Phase I/IIa clinical study of 4th generation BTK inhibitor HBW-3220 capsules in patients with B-cell malignancies.

e15143 Background: HBW-3220 is in Phase I/IIa trials. It is a reversible 4th generation Bruton’s tyrosine kinase inhibitor (BTKi) effective against BTK wild-type, C481S, L528W, and T474I mutations, addressing resistance issues in existing BTKi treatments. Methods: This multicenter Phase I/IIa study involves relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and other B-cell non-Hodgkin lymphoma patients. It assesses the safety, tolerability, efficacy, and pharmacokinetics (PK) of HBW-3220 capsules. Patients with at least two prior therapies take HBW-3220 orally once daily on an empty stomach for a 28-day cycle. Adverse events (AEs) are graded per NCI-CTCAE 5.0, and efficacy is evaluated using the 2018 IWCLL, IWWM-7, or 2014 Lugano criteria. The current analysis is approved by the study's Data and Safety Monitoring Committee. Results: 48 patients enrolled showed good safety and tolerability. AEs were similar to other BTKis, mostly Grade 1 or 2. AEs with ≥20% incidence included diarrhea (40%), fever (23%), infectious pneumonia (29%), nausea (23%), headache (17%), elevated C-reactive protein (21%), elevated aspartate aminotransferase (21%), decreased neutrophil count (50%), anemia (42%), and decreased platelet count (35%). Grade 3 or higher AEs included infectious pneumonia (16.6%), neutropenia (13.0%), decreased lymphocyte count (4.2%), hypokalemia (4.2%), and diarrhea (4.2%). The rates of Grade 3 or higher AEs for neutropenia, decreased hemoglobin, decreased platelets, and bleeding were all lower than those for Pirtobrutinib. 38 patients had at least one efficacy evaluation. The overall response rate (ORR) for CLL/SLL, marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) was 63% (n = 19), 75% (n = 4), and 43% (n = 7), respectively. All CLL/SLL patients had taken at least one irreversible BTKi, with 53% having TP53 mutations and 37% having BTKC481S mutations. CLL/SLL patients who had taken both irreversible BTKi and BCL2 inhibitors had an ORR of 82% (n = 11), compared to 72% for Pirtobrutinib. ORR for CLL/SLL patients with BTKC481S mutations was 71% (n = 7). With more treatment cycles and patient enrollment, ORR is expected to exceed 90%. For patients with both BTKC481S and BTKT474I mutations, tumor size reduced by over 50% after 6 cycles, indicating preliminary efficacy for T474 mutations. PK studies showed that Cmax and AUC of HBW-3220 increased with dose, with a median Tmax of ~2 hours and a half-life of ~20 hours. Conclusions: HBW-3220 capsules show good safety, tolerability, and outstanding efficacy in CLL/SLL patients, with significant potential to surpass existing treatments. Clinical trial information: CTR20221130 .