ASH 2022 | Ascentage Pharma to Present Initial Data of Bcl-2 Inhibitor Lisaftoclax (APG-2575) in Combination with BTK Inhibitors for the Treatment of R/R CLL/SLL, Including an ORR of 98%, in an Oral Report at the ASH Annual Meeting

Ascentage Pharma (6855.HK) today announced that the initial results from a global Phase II study of the company’s Bcl-2-selective inhibitor, lisaftoclax (APG-2575), as a monotherapy or in combination regimens for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL), have been selected for an oral presentation at the 64^th American Society of Hematology (ASH) Annual Meeting. In this presentation, Ascentage Pharma will release the first data of lisaftoclax in combination with acalabrutinib (CALQUENCE® ), a Bruton tyrosine kinase inhibitor (BTKi), or rituximab in patients with R/R CLL/SLL. This year, five studies of Ascentage Pharma’s three drug candidates (olverembatinib, lisaftoclax, alrizomadlin), have been selected for presentations, including four oral presentations.

This study of lisaftoclax, to be reported in an oral presentation at the ASH Annual Meeting, showed the promising therapeutic potential of lisaftoclax either as a monotherapy or in combinations in patients with R/R CLL/SLL, demonstrating an interim objective response rate (ORR) of 98% with lisaftoclax plus acalabrutinib and 87% with lisaftoclax plus rituximab. In addition, results from the monotherapy cohort are comparable to prior studies, suggesting favorable safety and promising efficacy of lisaftoclax. The combination therapies, especially lisaftoclax plus acalabrutinib, showed high response rates. In terms of safety profiles, the combination therapies maintained low incidence of tumor lysis syndrome (TLS) and hematologic adverse events.

The ASH Annual Meeting is one of the largest gatherings of the international hematology field, bringing together cutting-edge scientific and clinical research in hematology. The 64^th ASH Annual Meeting & Exposition will take place on December 11-14, 2022, both online and in-person in New Orleans, LA, the United States.

“Lisaftoclax is the first China-developed Bcl-2 inhibitor entering clinical development in China. It is also the world’s second and China’s first Bcl-2 inhibitor with clear clinical activity to have entered pivotal studies. Previously, we released multiple encouraging results of lisaftoclax monotherapy in patients with R/R CLL/SLL, drawing widespread interest and recognition from the field,” said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma.

Dr. Zhai continued, “The combined use of Bcl-2 inhibitors and BTKis has been a therapeutic approach of particular interest for the hematology community. This year, our presentation will feature the initial results from the first study evaluating the efficacy and safety of lisaftoclax plus acalabrutinib or rituximab in patients with R/R CLL/SLL. We are very encouraged by these results, as they signal the significant therapeutic potential of the combination regimens.”

“Moving forward, we will continue to accelerate the global clinical development of lisaftoclax and the drug’s journey to market. We hope our efforts will soon allow patients to benefit from this novel therapeutic.”

These data of lisaftoclax to be reported in an oral presentation at this year’s ASH Annual Meeting are as follows (for details of those oral presentations on olverembatinib, please refer to a parallel press release):

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

• Format: Oral Presentation
• Abstract: 160386
• Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Drugs in Development and COVID-19
• Time: Monday, December 12, 2022, 5:15 PM, Eastern Time / Tuesday, December 13, 2022, 6:15 AM, Beijing Time
• Highlights
• Lisaftoclax, a specific Bcl-2 inhibitor, is active in patients with R/R CLL/SLL, including patients whose disease harbored del(17p) and had progressive disease (PD) after BTKi therapies. This is the first report of lisaftoclax combined with acalabrutinib or rituximab in patients with CLL/SLL.

• Patients 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 six 28-day cycles. Primary objectives were to determine the recommended Phase II dose (RP2D), safety, and efficacy, including ORRs of lisaftoclax alone and combined with acalabrutinib or rituximab. Patients underwent lisaftoclax daily ramp-up over 4 to 6 days, with the monitoring of 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 Day 1 (C1D1) of lisaftoclax target doses of 400, 600, or 800 mg. Patients 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.

• As of July 4, 2022, 141 patients had been enrolled. The median age was 62 (range, 18-80) years; 98 (70%) were male; and the Eastern Cooperative Oncology Group (ECOG) score was 0-1 in 125 (89%) and 2 in 15 (11%). The median number of prior therapies was 2 (range, 1-15). A total of 17 (12%) patients had progressed on BTKi (n = 15) and/or after venetoclax (n = 3) therapy. In the combination cohorts (n = 95), 39 (41%) patients had the TP53 mutation or del(17p), 27 (28%) had del(11q), 36 (38%) had unmutated IGHV, 14 (15%) had mutated IGHV, and 47% were unknown. Median exposure to lisaftoclax was 10.0 (range, 0-30) cycles, including 16.5 in the lisaftoclax monotherapy group, 9.0 (1-15) in the rituximab, and 7.0 (0-18) in the acalabrutinib combination cohorts. 3 (2%) patients with bulky disease met the criteria for TLS (2 clinical/1 laboratory), and 2 of them fully recovered. No TLS was observed when acalabrutinib or rituximab was added to lisaftoclax on C1D8.

• Safety: Common (> 5%) adverse events (AEs) of any grade 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 aspartate aminotransferase (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 patients. No discontinuations were due to lisaftoclax alone or combined with the other agents. No dose-limiting toxicities were observed. No drug-drug interactions were observed in either combination group.

• Preliminary efficacy: Rapid normalization of absolute lymphocyte counts occurred in 56% of patients at the end of daily ramp-up. ORRs were 65% (n = 43) in the monotherapy group and 98% (n = 53) and 87% (n = 23) in the acalabrutinib and rituximab cohorts, respectively.

• Conclusions: Initiated with a daily dose ramp-up, lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and favorable clinical activity in patients with treatment-naïve or R/R CLL/SLL.