Efficacy and safety of rocbrutinib, a highly selective 4th-generation BTK inhibitor, in Chinese patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

Abstract Background Rocbrutinib, a highly selective, 4th-generation Bruton's tyrosine kinase (BTK) inhibitor, uniquely takes advantages of both covalent irreversible inhibition for wide-type BTK and non-covalent binding for C481-mutant variants. Here, we present the safety and efficacy results from the ongoing phase I trial (LP-168-CN101; NCT04993690) of rocbrutinib in Chinese patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods Eligible patients aged 18–80 with a confirmed diagnosis of CLL/SLL were treated with rocbrutinib monotherapy until disease progression or intolerable toxicity. Adverse events (AEs) were graded per CTCAE v5.0, and response was evaluated per 2018 iwCLL criteria. Results As of April 15, 2025, 41 (untreated (1L), n=12; relapsed/refractory (R/R) BTKi-naïve, n=17; R/R post-BTKi, n=12) CLL/SLL patients were enrolled and treated with rocbrutinib (100 mg ,n=1; 150 mg, n=28; 200 mg, n=10; 300mg, n=2) once daily. The median age was 60 (range, 35-79) years. Of the patients with evaluable samples, 26.9% (7/26) with del(17p), 42.9% (12/28) with TP53 mutation, 63.0% (17/27) with unmutated IGHV and 44.0% (11/25) with complex karyotype. Of the 29 R/R CLL/SLL patients, the median number of prior therapies was 2 (range, 1-5), including prior covalent BTKis (34.5%), BCL2 inhibitors (BCL-2i, 24.1%), and noncovalent BTKis (6.9%). In R/R post-BTKi CLL/SLL patients, most (91.7%) discontinued prior BTKi due to disease progression; 41.6% had prior BCL-2i ; 6/9 (66.7%) carried BTK mutations, including BTKC481S, BTKC481Y/R and BTKL528W. The most common treatment-related AEs (TRAEs, incidence≥20%)(any grade;≥grade 3) included decreased neutrophil count (41.5%; 19.5%), anemia (36.6%; 2.4%), decreased platelet count (29.3%; 2.4%), hyperuricemia (26.8%; 0) and rash (22.0%; 0), most of which were grade 1. No ≥grade 3 atrial fibrillation, hypertension or hemorrhage occurred. Dose interruption due to TRAEs occurred in 8 (19.5%) patients, however, only 1 (2.4%) patient underwent dose reduction. No drug discontinuation or death due to TRAEs has occurred. In 1L patients (n=12), the overall response rate (ORR, partial response with lymphocytosis or better) was 91.7%. The ORR and complete remission (CR)/CR with incomplete marrow recovery (CRi) rates in R/R BTKi-naïve patients (n=17) were 100% and 17.6%, respectively. In R/R post-BTKi patients, rocbrutinib monotherapy achieved 75% ORR including16.7% CR/CRi. In BTKi and BCL-2i double refractory population (n=5), ORR and CR/CRi rates were 80.0% and 40.0%, respectively; 3 patients are still in remission while the other 2 patients both had durable response of more than 17 months. 2 patients with BTKL528W mutation achieved PR and are still on treatment (DOR: 8.1 and 14.0 months). After median follow-up of 7.4 months, all 12 1L patients remained on treatment. In the R/R BTKi naive population (median follow-up 15.8 months), the estimated 12-month PFS rate as 94.1% (95% CI: 65.0-99.1); In the R/R post-BTKi population (median follow-up 15.5 months), the estimated 12-month PFS rate as 83.3% (95% CI: 48.2-95.6). Conclusion Rocbrutinib has a favorable safety profile and shows durable responses in patients with CLL/SLL, including those with prior BTK inhibitor exposure and/or with covalent and noncovalent BTKi-resistant mutations.