Efficacy and safety of mesutoclax (ICP-248) in combination with orelabrutinib in patients with B-cell malignancies: A pooled analysis.

Abstract

7073 Background: Mesutoclax (ICP-248) is a next-generation BCL2 inhibitor, and orelabrutinib is a marketed BTK inhibitor for CLL/SLL, MCL, and MZL. However, the clinical activity of their combination in these malignancies remains undefined. This analysis evaluated the combination of mesutoclax and orelabrutinib across B-cell malignancies. Methods: Patients with relapsed and refractory (R/R) MCL, MZL were enrolled in a phase 1 study (NCT05728658), and treatment-naive (TN) CLL/SLL were enrolled in a phase 2 study (NCT06378138). R/R MCL and MZL patients received continuous daily mesutoclax (125 mg) and orelabrutinib (150mg) from cycle 1 day 1 continuously until disease progression or unacceptable toxicity. For CLL/SLL patients, induction therapy with orelabrutinib (150 mg QD, Cycles 1-17) was administered first, followed by mesutoclax (100 mg or 125 mg QD, Cycles 3-14). The orelabrutinib treatment continued beyond cycle 17 if the uMRD (≤10-4) was not achieved. Mesutoclax was implemented with a ramp-up schedule in all patients to mitigate the risk of TLS. Results: As of 05 Jan 2026, 60 patients were enrolled and treated in the studies: 8 R/R MCL, 10 R/R MZL, and 42 TN CLL/SLL (mesutoclax 100 mg, n=21; 125 mg, n=21). In R/R patients, the median number of prior lines of therapy was 1 (1-4). 6 (33.3%) were refractory to the last line of therapy. For TN CLL/SLL, 76.2% (32/42) of patients had moderate or high TLS risk, and 14.3% (6/42) had TP53 mutation or del (17p). Among 5 MCL and 8 MZL patients who had at least one disease evaluation, the overall response rate (ORR) was 100%, with CRR of 100% and 50%, respectively. Five patients (38.5%) achieved peripheral blood (PB) uMRD. In the 21 CLL/SLL patients receiving mesutoclax 125 mg, the ORR was 100% and the CRR was 38.1%, and the peripheral blood uMRD rate at 36-week was 65%. The median time to CR was 3.7 months in R/R group and 7.1 months in TN group. The 12-month PFS rate was 100% in CLL/SLL, while data for MCL and MZL are immature due to short follow-up. As the safety data cutoff (31 Dec 2025), the combination of mesutoclax and orelabrutinib was well tolerated with a favorable safety profile, and no new safety signals were identified compared to either agent as monotherapy. Most TEAEs were grade 1-2, with no TEAEs leading to drug discontinuation or death reported. The most common grade ≥3 TEAEs include neutrophil count decreased (35%), platelet count decreased (11.7%). Notably, no grade ≥3 anemia was reported. No clinical or laboratory TLS occurred. Conclusions: Mesutoclax in combination with orelabrutinib demonstrated a tolerable safety profile across B cell malignancy subtypes (MCL, MZL, CLL/SLL). Significant 100% ORR and deep response were observed in patients receiving mesutoclax 125mg combined with orelabrutinib. This all oral, chemo-free regimen has the potential to establish a novel therapeutic option for B-NHLs. Clinical trial information: NCT05728658 .