News & Events
The 66th ASH Annual Meeting took place on December 7th, 2024, in San Diego, California, USA.
At this event, posters highlighting the latest updates on Rocbrutinib (LP-168), a novel covalent and non-covalent new generation BTK inhibitor were presented. The presentations included both clinical and pre-clinical studies results from China and the United States. Some presentations represented continuation of the clinical research initially introduced at the last ASH Annual Meeting. For comprehensive insights, the complete abstracts and corresponding links are provided below:
Abstract#: 1635
Safety and Efficacy of Rocbrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster I
Time: Saturday, December 7, 2024, 5:30 PM-7:30 PM
First Author : Yuqin Song, MD（Department of Lymphoma, Peking University Cancer Hospital, BEIJING, China）
Background: Marginal zone lymphoma (MZL) comprises approximately 8% to 12% of non-Hodgkin lymphomas (NHL), characterized by malignant cells that consistently rely on B-cell receptor signaling. Covalent Bruton’s tyrosine kinase inhibitors (cBTKis) have shown activity in relapsed or refractory (R/R) MZL, achieving an overall response rate (ORR) of 40-60%. Rocbrutinib, a new-generation BTKi, is highly selective with excellent bioavailability and a unique dual binding mechanism: covalent binding, otherwise non-covalent with C481 mutation. Here, we present the efficacy and safety outcomes of rocbrutinib in patients with R/R MZL enrolled in an ongoing phase 1 study (NCT04993690) in B-cell malignancies.
Methods: Patients with R/R MZL who received ≥1 line of prior therapies, including an anti-CD20 antibody-containing regimen, were enrolled. Adverse events (AEs) were graded per CTCAE v5.0 and disease responses were assessed per Lugano 2014 response criteria.
Results: Between 30 July 2021 and 31 May 2024, 30 R/R MZL patients were enrolled and received treatment of rocbrutinib at 100mg (n=3), 150mg (n=21) and 200mg (n=6) QD respectively, till disease progression or unacceptable toxicities. The median age was 65 (range, 32 to 79) years. 22 were with extra-nodal MZL (73.3%), and 5 nodal MZL (16.7%). Most patients (90%) were with advanced-stage disease; 46.7% had intermediate to high-risk disease per International Prognostic Index (IPI). All 30 patients received at least one prior line of CD20-based treatment per study eligibility. The median line of prior therapies was 1 (range, 1-4), and 26.7% of patients had refractory disease at study entry.
The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% patients) were platelet count decreased or thrombocytopenia (30.0%), white blood cell count decreased (26.7%), serum creatinine increased (23.3%), petechiae (23.3%), infectious pneumonia (23.3%), neutrophil count decreased or neutropenia (20.0%) and hyperuricemia (20.0%), most of which were Grade 1. 13 (43.3%) patients experienced ≥grade 3 TEAE. Serious AEs occurred in 9 (30.0%) patients. Dose interruptions and dose reductions due to AEs were observed in 8 patients (26.7%) and 1 patient (3.3%), respectively; however, no AE led to drug discontinuation. One fatal case of hypotension was assessed by the investigator as unlikely related to the study treatment.
Of 29 efficacy evaluable patients with median follow-up of 10.9 months (range: 2.0-32.0), 21 (72.4%) achieved response including 3 (10.3%) complete response (CR). The ORR for the extra-nodal (n=21), nodal (n=5), and unknown (n=3) subtypes was 76.2%, 80.0%, and 33.3%, respectively. For the 13 patients who had received ≥2 lines of prior therapies, the ORR was 53.8% with a CR rate of 15.4%. Among the 7 patients who had refractory disease, the ORR was 71.4%. Of 2 patients who had progressed on prior cBTKi, 1 (50.0%) responded to rocbrutinib. As of data cutoff, the median duration of response (DOR) and median progression-free survival (PFS) have not reached.
