Efficacy and safety of rocbrutinib, the fourth generation bruton's tyrosine kinase inhibitor, in patients with BTK inhibitor pre-treated relapsed or refractory Mantle Cell Lymphoma: Results from a Phase II rock-1 trial

Abstract Introduction Patients with relapsed or refractory mantle cell lymphoma (r/r MCL) following prior covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy face extremely poor outcomes, characterized by unsatisfactory response rate and dismal survival. This population represents a substantial unmet clinical need in the field of hematologic malignancies, highlighting an urgent need for novel agents. Rocbrutinib is a novel, highly selective, the fourth generation covalent (non-reversible) and non-covalent (reversible) BTKi. It showed dual effects on both wild-type and C481 and some other mutant BTKs, and promising efficacy and favorable safety in multiple types of B cell non-Hodgkin lymphoma in a phase I study (ASH 2023). Here we report the safety and efficacy of rocbrutinib in Chinese heavily pre-treated r/r MCL patients with prior covalent BTK inhibitors from the phase II ROCK-1 study (NCT05716087). Methods The ROCK-1 trial (LP-168-CN201) is a single-arm, multicenter, open-label phase II study conducted across 27 study centers in China. Eligible adult cBTKi pre-treated r/r MCL patients received oral rocbrutinib at 150 mg once daily (QD) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by independent review committee (IRC) per Lugano 2014 criteria. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Adverse events (AEs) were graded per CTCAE v5.0. Results Between May 2023 and June 2025, 61 centrally confirmed r/r MCL patients were enrolled, of which 19.7% patients have blastoid or pleomorphic histology. The median age was 61 years (range, 37-79), 73.8% was male, 62.2% with intermediate- or high-risk simplified MCL International Prognostic Index score (sMIPI), and 68.9% have high baseline ki-67 level (≥30%). The median number of prior therapies was 3 (range, 1-10), including cBTK inhibitor (100%), anti-CD20 antibody (95.1%), immunomodulator (31.1%), BCL-2 inhibitor (9.8%), and stem cell transplant (6.6%). The median number of prior cBTKi treatment was 1 (range, 1-4), with 34.4% received more than two lines of prior cBTKi regimens. Per IRC's assessment, the ORR was 63.9% (95% CI, 50.6-75.8), including 23.0% complete response. The median PFS was 7.39 months (95% CI, 3.71-18.30). At a median follow-up of 11.27 months, the median DOR was 16.46 months (95% CI, 8.25-not reached), with the 12-month estimated DOR rate was 61.2%. After a median follow-up of 17.02 months (range, 14.78-18.46), median OS was not reached. Treatment emergent adverse events (TEAEs) of any grade occurred in more than 20% of patients were thrombocytopenia (43.5%), anemia (30.6%), neutropenia (29.0%), increased white blood cell count (24.2%), lymphocytosis (24.2%), increased blood creatinine (21.0%), hyperuricemia (21.0%), predominantly Grade 1 or 2. Grade ≥3 TEAEs with an incidence of 5% or higher included lymphocytosis (12.9%), anemia (11.3%), pneumonia (11.3%), neutropenia (9.7%), and thrombocytopenia (6.5%). AEs of special interest related to BTKi were less frequent, with major bleeding (Grade ≥3 hemorrhage) of 3.2% and no atrial fibrillation or flutter of any grade was reported. Dose interruptions due to TEAEs occurred in 33.9% of patients, while only 3.2% required dose reduction. There was no permanent discontinuation of rocbrutinib or death attributed to TEAEs. Conclusions Rocbrutinib demonstrated clinically meaningful and durable efficacy with a manageable safety profile in heavily pretreated, cBTKi-exposed Chinese r/r MCL patients. The high ORR (63.9%) and prolonged DOR (median 16.46 months) observed in this trial, coupled with a low incidence of BTKi-associated toxicities, position rocbrutinib as a promising therapeutic option for this difficult-to-treat population. The clinical benefit of rocbrutinib in patients with MCL will be further confirmed in randomized phase III studies.