LP-168 (Rocbrutinib), a Novel Covalent and Non-Covalent Next-Generation Inhibitor of Bruton's Tyrosine Kinase: Updates on the Phase 1 Trial and Initial Results of the CLL Gatekeeper Mutation Cohort
Authors: Woyach Jennifer A. , Brander Danielle M. , Hu Boyu , Rogers Kerry A. , Omer Zulfa , Stephens Deborah M. , Sitlinger Andrea , Tan Fenlai , Chen Yi , Anthony Stephen P. , Chen Yu , Shang Kewei , Byrd John C. 
Published: December 2024

Introduction: Covalent Bruton's Tyrosine Kinase inhibitors (cBTKi) and non-covalent BTKi (ncBTKi) have been transformative for the treatment of chronic lymphocytic leukemia (CLL). However, second-site T474 gatekeeper mutations (GM) have been commonly observed in patients (pts) resistant to ncBTKi such as pirtobrutinib. LP-168 (rocbrutinib) is a selective next generation inhibitor of BTK that targets wild type (WT) BTK irreversibly, C481 mutant BTK (C481S, C481F and C481R) reversibly, and other non-C481 mutations such as gatekeeper mutation T474I irreversibly, with preclinical activities in C481 and T474 mutants and clinical activities in relapsed/refractory (R/R) CLL (ASH 2023). Pts with GM have poor outcomes and short survival and demonstrate an increasing unmet need in the field of CLL. Below we describe initial safety and efficacy results of a R/R CLL gatekeeper mutation cohort of rocbrutinib and overall study updates.
Methods: NCT04775745 is a multicenter phase 1 dose escalation study of rocbrutinib monotherapy in pts with R/R B-cell malignancies. Pts with GM pts were identified using pt medical history with redacted sequencing panel reports. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were evaluated using iwCLL 2018 criteria. Overall response rate (ORR) included patients with complete response (CR), partial response (PR), or partial response with lymphocytosis (PR-L)
Results: From 16 Sep 2021 to 15 May 2024, 10 GM R/R CLL pts were enrolled in a separate cohort at continuous doses from 150mg twice daily (n=2) to 300mg daily (n=8). Patients in this cohort had a median age of 62.5 years (range 52 - 75), and 30% were female. GM CLL pts received a median of 2 prior therapies (range 2-9), with 100% receiving a prior cBTKi and 40% a ncBTKi. 6 pts had alterations in Del(17p) and/or TP53 mutation, 4 pts had Del11q, 7 pts had C481S BTK mutations and 1 pt had C481Y BTK mutation. All ten pts had gatekeeper mutations at T474 BTK with median variant allele frequency (VAF) of 15.6% (1.9%-89%). 1 had an additional BTK A428D mutation, and none had a resistance mutation in PLCγ2.
At data lock on 15 May 2024, 9/10 GM CLL pts have response data with median follow-up of 14 months (range 2.6-20.1). ORR including all dose levels was 77.8% (7/9) - all were PR or PR-L. At the time of this report, all GM CLL patients are still on treatment although the patient with BTK A428D mutation is demonstrating expansion of this clone.
All 10 GM CLL patients were evaluated for safety. No DLT has been observed, and most AEs have been low grade. TEAE seen in &gt;20% of pts included nausea, constipation, headache, abdominal pain, cough, diarrhea, dizziness, fatigue, petechiae; of those, grade 3 or higher AE included constipation and fatigue in 1 pt each. Serious AEs (scrotal infection, pneumonia, middle ear inflammation, altered state of consciousness) were seen in 4 pts, with dose interruption in one. No atrial fibrillation/flutter has been reported. No Grade 3 or higher hypertension has been reported in this GM cohort. Grade 3 or higher infection (scrotal infection and pneumonia) and neutropenia are seen in 3 pts (scrotal infection, neutropenia, neutropenia and pneumonia). 1 pt experienced low-grade bleeding and 4 pts experienced low-grade bruising.
Pharmacokinetics data in this GM cohort is similar to main cohort with medium steady state AUC24h of 84.8 h*µg/ml, medium steady state Cmax of 4821 ng/ml, and medium half-life of 16.65 hours.
Updated enrollment numbers, median follow-up, responses and safety data are provided for the current ongoing Phase 1a study, which includes the GM cohort. Overall, the trial has enrolled 50 DLT-evaluable pts. CLL pts make up 47 of them and now have efficacy data. The estimated 18-month progression free survival (PFS) rate of CLL pts is 68.5% (95% CI 44.1 - 83.9%). For 22 CLL pts with starting doses ≥ 200mg, the ORR is 77.3% (17/22) with median follow-up of 13.95 months (range 2.5-23.3). There was no new safety signals to report.
Conclusions: Rocbrutinib has been well tolerated in this GM cohort and the overall cohort, with no DLTs identified at doses up to 300 mg daily. Preliminary encouraging efficacy is observed in this GM cohort, including those treated with one or more BTKi such as pirtobrutinib and nemtabrutinib. Rocbrutinib could potentially fill an unmet need in CLL for pts with resistant CLL. Ongoing and future clinical trials will focus on dose optimization and combination studies.