Efficacy and tolerability of mesutoclax monotherapy in Relapsed/Refractory Mantle Cell Lymphoma patients: High remission rates even in prior BTKi-refractory patients

Abstract Background: Venetoclax is the only approved BCL2 inhibitor for treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia (AML). However, the single agent efficacy in mantle cell lymphoma (MCL), remains unsatisfactory. Mesutoclax is a novel BCL2 inhibitor and preliminary clinical results have showed its promising efficacy and safety in B-NHLs. Methods: ICP-CL-01201 (NCT05728658) and ICP-CL-01202 (NCT06351527) are two ongoing phase I studies of Mesutoclax for the treatment of Chinese and Caucasian patients with B-cell malignancies, respectively. Both studies contain dose escalation and dose expansion parts. Eligible patients include relapsed and refractory (r/r) MCL, CLL/SLL and other B-NHLs. Safety and tolerability were assessed across all dose levels, from 50 mg to 150 mg. Oral treatment was administered once daily until disease progression or intolerable toxicities. Key exclusion criteria comprise CNS involvement, prior resistance to BCL2 inhibitors, and significant cardiovascular conditions. Efficacy of MCL and other B-NHLs patients was evaluated according to the Lugano 2014 criteria. Herein, we report the pooled analysis of efficacy and safety in mantle cell MCL patients treated with Mesutoclax across these two studies. Results: As of 10Jul 2025, 43 MCL patients were enrolled in ICP-CL-01201 study and treated with Mesutoclax monotherapy. The median age was 66 years (range 30-79). Of the patients, 32 (74.4%) were previously treated with and refractory to BTK inhibitors, and 35 (81.4%) were refractory to the last line of therapy. The median prior therapeutic line was 2 (range 1-8). Mesutoclax was well tolerated through all dose levels, with no dose-limiting toxicities (DLTs) observed, and maximum tolerated dose (MTD) not reached. One patient experienced dose reduction due to TEAE. Toxicity leading to drug discontinuation was not reported. Most of the TEAEs were in grade 1-2. The most frequent (≥10%) ≥grade3 TEAEs were neutrophil count decreased (18.6%), white blood cell count decreased (16.3%), and platelet count decreased (14.0%). Noteworthily​, there is no reported ≥grade3 anemia, which is a common toxicity of BCL2 inhibitors, in this study (72 patients with monotherapy in total). Serious adverse events (SAEs) were reported in 10 (23.3%) patients. Treatment-related SAE reported in ≥2 patients were pneumonia (14.0%), neutrophil count decreased (4.7%), platelet count decreased (4.7%), and herpes zoster (4.7%). As of cutoff date, 32 MCL patients treated with Mesutoclax monotherapy in 125 mg dose level (recommended phase 2 dose) had at least one disease assessment. In total, ORR was 87.5% and CRR was 46.9%. Notably, in 25 MCL patients who were BTK inhibitor refractory (2 blastoid or pleomorphic subtype and median 2 [1-8] prior treatment lines), highly encouraging efficacy was achieved following Mesutoclax treatment: an ORR of 84.0%, CRR of 36.0%, and a median PFS of 8.3 months (95% CI 5.5, NA). mDOR was not reached, and the 6 months DOR rate was 74.5%. Conclusion: The clinical data from Mesutoclax monotherapy demonstrate low toxicity and potential best in class efficacy in MCL patients, particularly in heavily treated patients with BTK inhibitors refractory disease. These findings support further development of Mesutoclax to address the unmet need in r/r MCL patients who failed previous BTK inhibitors.