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Rocbrutinib is a 4th generation Bruton’s tyrosine kinase inhibitors (BTKi) with high selectivity, excellent bioavailability and a unique dual (covalent and non-covalent) binding activity. It can target wild type (WT) BTK irreversibly (covalent binding), C481 mutant BTK (C481S, C481F and C481R) reversibly (non-covalent binding), and other non-C481 mutations such as the gatekeeper mutation T474I irreversibly. Therefore, it can inhibit the activity of both wild-type (WT) and mutant BTK.
The clinical study results for Rocbrutinib in the treatment for patients with relapsed/refractory B cell malignancies were formally presented at the 28th CSCO (Chinese Society of Clinical Oncology) conference, which was held in Jinan, China from September 10th to 14th, 2025.
Oral Presentation 1
Title:
Efficacy and safety of Rocbrutinib – a highly selective 4th-generation BTK inhibitor in the treatment for patients with relapsed/refractory mantle-cell lymphoma previously treated with BTK inhibitors
Session:
CSCO Lymphoma Expert Committee, Lymphoma Session 1
Time & Venue:
Qilu Hall, 1st Floor, Shandong Mansion
Sept 11th, 2025, 4:50–5:00 pm
Presenter:
Prof. Cai Qingqing, Sun Yat-sen University Cancer Center
Abstract
Objective
Mantle-cell lymphoma (MCL) is an aggressive yet indolent B-cell non-Hodgkin lymphoma with poor overall prognosis. Its pathogenesis is related to abnormal activation of B-cell-receptor (BCR) signaling pathway. Medicines such as Bruton’s tyrosine kinase (BTK) inhibitors targeting BCR signaling pathway have markedly improved patients’ outcomes. Nevertheless, patients who failed or relapsed after BTKi treatment have limited options and face low chances of survival. Therefore, there is an urgent need for new drugs that can solve this problem. Rocbrutinib (LP-168) is a 4th-generation, highly selective, dual binding BTKi that can inhibit wild-type BTK covalently and irreversibly as well as mutant BTK non-covalently and reversibly. The LP-168-CN201 study reports the efficacy and safety of Rocbrutinib monotherapy in the patients with relapsed/refractory (R/R) MCL previously treated with BTKi.
Methods
LP-168-CN201 is a single-arm, multicenter, open-label phase II pivotal trial (NCT05716087). Adult patients with R/R MCL received Rocbrutinib 150 mg once daily until the development of disease progression or intolerable toxicity. The primary endpoint is overall response rate (ORR) evaluated by an independent review committee (IRC). The secondary endpoints include other efficacy and safety measures.
Results
As of December 5th, 2024, 61 BTKi-pretreated R/R MCL patients (19.7 % blastoid/pleomorphic variant) were enrolled and had at least 6 months’ follow-up after the enrollment. The median age of the patients was 61 years (37–79 years). 62.2% of patients had intermediate or high MIPI (Mantle cell lymphoma international prognostic index). The median line of previous treatment was 3 (range: 1-10). The median line of prior BTKi treatment was 1 (range: 1–4). Among them, 34.4 % of patients had 2 or more lines prior BTKi treatments. Per IRC evaluation, the ORR in BTKi pretreated R/R MCL patients after treatment with Rocbrutinib was 63.9 % (95 % CI: 50.6, 75.8). The complete response (CR) rate was 19.7%. At the time of 7.36 months’ median follow-up, the median PFS (progression-free survival) was 7.39 months (95 % CI 3.71, not reached). 71.7 % (28/39) patients remained in remission. The median DOR (duration of response) has not been reached yet. The estimated 6-month DOR rate was 73.1 %. In terms of safety, the incidence of common adverse events (AEs) was greater than 10%, including thrombocytopenia (38.7 %), leukocytosis/leukopenia (24.2 %/14.5 %), lymphocytosis/lymphopenia (24.2 %/11.3 %), neutropenia (24.2 %), hypercreatininemia (14.5 %), hypoalbuminemia (14.5 %), hyperuricemia (12.9 %) and petechiae (11.3 %). The AEs are mostly grade 1 or 2. The incidence of grade 3 or higher AEs was greater than 5 %, including: lymphocytosis (12.9 %), anemia (9.7 %), thrombocytopenia (6.5 %) and neutropenia (6.5 %). Overall adverse events are manageable. The incidence of BTKi-specifically related AEs such as grade 3 or higher bleeding was 1.6 %. There wereno atrial fibrillation/flutter AEs occurred.
Conclusion
Rocbrutinib monotherapy demonstrated significant clinical benefit with a manageable safety profile in BTKi-pretreated R/R MCL patients, offering a promising new option for this patient population.
Oral Presentation 2
Title
Safety and efficacy of highly selective 4th-generation BTK inhibitor Rocbrutinib in the treatment for relapsed/refractory marginal-zone lymphoma (R/R MZL)
Session:
Innovative Drug Clinical Data Session 1
Time & Venue
Shandong Hall, 1st Floor, Shandong Mansion
September 11th ,2025, 3:30–3:42pm
Presenter
Professor Song Yuqin, Peking University Cancer Hospital
Abstract
Objective
Marginal-zone lymphoma (MZL) accounts for 8–12 % of non-Hodgkin lymphomas, characteristically demonstrating continuous activation of B-cell-receptor signaling pathway. Existing Bruton tyrosine-kinase inhibitors (BTKi) have already showed effect in the treatment of R/R MZL, however, their efficacy can still be improved. Rocbrutinib is a highly selective 4th-generation BTKi with dual binding activity that combined the advantages of covalent binding of 1st/2nd-generation agents and the non-covalent binding of 3rd-generation agents. It can achieve higher exposure dose, tens of folds greater than approved covalent BTKi. LP-168-CN101 Phase I study data (NCT04993690) were reported at ASH 2024 and here is an update.
