Background: The effectiveness of BCL-2 inhibition in hematologic malignancies has been demonstrated by venetoclax, a globally approved BCL-2 inhibitor that requires weekly dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and its efficacy in Chinese patients with non-Hodgkin lymphomas (NHL) is obscure. LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown favorable pharmacokinetic and safety profiles and preliminary antitumor activity under daily dose ramp-up scheme in patients with relapsed or refractory (R/R) B-cell NHL at tested doses up to 600 mg (EHA 2022. Abstract P684).
Aims: We present updated safety and efficacy results from the ongoing phase 1 study of LP-108 in Chinese patients with R/R B-cell NHL, including patients who had received prior Bruton’s tyrosine kinase inhibitor (BTKi) treatments (NCT04356846).
Methods: Adult R/R B-cell NHL patients are treated with LP-108 at doses ranging from 20 mg to 1000 mg per day in dose-escalation phase to evaluate dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), and further expanded at 3 dose cohorts (200 mg, 400 mg or 600 mg), with 8 to 12 patients in each cohort, to determine recommended phase 2 dose. A daily ramp-up scheme was used before reaching the target dose (28 days per cycle).
Results: As of Dec 12, 2022, 49 patients were enrolled and evaluable for safety. Diagnosis includes mantle cell lymphoma (MCL, n = 20), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, n = 19) or other B-cell NHL (n = 10). Patients had a median age of 64 years (range, 39-84) and received a median of 2 prior lines of therapies (range, 1-7), of which 28 (57.1%) patients were previously exposed to BTKi. No DLT has been observed up to 800 mg/day, thus MTD has not been reached. With a median duration of treatment (DOT) of 3.8 cycles (range, 0.2-27.4), treatment-related adverse events (TRAEs) of any grade occurred in ≥ 15% of patients were neutropenia (46.9%), leukopenia (30.6%), hyperuricemia (28.6%), hyperbilirubinemia (24.5%), hyperphosphatemia (24.5%), thrombocytopenia (24.5%), anemia (20.4%), AST elevation (18.4%), and hypocalcemia (16.3%), most of which were Grade 1 or 2. Grade 3 or 4 TRAEs (≥ 5%) were hematological toxicities including neutropenia (30.6%), anemia (12.2%), thrombocytopenia (12.2%), and leukopenia (10.2%), which were manageable. Serious TRAEs occurred in 8 (16.3%) patients, including neutropenia (3 [6.1%]), rash, anemia, laboratory TLS, hyperphosphatemia, asymptomatic pneumonia, upper respiratory tract infection and lung infection (1 [2%] each). One patient (2%) at 400 mg/day experienced dose reduction due to Grade 4 neutropenia. No patient discontinued treatment due to toxicity, and no clinical TLS or treatment-related death was observed, even with the rapid dose ramp-up. At doses ≥ 200 mg/day, 21 of 39 (overall response rate (ORR), 53.8%) efficacy evaluable patients achieved objective response. For R/R CLL/SLL, with a median DOT of 6.4 (range, 0.4-18.7) cycles, the ORR was 75% (12/16), including 3 patients achieving CR/CRi (18.7%). Among 6 CLL/SLL patients who had prior BTKi exposure, the ORR was 66.7% (4/6). For MCL (5 patients were with pleomorphic or blastoid variant), follicular Lymphoma (FL), and marginal zone lymphoma (MZL), the ORR was 40% (6/15), 100% (2/2) and 100% (1/1), respectively.
Summary/Conclusion: LP-108 was well tolerated up to 800 mg/day with daily dose ramp-up schedule and showed encouraging antitumor activity in multiple types of B-cell NHL, even in those who had prior BTKi exposure.
Keywords: BCL2, Phase I, Non-Hodgkin’s lymphoma, Chronic lymphocytic leukemia