Conclusion: Rocbrutinib is well tolerated and has shown promising anti-tumor activity in terms of response rate in patients with R/R MZL. Longer follow-up is needed to assess the long-term benefit.
Click here for more:
https://ash.confex.com/ash/2024/webprogram/Paper194572.html
Abstract#: 3119
Rocbrutinib, a New-Generation BTK Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Non-GCB Diffuse Large B Cell Lymphoma
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Poster II
Time: Sunday, December 8, 2024, 6:00 PM-8:00 PM
First Author: Yuqin Song, MD（Department of Lymphoma, Peking University Cancer Hospital, BEIJING, China）
Background: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) either fail to respond to initial standard therapy or experience a relapse, resulting in a dismal prognosis. Non-germinal center B-cell-like (GCB) DLBCL has an even worse outcome. The early data of covalent bruton’s tyrosine kinase inhibitor (cBTKi) in R/R non-GCB DLBCL showed an overall response rate (ORR）of 20-40%. Rocbrutinib (LP-168) is a highly selective, new-generation BTKi with superb bioavailability and unique dual binding mode: covalent binding, otherwise non-covalent with C481 mutation. Here, we report the safety and efficacy of Rocbrutinib monotherapy in the R/R non-GCB DLBCL from an ongoing phase 1 study (NCT04993690) in B-cell malignancies.
Methods: Patients（age>=18 years） with R/R DLBCL after ≥2 prior lines of therapies including ≥1 anti-CD20 antibody-containing regimen were enrolled. Adverse events (AEs) were graded per CTCAE v5.0 and responses of patients with R/R non-GCB DLBCL were assessed according to the Lugano 2014 response criteria.
Results: Between 30 July 2021 and 31 May 2024, 33 efficacy evaluable patients with R/R non-GCB DLBCL were enrolled. They received daily treatment of rocbrutinib at 100mg (n=2), 150mg (n=23), 200mg (n=6) and 300mg (n=2) respectively till progressive disease or unacceptable toxicities. The median age was 59 (range, 21-73) years old; 20 (60.6%) were male. One-third of the patients had at least one lesion of >=5cm in diameter. 51.5% had intermediate to high-risk disease per International Prognostic Index (IPI). The median line of prior therapies was 2 (range, 2-5) and most patients (87.9%) were refractory to any prior treatments.
The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% patients) were neutrophil count decreased or neutropenia (63.6%), white blood cell count decreased (45.5%), platelet count decreased or thrombocytopenia (45.5%), anemia (30.3%), petechiae (30.3%), lymphocyte count increased (27.3%), lymphocyte count decreased (27.3%), hypertriglyceridemia (24.2%), hyperuricemia (24.2%) and serum creatinine increased (21.2%), most of which were grade 1. 14 (42.4%) patients experienced ≥grade 3 TEAEs . Serious AEs (lung infection, grade 3) occurred in 2 (6.1%) patients. 8 patients (24.2%) had dose interruptions due to AEs, but no AE has led to dose adjustment or drug discontinuation. AE leading to death was reported for one patient (lung infection, not related to rocbrutinib).
Of 33 efficacy evaluable patients with median follow-up of 6.7 months (range: 1.8-26.9), 20 (60.6%) achieved response including 11 (33.3%) complete response (CR). For the 10 patients who had received ≥3 lines of therapy previously, the ORR and CR rate was 90% and 50%, respectively. Notably, the response rate of rocbrutinib in patients refractory to last prior therapy (n=28) was 57.1%, with CR rate of 28.6%. As of data cut-off, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) are not mature yet.
Conclusion: In conclusion, rocbrutinib has demonstrated a high CR and response rate in heavily pre-treated R/R non-GCB DLBCL with favorable safety profiles. Based on the encouraging data, rocbrutinib has received breakthrough therapy designation for the treatment of patients with non-GCB DLBCL who have received at least 2 lines of prior therapies from China CDE (center of drug evaluation). A Phase 1b study of rocbrtuinib in combination with R-CHOP for untreated non-GCB DLBCL is also ongoing (NCT06251180).