Methods
R/R MCL patients with age ranging from 18–80 years old and at least 1 line of prior therapy (including an anti-CD20-containing regimen), received Rocbrutinib monotherapy until the development of disease progression or intolerable toxicity. Adverse events (AEs) were graded CTCAE v5.0. The efficacy was assessed per Lugano 2014 standards.
Results
As of February 28th, 2025, 33 BTKi-naïve R/R MZL patients received Rocbrutinib 100 mg (n = 3), 150 mg (n = 24) or 200 mg (n = 6) once daily. The median age of the patients was 65 years (range 32–79 years). The MZL subtypes were as follows: 66.7 % extranodal mucosa-associated lymphoid tissue, 21.2 % nodal, 13.0 % splenic and 9.1 % unknown. 87.9 % of patients were stage III or IV per Ann Arbor staging. 48.5 % of patients were graded as high-intermediate risk or high risk per IPI (international prognostic index). All patients had at least one prior line of treatment including anti-CD 20 antibody. The median prior line of treatment was 1a (range: 1-4). 21.2 % of the patients had refractory outcomes to at least 1line of prior treatment.
Most common treatment-related AEs (TRAEs, ≥20 %) were neutropenia (33.3 %), thrombocytopenia (33.3 %), leukopenia (30.3 %), infective pneumonia (30.3 %), lymphocytopenia (24.2 %) and petechiae (21.2 %). Among them, most were classified as grade 1. Grade 3 or higher TRAEs occurred in 42.4 % and severe TRAEs in 27.3 % of the patients with dose interruption and reduction happened in 21.2 % and 6.1 %, respectively; however, no patient needed to be discontinued for the treatment permanently or died of TRAEs.
Among 33 evaluable patients, 25 were in remission with ORR of 75.8 %, including 8 (24.2 %) cases of complete responses (CR). In 13 patients with 2 or more prior lines treatment, ORR was 61.5 % and CR 30.8 %. In 7 refractory patients, ORR was 71.4 %. The median follow-up period was16.2 months (range 0–27.6) and17.9 months (range 1.7–40.6) months, both DOR (duration of response) and PFS (progression-free survival) have been not reached. 57.6 % of patients remain on treatment. Twelve-month DOR and PFS rates are 86.2 % (95 % CI: 62.9–95.4 %) and 71.9 % (95 % CI: 52.8–84.3 %), respectively.
Conclusion
Rocbrutinib demonstrates a favorable safety profile and encouraging clinical efficacy in R/R MZL, with high remission rate and durable disease control, warranting further development.
Poster Session
Title
Efficacy and safety of the highly selective 4th-generation BTK inhibitor Rocbrutinib in the treatment of patients with relapsed/refractory non-GCB DLBCL
Background
Rocbrutinib is a highly selective 4th-generation BTK inhibitor with dual binding activity that combined the advantages of irreversible covalent binding activity of 1st/2nd-generation agents and the reversible non-covalent binding activity of 3rd-generation agents. It can also achieve exceptionally high exposure dose and favorable PK/PD. Clinically, Rocbrutinib monotherapy demonstrated pronounced activity and an acceptable safety profile in non-GCB DLBCL patients who had failed 2 or more prior lines of treatment. Based on above facts, Rocbrutinib was granted BTD (Breakthrough Therapy Designation) by the Center for Drug Evaluation (CDE) in China in May 2024.
Methods
Adult patients (18–80 y) with R/R non-GCB DLBCL and 2 or more prior lines of treatment including at least 1 line containing anti-CD20, received Rocbrutinib until the development of disease progression or intolerable toxicity. AEs were graded by CTCAE v5.0 and efficacy was assessed per Lugano 2014 standards.
Results
Baseline characteristics: as of Feb 28th, 2025, 45 R/R non-GCB DLBCL patients received Rocbrutinib 100 mg (n = 2), 150 mg (n = 25), 200 mg (n = 15) or 300 mg (n = 3) once daily. The median age of patients was 59 years. 44.4 % of them had high-intermediate or high IPI. 77.8 % of patients had extranodal disease. The median line of prior treatment was 2 (range 2 - 5). 26.7 % of patients had prior BTKi treatment. 84.4 % of patients were refractory to their last therapy.
Safety: The most common treatment-related AEs (TRAEs, ≥ 20 %) were grade 1. Grade 3 or higher TRAEs occurred in 40.0 % of patients and severe TRAEs in 11.1 % of patients. Dose interruption and reduction were required in 20.0 % and 2.2 % of patients, respectively. There was no patient who discontinued treatment permanently or died because of TRAEs.
Efficacy: ORR was 57.8 %; complete response (CR) rate was 31.3 %. In 16 patients with 3 or more prior lines of treatment, ORR was 68.8 % and CR 43.8 %. Among patients received the recommended phase-II dose (≥ 200 mg QD), ORR was 72.2 % and CR 33.3 %. After median follow-up of 8.1 months (range 0–25.2), the median DOR (duration of response) was not reached (NR; 95 % CI: 3.1- not reached). 12-month DOR rate was 64.2 % (95 % CI: 30.2%–84.8 %). For PFS, the median follow up is 8.1 months (ranging from 0-27.0). The median PFS was 7.1 month (95 % CI: 1.7–NR). The12-month PFS rate was 48.7 % (95 % CI: 22.8%–70.4 %).
Conclusion
Rocbrutinib monotherapy demonstrated high CR rate and ORR with a manageable safety profile in heavily pretreated R/R non-GCB DLBCL patients. A pivotal phase II registrational study had recently been approved by the CDE in China and further studies are ongoing.