Rocbrutinib, a New-Generation BTK Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Non-GCB Diffuse Large B Cell Lymphoma

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).