically meaningful impact across a multitude of symptoms resulting in an impressive improvement in overall quality of life [QOL],” Frank Siebenhaar, MD, head of the University Outpatient Clinic at the Institute of Allergology, Charité - Universitätsmedizin Berlin in Germany, stated in a news release.²

Part 1 of the SUMMIT trial enrolled patients with indolent systemic mastocytosis or smoldering systemic mastocytosis based on the 2016 World Health Organization classification. Patients were also required to have moderate to severe symptoms on at least 2 antimediator therapies.¹

In part 1a, patients (n = 20) were randomly assigned 1:1:1 to receive bezuclastinib at 100 mg per day plus BSC, bezuclastinib at 200 mg per day plus BSC, or placebo plus BSC. Those enrolled in part 1b (n = 34) were randomly assigned 1:1:1 to 100 mg of bezuclastinib per day plus BSC, 150 mg of bezuclastinib per day plus BSC, or placebo plus BSC. Notably, treatment was double blinded for 12 weeks during part 1.

In the part 2 expansion of SUMMIT, which is actively enrolling, patients are being randomly assigned 2:1 to receive 100 mg of bezuclastinib per day plus BSC or placebo plus BSC. Part 2 is double blinded for 24 weeks.

End points for part 1 of the study included safety, pharmacokinetics, biomarkers, and symptom improvement based on patient-reported outcomes (PROs).

Among all patients enrolled in part 1b, the median age was 52.0 years (range, 27-76), and 61.8% of patients were female. ECOG performance statuses included 0 (47.1%), 1 (50%), and 2 (2.9%). The majority of patients had indolent systemic mastocytosis (97%), and the median mastocytosis activity score was 43.44 (range, 28.6-65.4).

Furthermore, 82.4% of patients were positive for KIT D816V in whole blood, and the median KIT D816V variant allele frequency was 0.085 (range, below the limit of detection-19.58). The median bone marrow mast cell burden was 15% (range, 2%-50%), and the median serum tryptase was 37.15 ng/mL (range, 9.2-206.0). Notably, 79.4% of patients had a serum tryptase of at least 20 ng/mL.

One patient (2.9%) received prior treatment with avapritinib (Ayvakit). Patients received a median of 2.5 baseline supportive care medications (range, 2-9), including H1 blockers (88.2%), H2 blockers (79.4%), leukotriene receptor antagonists (41.2%), proton pump inhibitors (26.5%), cromolyn sodium (8.8%), omalizumab (Xolair; 2.9%), and corticosteroids (2.9%).

Patients were on study for a median of 4.09 months (range, 2.7-6.6). At the data cutoff date of December 18, 2023, 97.1% of patients remained on the study. One patient (2.9%) discontinued treatment due to an adverse effect (AE).

Additional data showed patients treated with 100 mg of bezuclastinib experienced a 49% mean improvement in QOL at week 12 per the MC-QOL questionnaire, compared with 24% for placebo. Those in the 100-mg cohort achieved a significant improvement in QOL at 12 weeks vs placebo (–24.86 vs –12.39; P = .046).

Regarding safety, most treatment-emergent AEs (TEAEs) were low grade and reversible without dose modification. Notably, no patients treated with bezuclastinib experienced bleeding or cognitive impairment events. No dose reductions were required in the 100-mg cohort; however, 2 patients required dose reductions in the 150-mg cohort due to grade 1 increased alanine aminotransferase (ALT) and grade 2 abdominal pain. One patient treated with 150 mg of bezuclastinib experienced a serious AE—increased ALT/aspartate aminotransferase (AST)—that led to treatment discontinuation.

Grade 1/2 TEAEs reported in the 100-mg cohort included hair color changes (n = 3), diarrhea (n = 2), nausea (n = 3), taste disorder (n = 1), and COVID-19 (n = 1). In the 150-mg cohort, grade 1/2 TEAEs were comprised of hair color change (n = 7), diarrhea (n = 2), nausea (n = 1), taste disorder (n = 2), dizziness (n = 2), fatigue (n = 2), noncardiac chest pain (n = 2), increased ALT/AST (n = 1), and neutropenia (n = 1).

“We are pleased to announce these positive results from our SUMMIT part 1b trial, the specifics of our new MS2D2 symptomatic severity PRO measure, and the news that we have initiated Summit part 2, with extremely positive support from the [nonadvanced systemic mastocytosis] community,” Andrew Robbins, president and chief executive officer of Cogent, stated in a news release.²

“The magnitude and speed of symptomatic reductions, along with corresponding improvements in QOL, reported by patients in SUMMIT part 1b has not been seen previously with other treatment options in this patient population,” he added. “We are fully dedicated to our three actively enrolling, registration-directed clinical trials and see a clear path to establishing bezuclastinib as the best-in-class KIT inhibitor for patients fighting systemic mastocytosis and gastrointestinal stromal tumors.”

References

1. Modena BD, Rein LAM, Oh ST, et al. Initial results from Summit: an ongoing, 3-part, multi-center, randomized, double-blind, placebo-controlled phase 2 clinical study of bezuclastinib in adult patients with nonadvanced systemic mastocytosis (NonAdvSM). Presented at: AAAAI Annual Meeting; February 23-26, 2024; Washington, DC. Poster 694.
2. Cogent Biosciences announces positive part 1b data from summit trial evaluating bezuclastinib in patients with nonadvanced systemic mastocytosis. News release. February 22, 2024. Accessed February 26, 2024. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-positive-part-1b-data-summit-trial