Abstract Introduction: LP-168 (rocbrutinib) is a new selective next-generation inhibitor of BTK that broadly targets wild-type (WT) BTK irreversibly, C481 mutant BTK (C481S, C481F, and C481R) reversibly, and other non-C481 mutations in relapsed/refractory (R/R) CLL. R/R CLL that has been treated with prior BTKi and/or Bcl-2 inhibitor, such as venetoclax, remains an unmet need in resistant CLL despite pirtobrutinib's accelerated approval. Resistance to pirtobrutinib—often through non-C481 BTK mutations—can limit durability of response, and outcomes in double-exposed patients remain poor. Below, we describe the updated safety and efficacy results of R/R CLL with prior exposure to BTKi and/or Bcl-2 inhibitor in the rocbrutinib phase 1 trial (NCT06978088). Methods: NCT04775745 is a multicenter phase 1 dose escalation study of rocbrutinib monotherapy in pts with R/R B-cell malignancies. Overall response rate (ORR) included patients with complete response (CR), partial response (PR), or partial response with lymphocytosis (PR-L). Results: From 16Sep2021 to 28Mar2025, 42 post-BTKi R/R CLL pts (including 19 post-BTKi/Bcl-2i pts) were enrolled. The median age was 66 years (range, 45–81), and 83.3% of the participants were male. Post-BTKi CLL patients had 4 median prior therapies (range, 2-9), with 45.2% receiving more than one prior cBTKi and 21.4% receiving both cBTKi(s) and ncBTKi(s). 31 pts (31/33, 93.9%) had unmutated IGHV, 12 pts (12/39, 30.8%) had complex karyotype, 24 pts (24/41, 58.5%) had Del(17p) and/or TP53 mutation, 17 pts (17/42, 40.5%) had Del11q, 26 pts (26/40, 65.0%) had C481S BTK mutations and 7 (7/40, 17.5%) pts had C481F/Y/R/V BTK mutation, 12 pts (12/39, 30.8%) had gatekeeper mutations at T474 BTK, 2 pts (2/39, 5.1%) had BTK L528W mutation, 1 pt (1/39, 2.6%) had BTK A428D mutation, 1 pt (1/39, 2.6%) had BTK V416L mutation and 4 pts (4/39, 10.3%) had a resistance mutation in PLCγ2. As of 28 March 2025, 40 post-BTKi CLL pts have available response data with median duration of treatment (DOT) of 22.4 months (range 2.8, 42.1). ORR with dose levels (DLs) of 200mg daily and 300mg daily was 78.3% (18/23), with 16 pts of PR and 2 pts of PR-L. Of the 40 CLL patients by the data cutoff date, estimated median progression-free survival (PFS) is 28.1 months (95%CI 17.58, NE) with the median follow-up of 30.3 months (95%CI 24.5, 38.8), and estimated median duration of response (DOR) is not reached (95%CI 19.42, NE). 19 pts (19/42, 45.2%) remained on therapy. Among the 40 post-BTKi CLL pts, 17 pts were also exposed to Bcl-2i venetoclax. ORR in DLs 200-300mg daily being 80.0% (8/10). Among the 17 pts, 4 pts were exposed to cBTKi, ncBTKi, and Bcl-2i, and in these pts ORR with all DLs was 50.0% (2/4) and was 100.0% (2/2) for pts treated at the 300mg DL. Best response for the remaining 2 pts (2/4) that did not respond was both stable disease(SD). All 42 post-BTKi CLL patients were evaluated for safety. Most AEs have been low grade. TEAEs seen in 20% of pts included diarrhea (40.5%), cough (35.7%), headache (35.7%), arthralgia (31.0%), constipation (31.0%), fatigue (28.6%), nausea (28.6%), dizziness (26.2%), nasal congestion (23.8%), contusion (21.4%), muscle spasms (21.4%), sinusitis (21.4%) and vomiting (21.4%); of those, grade =3 AE included fatigue in 2 pts (4.8%), diarrhea, headache, constipation and sinusitis in 1 pt (2.4%) each. Febrile neutropenia occurred in 2 pts (4.8%) and both were of grade =3 in severity. Serious AEs (acute kidney injury, adenocarcinoma of colon, altered state of consciousness, anaemia, angina pectoris, COVID-19, cystitis, dacryocystitis, fall, febrile neutropenia, headache, hypercalcaemia, hyperkalaemia, microcytosis, middle ear inflammation, pleural effusion, pneumonia, presyncope, scrotal infection, sepsis, shock, sinusitis fungal, tumour flare) were seen in 19 pts (45.2%). Adverse events of special interest (AESIs) of any grade included infections(52.4%), bruising(26.2%), neutropenia(19.0%), bleeding(16.7%), hemorrhage(11.9%), hypertension (11.9%) and atrial fibrillation or flutter(2.4%). Grade =3 AESIs included infections in 9 pts (21.4%), neutropenia in 7 pts (16.7%), hemorrhage in 1 pt (2.4%) and hypertension in 1 pt (2.4%). Conclusions: Encouraging safety and efficacy are observed in the population exposed to BTKi (including both cBTKi and ncBTKi) and/or Bcl-2i. Rocbrutinib could be a potential therapy for double or triple-exposed CLL patients who currently have limited treatment options.
Brander et al. (2025) studied this question.