Preliminary safety and efficacy data of ICP-248, a novel BCL2 inhibitor, in patients with relapsed or refractory B-cell malignancies.

7038 Background: BCL2, a critical protein regulator of the apoptotic pathway, highly expressed in various malignancies, including B-cell non-Hodgkin lymphomas (B-NHLs). The only approved BCL2 inhibitor, Venetoclax, has been approved for the treatment of chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) or acute myeloid leukemia (AML). However, hematologic toxicities and tumor lysis syndrome (TLS) remain as safety challenges in clinical practice. ICP-248 was developed as a potent and highly selective BCL2 inhibitor. Preclinical studies have demonstrated favorable pharmacokinetics profile and excellent safety profile. Methods: ICP-CL-01201 is an ongoing phase I study (NCT05728658) including dose escalation and dose expansion parts. Safety and tolerability of ICP-248 was evaluated from target doses of 50 mg to 200 mg. Patients receive oral treatment every day until disease progression or intolerable toxicities. Eligible patients include those aged 18-80 years, diagnosed with CLL/SLL and B-NHLs who are in relapsed or refractory disease. Key exclusion criteria include CNS involvement, resistance to BCL2 inhibitors and clinically significant cardiovascular disease. Efficacy was evaluated according to the Lugano 2014 or iwCLL 2018 criteria. Results: As of 12 Dec 2024, 55 patients were enrolled in the study: 18 in dose escalation and 37 in dose expansion. 24 patients were CLL/SLL, 26 patients were mantle cell lymphoma (MCL), 5 patients were other B-NHLs. The median age was 65 years, and 72.7% of patients were refractory disease and 56.4% of the patients were previously treated with BTK inhibitors. The median prior therapeutic line was 2 (1-8). ICP-248 was well tolerated through all dose levels, with no dose-limiting toxicities (DLTs) observed, and maximum tolerated dose (MTD) not reached. Toxicity leading to drug discontinuation and death was not observed. Most of TEAEs were in grade 1-2. The most frequent TEAEs were hematologic AEs including neutropenia, leukopenia, and thrombocytopenia. Serious adverse events (SAEs) were reported in 16.4% patients. As cutoff date, 20 CLL/SLL and 19 MCL patients treated with ICP-248 dose ≥100 mg had at least one response assessment: ORR was 80% and CRR was 15% in r/r CLL/SLL patients, while those for r/r MCL patients were 78.9% and 42.1% respectively. uMRD was reported in 10% CLL/SLL and 15.8% MCL patients. In 10 patients with previous BTK inhibitor refractory MCL patients (2 blastoid or pleomorphic subtype and median 3.5 prior treatment lines), the ORR was 80% and CRR was 30%; in 11 patients with previous BTK inhibitor failure CLL/SLL, the ORR was 81.8% and CRR was 18.2%. Conclusions: The preliminary results of ICP-248 monotherapy suggests a well-tolerated safety profile and an exciting efficacy with dose-dependent effect in BTK failed, heavily treated, relapsed or refractory B-cell malignancies. Clinical trial information: NCT05728658 .