Click here for more:
https://ash.confex.com/ash/2024/webprogram/Paper194561.html
Abstract#: 4622
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
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Time: Monday, December 9, 2024, 6:00 PM-8:00 PM
First Author: Jennifer A. Woyach, MD (The Ohio State University, Columbus, OH)
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 >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.
Click here for more:
https://ash.confex.com/ash/2024/webprogram/Paper205775.html
Abstract#: 3587
Genome-Wide CRISPR/Cas9 Knockout Screen Reveals Novel LP-168 (Rocbrutinib) Combinations Targeting BCL-2 Protein Members for Chronic Lymphocytic Leukemia
Session: 802. Chemical Biology and Experimental Therapeutics: Poster II
Time: Sunday, December 8, 2024, 6:00 PM-8:00 PM
First Author: Britten K. Gordon, BS （The Ohio State University, Columbus, OH）
Background: Treatment of chronic lymphocytic leukemia (CLL) has been transformed with therapies targeting Bruton’s tyrosine kinase (BTK) and BCL-2, but are limited due to the development of resistance. Dual targeting of BTK and BCL-2 has been efficacious in the clinic, with many patients achieving uMRD and prolonged remission off therapy. We have previously demonstrated the pre-clinical efficacy of LP-168 (Rocbrutinib), a novel selective 4th generation BTKi with an active warhead capable of covalent interaction with WT and T474I BTK and non-covalent binding when a BTK C481 mutation is present (Gordon et al. 2023). This allows for continued BTK inhibition despite development of common resistance mutations. To explore potential combination strategies with LP-168, we utilized a genome wide CRISPR/Cas9 knockout screen with validation of identified targets.
Methods: Genome wide CRISPR/Cas9 knockout screening was performed in HG-3 CLL cells using the Brunello library with analysis via the MAGeCK pipeline. Cells were treated with IC20 (1 uM) of LP-168 for 3 days. Following exclusion of essential genes, negatively selected sgRNAs that were differentially expressed in the LP-168 group were used for analysis. Validation of hits was performed via pharmacological inhibition utilizing CellTiter-Glo, Annexin V/PI, and western blots using HG-3, OSU-CLL, TMD8 WT BTK, TMD8 C481S BTK, and TMD8 T474I BTK cells in addition to primary patient samples. Experiments using TMD8 cells were performed following CRISPR modification to insert either C481S or T474I BTK.
Results: The CRISPR/Cas9 screen revealed 1875 genes with at least 3 out of the 4 sgRNAs depleted in both replicates of the LP-168 treated group vs control. KEGG/GO analysis demonstrated significant enrichment of regulation of mitochondrial membrane potential (p=0.00195) and reactive oxygen species pathways (p=0.00195). As BCL-2 interacts with both pathways, and was amongst the top-ranking genes depleted, we chose to target it with either venetoclax (BCL-2i) or with LP-118, a dual BCL-2/-xL inhibitor currently under investigation for R/R hematological malignancies.
Pharmacologic inhibition of BTK + BCL-2, with either venetoclax (ven) or LP-118, showed synergistic reductions in proliferation of HG-3 (p
Conclusions: These data show combined use of LP-168 with pharmacological inhibitors targeting BCL-2 and BCL-xL display synergistic activity in CLL, even in the presence of mutations that mediate resistance to BTKi and BCL-2i. These data are consistent with clinical data showing dual targeting of BTK, with previous generation inhibitors, and BCL-2 has been effective in the clinic, with many patients achieving uMRD and prolonged remission off therapy and supports continued preclinical and future clinical investigation of LP-168 with inhibitors of BCL-2 and BCL-2/-xL.
Click here for more:
https://ash.confex.com/ash/2024/webprogram/Paper203522.html