Lisaftoclax Plus Acalabrutinib Received Breakthrough Therapy Designation in China for Treatment-Naive CLL/SLL

China's Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has granted breakthrough therapy designation to lisaftoclax (APG-2575) in combination with acalabrutinib (Calquence) for the treatment of adult patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).¹

The combination is under evaluation as first-line therapy in the global, registrational phase 3 GLORA-2 trial (NCT06319456), which is comparing fixed-duration lisaftoclax plus acalabrutinib vs immunochemotherapy.^1,2

Although BTK inhibitors and chemoimmunotherapy are established first-line treatment options in CLL/SLL, Ascentage Pharma cited a need for fixed-duration combination strategies in this setting, noting that immunochemotherapy has limited efficacy in patients with high-risk features such as del(17p) or TP53 mutations, complex karyotypes, and unmutated IGHV, and that BTK inhibitor monotherapy requires continuous treatment and can provide insufficient depth of response.¹

"This breakthrough therapy designation recognizes the clinical potential of lisaftoclax in combination with acalabrutinib for patients with treatment-naïve CLL/SLL and the urgent unmet need in this setting. Moving forward, we are continuing to accelerate the global clinical development of lisaftoclax across relevant indications and are striving to bring this treatment to more patients as quickly as possible," Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, stated in a news release.

In July 2025, China’s NMPA approved lisaftoclax for adult patients with CLL/SLL who previously received at least 1 systemic therapy including a BTK inhibitor, making it the first China-developed BCL-2 inhibitor approved in China.³ In the United States, lisaftoclax is investigational, and the combination of lisaftoclax and acalabrutinib is not approved in any market.¹

What is the mechanism of action of lisaftoclax?

Lisaftoclax is a novel, oral, selective BCL-2 inhibitor that targets a key protein in the apoptotic pathway.

The agent has shown activity in patients with relapsed/refractory CLL/SLL, including those whose disease harbored del(17p) and those whose disease progressed after BTK inhibitor therapy.⁴ In the global phase 1b APG-2575CU101 study (NCT04215809), lisaftoclax was initiated with a daily dose ramp-up over 4 to 6 days before patients reached the target dose, and 600 mg daily was established as the recommended phase 2 dose for combination therapy with acalabrutinib or rituximab (Rituxan).

How is the GLORA-2 trial designed?

The global, multicenter, open-label, randomized phase 3 GLORA-2 trial is enrolling adult patients with newly diagnosed CLL/SLL who meet at least 1 criterion for treatment per 2018 International Workshop on CLL guidelines, have measurable disease, and have an Eastern Cooperative Oncology Group performance status of 0 to 2.² Patients who received any prior CLL-specific treatment, had significant cardiovascular disease within 6 months of study entry, or required warfarin or other anticoagulants are excluded.

Patients are randomly assigned to receive lisaftoclax at 600 mg daily plus acalabrutinib at 100 mg twice daily for a fixed duration of up to 18 cycles, or immunochemotherapy. The control arm consists of fludarabine at 25 mg/m² and cyclophosphamide at 250 mg/m² on days 1 to 3 plus rituximab, or chlorambucil (Leukeran) at 0.5 mg/kg on days 1 and 15 plus rituximab, for cycles 1 to 6; rituximab is given at 375 mg/m² on cycle 1, day 1, and at 500 mg/m² on day 1 of cycles 2 to 6.

The primary end point is progression-free survival. Secondary end points include objective response rate, minimal residual disease negativity rate in bone marrow and/or peripheral blood, and the incidence of treatment-emergent and treatment-related adverse effects.

What are the next steps for lisaftoclax in CLL/SLL?

Ascentage Pharma is conducting 4 global registrational phase 3 trials of lisaftoclax, including GLORA-2 and the FDA- and EMA-cleared phase 3 GLORA trial (NCT06104566), which is evaluating lisaftoclax plus a BTK inhibitor in patients with CLL/SLL who have received a BTK inhibitor for more than 12 months with a suboptimal response.¹

References

1. Ascentage Pharma's lisaftoclax granted breakthrough therapy designation in China for treatment-naïve CLL/SLL. News release. Ascentage Pharma. October 20, 2026. Accessed October 21, 2026. https://www.globenewswire.com/news-release/2026/10/20/3385051/0/en/ascentage-pharma-s-lisaftoclax-granted-breakthrough-therapy-designation-in-china-for-treatment-na%c3%afve-cll-sll.html
2. A study of lisaftoclax (APG-2575) combined with acalabrutinib versus immunochemotherapy for newly diagnosed CLL/SLL. ClinicalTrials.gov. Updated July 28, 2026. Accessed October 21, 2026. https://clinicaltrials.gov/study/NCT06319456
3. Ascentage Pharma announces its novel Bcl-2 inhibitor lisaftoclax approved by China NMPA, ushering in a new era for the treatment of CLL/SLL. News release. Ascentage Pharma. July 10, 2025. Accessed October 21, 2026. https://www.ascentage.com/ascentage-pharma-announces-its-novel-bcl-2-inhibitor-lisaftoclax-approved-by-china-nmpa-ushering-in-a-new-era-for-the-treatment-of-cll-sll/
4. Davids MS, Chanan-Khan AA, Mudenda B, et al. 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. Blood. 2022;140(suppl 1):2326-2328. doi:10.1182/blood-2022-160386