Introduction: BCL2 inhibition is an established CLL/SLL therapeutic strategy, and combination with Bruton tyrosine kinase inhibition (BTKi) achieves therapeutic synergy. Mesutoclax (ICP-248) is highly selective and potent BCL2 inhibitor with improved pharmokinetical profile and metabolic stability. Orelabrutinib is a marketed second-generation BTKi with best kinase selectivity and good efficacy and safety in CLL/SLL. Herein, we present updated results of two ongoing studies of mesutoclax alone or combined with orelabrutinib in patients with treatment-naive (TN) or relapsed/refractory (R/R) CLL/SLL (NCT06378138; NCT05728658).

Methods: Patients with TN CLL/SLL were randomized 1:1 with stratification, by age and TP53/del (17p) status, to receive mesutoclax (100 mg or 125mg once daily [cycles 3-14]) after two cycles orelabrutinib (150mg once daily [cycles 1-17]) lead in. Patients with R/R CLL/SLL received mesutoclax monotherapy until disease progression or unacceptable toxicity. Mesutoclax was administrated with a 5-week ramp-up schedule to the target dose to mitigate risk of tumor lysis syndrome (TLS). TN CLL/SLL can be continuously treated with orelabrutinib if stopping rules (undetectable MRD [uMRD; ≤10-4] at cycle 17) are not reached.

Results: Between Apr 2023 and Sep 2024, 66 patients were enrolled: 42 patients were TN (mesutoclax 100 mg, n=21; 125 mg, n=21) and 24 patients were R/R. The median age for TN and R/R CLL/SLL were 59.5 y and 61.7 y, respectively. At baseline, 76.2% (32/42) of TN CLL/SLL patients had moderate or high TLS risk, while 70.8% of R/R CLL/SLL patients were refractory disease, among which 41.7% of patients were previously treated with BTKi. The median prior therapeutic line was 2 (range 1-7).

Mesutoclax is well tolerated with good safety profile. No dose-limiting toxicities (DLTs) observed up to 150 mg QD, and maximum tolerated dose (MTD) not reached. As of Jul 21, 2025, all patients were still on treatment. Most treatment emergent adverse events (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, white blood cell count decreased and platelet count decreased.

After 2 cycles of orelabrutinib lead in, 100% TN patients with high TLS risk were effectively debulked to moderate or low risk, and no clinical or laboratory TLS occurred.

In TN CLL/SLL, the overall response rate (ORR) was 100% and the complete remission rate (CRR) was 28.6% at 125 mg. At week 36 of the combination therapy, the peripheral blood (PB) uMRD rate was 65% (13/20) at 125 mg. The median time to CR was 7.1 mo (range, 3.5-9.4 mo), the median time to uMRD was 5.8 mo (range, 5.5-11.3 mo). The ORR was 100% and CRR was 27.8% in R/R CLL/SLL patients at 125 mg. In 10 R/R CLL/SLL patients who failed prior BTKi treatment, the ORR was 100% and CRR was 30.0%, PB uMRD rate was 20.0%. 12-mo progression-free survival (PFS) rate was 100%.

Conclusions: Mesutoclax monotherapy or in combination with orelabrutinib demonstrated a tolerable safety profile across all dose levels tested. Substantial efficacy and deep remission were observed in both TN CLL/SLL patients receiving mesutoclax 125mg combined with orelabrutinib and R/R CLL/SLL treated with mesutoclax alone.

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2025
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