Lisaftoclax (APG-2575) Safety and Activity As Monotherapy or Combined with Acalabrutinib or Rituximab in Patients (pts) with Treatment-Naïve, Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): Initial Data from a Phase 2 Global Study

Introduction Lisaftoclax, a specific BCL-2 inhibitor, is active in pts with R/R CLL/SLL, including pts whose disease harbored del(17p) and had progressive disease (PD) after Bruton tyrosine kinase inhibitor (BTKi) therapy. This is the first report of lisaftoclax combined with acalabrutinib or rituximab in pts with CLL/SLL (NCT04215809). Methods Pts with R/R CLL/SLL were treated daily with oral lisaftoclax (400, 600, and 800 mg) alone or combined with continuous acalabrutinib or rituximab for 6 cycles of 28-day cycles. Primary objectives were to determine recommended phase 2 dose (RP2D), safety, and efficacy, including overall response rates (ORRs) of lisaftoclax alone and combined with acalabrutinib or rituximab. Pts underwent lisaftoclax daily ramp-up over 4 to 6 days with monitoring of tumor lysis syndrome (TLS) as follows: Day 1 (D1) 20 mg; D2 50 mg; D3 100 mg; D4 200 mg; and D5 400 mg. Dose ramp-up was followed by Cycle 1 D1 of lisaftoclax target doses of 400, 600 or 800 mg. Pts in the combination groups completed ramp-up as well as an additional 7 days of lead-in of lisaftoclax at the target dose, before acalabrutinib or rituximab was added on C1D8, and then treated until PD or unacceptable toxicity was observed. Results As of July 4, 2022, 141 pts were enrolled. Median (range) age was 62 (18-80) years; 98 (70%) were male; ECOG score was 0-1 in 125 (89%) and 2 in 15 (11%). Median number of prior therapies was 2 (1-15). Seventeen (12%) pts had progressed on BTKi (n = 15) and/or after venetoclax (n = 3) therapy. β-2 microglobulin levels > 3.5 mg/L were observed in 94 (67%) pts and lymphadenopathy ≥ 5 cm in 51 (36%). In the combination cohorts (n = 95), TP53 mutation or del(17p) was seen in 39 (41%) pts, del(11q) in 27 (28%), unmutated IGHV in 36 (38%), mutated IGHV in 14 (15%), and 47% were unknown. Median exposure to lisaftoclax was 10.0 (0-30) cycles, including 16.5 in the lisaftoclax monotherapy group and 9.0 (1-15) in the rituximab and 7.0 (0-18) in the acalabrutinib combination cohorts. Three (2%) pts with bulky disease met the Cairo-Bishop and Howard criteria for TLS (2 clinical/1 laboratory). Clinical TLS pertained to 1 pt with anuria after first 600 mg dose and 1 pt with grade 1 creatinine increase after second 600 mg dose; both pts fully recovered. A total of 6 pts with bulky disease had transient phosphate levels > 3 mmol/L and/or AST levels > 150 u/L associated with rapid decline in lymphocyte count. Phosphate ≥ 3 mmol/L was managed using binders and/or delayed dose increases. No TLS was observed when acalabrutinib or rituximab was added to lisaftoclax on C1D8. Common (> 5%) any-grade AEs in all cohorts were: neutropenia (30% [26% grade 3/4]); COVID-19 infection (26%); anemia (24% [12% grade 3/4]), diarrhea (20%); thrombocytopenia (17% [5% grade 3/4]), hyperuricemia or pyrexia (9% each); nausea, headache, or fatigue (8% each); increased AST levels (7%); hyperphosphatemia (6%); and increased creatinine (6%). First onset of grade ≥ 3 cytopenias occurred during ramp-up or C1 and rarely after C2 (n = 3 [2%]). Grade ≥ 3 neutropenia was manageable with growth factor support in 13% of pts. No discontinuations were due to lisaftoclax alone or combined with the other agents. Nineteen pts discontinued due to PD (13%), of whom 18 were in the monotherapy group; 4 (3%) pts withdrew consent; 2 (1.4%) had a second primary malignancy; 2 (1.4%) an infection; and 10 (7%) died-8 due to COVID-19 infections as well as 1 multiorgan failure and 1 unknown cause, both unrelated to therapy. No dose-limiting toxicities were observed. Lisaftoclax 600 mg QD was determined as the combination therapy RP2D. No drug-drug interaction was observed in either combination group. Rapid normalization of absolute lymphocyte counts occurred in 56% of pts at the end of daily ramp-up, 58% at the end of C1, and 65% at the end of C2. A total of 43 (65%) ORRs (per 2018 iwCLL criteria) occurred in the monotherapy group, and 53 (98%) and 23 (87%) in the acalabrutinib and rituximab cohorts, respectively. Collection of complete response rate and undetectable minimal residual disease data is in progress. Conclusions The RP2D of lisaftoclax was 600 mg daily. Initiated with a daily dose ramp-up, lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and was active in pts with treatment-naïve or R/R CLL/SLL.