On December 11, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported positive updated clinical data from its ongoing Phase 2 APEX clinical trial evaluating the selective KIT D816V inhibitor bezuclastinib in patients with advanced systemic mastocytosis (AdvSM) (Press release, Cogent Biosciences, DEC 11, 2022, View Source [SID1234625014]). The data are being presented in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, LA.
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"Advanced systemic mastocytosis is a rare and life-threatening disease," said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and APEX clinical trial investigator. "Updated results from the APEX trial demonstrate rapid and deep responses with bezuclastinib while maintaining an impressive safety and tolerability profile."
"We are very encouraged by the clinical profile that bezuclastinib has shown to date," said Andrew Robbins, President and Chief Executive Officer at Cogent Biosciences. "We are especially excited that a growing body of data supports bezuclastinib’s differentiated safety and tolerability profile enabling therapeutic exposures that could support key differentiation for both AdvSM patients and non-advanced systemic mastocytosis patients."
Updated Data from Ongoing Phase 2 APEX Clinical Trial
APEX is a global, open-label, multi-center, two-part Phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. As of the data cutoff date of October 26, 2022, 16 patients had been treated in Part 1 at one of four dose levels (50 mg BID, 100 mg BID, 200 mg BID or 400 mg QD). The median age of patients at study entry was 69 years (ranging from 33-87 years). Patients were enrolled with the following sub-types: three patients with aggressive systemic mastocytosis (ASM), 12 patients with systemic mastocytosis with associated hematologic neo-plasm (SM-AHN), and one patient with mast cell leukemia (MCL). Three patients had received prior avapritinib and midostaurin treatment.
Updated Safety Data
As of the cutoff date October 26, 2022, bezuclastinib was generally well-tolerated at all doses. The majority of adverse events were Grade 1/2 and occurred in no more than one patient. Grade 3 events reported as at least possibly related to bezuclastinib were neutropenia (2 patients), thrombocytopenia (1 patient), anemia (1 patient) and hypersensitivity/mediator flare (1 patient). Importantly, there were no related cases of cognitive impairment and no reported intracranial bleeding events, which have been associated with other KIT inhibitors. Limited low-grade edema was observed, and analysis of platelet counts in bezuclastinib-treated patients showed no trend in platelet reduction at any dose.
Updated Clinical Activity Data
As of the cutoff date of October 26, 2022, 11 patients were evaluable for response per the modified IWG-MRT-ECNM criteria, and 12 patients were evaluable for response using pure pathological response (PPR) criteria. Reported ORR per mIWG-MRT-ECNM criteria includes centrally adjudicated confirmed and unconfirmed CR, CRh, PR, and CI.
89% ORR in TKI therapy naïve patients, including 67% of patients achieving CR, CRh or PR, and 22% of patients achieving CR or CRh
73% ORR in all patients, regardless of prior treatment
75% ORR in all patients by PPR criteria, regardless of prior treatment
Additionally, results of key markers of clinical activity were reported from 16 patients.
14/16 patients achieved ≥ 50% reduction in serum tryptase levels by central assessment
85% median reduction in serum tryptase
Eight of these patients achieved reduction to <20 ng/mL
13/13 patients with ≥2 cycles of treatment achieved ≥50% reduction in bone marrow mast cells by central review
10 of these patients achieved complete clearance of bone marrow mast cell aggregates
11/12 patients with baseline D816V mutation and ≥2 cycles of treatment achieved ≥50% reduction in KIT D816V variant allele fraction (VAF) by droplet digital polymerase chain reaction (ddPCR)
Bezuclastinib Clinical Development
Based on the continued favorable safety and tolerability profile and clinical activity observed to date in the Phase 2 APEX clinical trial with bezuclastinib for patients with AdvSM, Cogent will continue enrolling patients in Part 1 of APEX to determine a recommended dose for use in Part 2 of the trial.
In addition, Cogent continues to actively enroll patients in SUMMIT, a Phase 2 clinical trial with bezuclastinib for patients with non-advanced systemic mastocytosis (NonAdvSM), and PEAK, a registrational randomized, open-label, global, Phase 3 clinical trial in patients with imatinib-resistant Gastrointestinal Stromal Tumors (GIST). Cogent plans to present initial clinical efficacy results from the PEAK lead-in study during the first half of 2023 and present initial clinical data from SUMMIT in the second half of 2023.
Webcast Information & ASH (Free ASH Whitepaper) Poster
Cogent will host a webcast on December 12, 2022 at 8:00 a.m. ET (7:00 a.m. CT) to discuss today’s updated clinical data from the ongoing APEX trial. The live event can be accessed on the Investor page of Cogent’s website at investors.cogentbio.com. A replay of the webcast will be available approximately two hours after the completion of the event and will be archived for up to 30 days.
The ASH (Free ASH Whitepaper) poster is available to registered conference attendees as well as on the Posters and Publications section of Cogent’s website at www.cogentbio.com/research.