clinical topic updates
New BCL-2 Inhibitors in Development for Chronic Lymphocytic Leukemia
The BCL-2 inhibitor venetoclax has an established role in the treatment of chronic lymphocytic leukemia (CLL), but its utilization in the community may be limited. Our featured expert considers the current landscape and reviews early data on novel, investigational BCL-2 inhibitors for CLL.
Susan O’Brien, MD
“What would render a novel BCL-2 inhibitor more attractive than venetoclax? I would say that the answer is if it did not require a dose ramp-up and monitoring. With both of the newer BCL-2 inhibitors that are currently in development, the goal is a faster ramp-up, but the monitoring is still intensive.”
The main problem associated with the use of venetoclax is the risk of developing tumor lysis syndrome (TLS). Beyond that, venetoclax carries a small risk of neutropenia and some occasional gastrointestinal toxicities, but otherwise, most patients tolerate the drug quite well. Nevertheless, venetoclax is utilized more at academic centers and less frequently in the community, in part because of the cumbersome monitoring that is required to reach the target dose.
Novel, investigational BCL-2 inhibitors were highlighted at the recent 64th American Society of Hematology (ASH) Annual Meeting and Exposition. Reports included initial data from a phase 2 global study with lisaftoclax (APG-2575) and preliminary data from a phase 1 trial with BGB-11417. Both trial designs included BCL-2 monotherapy and the pairing of the novel BCL-2 inhibitor with a Bruton tyrosine kinase (BTK) inhibitor. Lisaftoclax was paired with acalabrutinib or rituximab, and BGB-11417 was paired with zanubrutinib.
Based on our experience with venetoclax, I would not expect to see a lot of added toxicity with these combinations compared with BTK inhibitor monotherapy. There is just not a lot of toxicity associated with venetoclax use, and there is not much at all in terms of cardiac toxicity.
In the aforementioned phase 2 global trial (NCT04215809) that was presented at ASH 2022 by Davids et al, oral lisaftoclax was administered as monotherapy or in combination with continuous acalabrutinib or rituximab in 141 patients with treatment-naive relapsed/refractory CLL/small lymphocytic lymphoma. At data cutoff, the overall response rate was 65% in the monotherapy group, 98% in the acalabrutinib cohort, and 87% in the rituximab cohort.
Also at ASH 2022, Cheah and colleagues reported the preliminary findings of a phase 1 study in which the novel BCL-2 inhibitor BGB-11417 was administered as monotherapy or in combination with the BTK inhibitor zanubrutinib in 50 patients with CLL. Cytopenias were the most common treatment-emergent adverse events reported in patients receiving monotherapy, with 33% of patients experiencing grade 3 or higher. Most individuals with CLL/small lymphocytic lymphoma experienced notable reductions in absolute lymphocyte count, with early responses observed at dose escalation and at doses of 1 mg or higher, reflecting the improved potency of BGB-11417 compared with venetoclax.
Data on lisaftoclax was also presented at the 2021 American Society of Clinical Oncology Annual Meeting. In the first-in-human global phase 1 study of lisaftoclax by Ailawadhi et al, 35 pretreated patients with relapsed/refractory CLL or other hematologic malignancies received oral lisaftoclax at doses ranging from 20 mg per day to 1200 mg per day in a 28-day cycle. No dose-limiting toxicities were reported, the maximum-tolerated dose was not reached, and no clinical or laboratory cases of TLS were observed. Any-grade treatment-related adverse events occurring in more than 10% of patients included neutropenia, anemia, fatigue, diarrhea, and nausea.
What would render a novel BCL-2 inhibitor more attractive than venetoclax? I would say that the answer is if it did not require a dose ramp-up and monitoring. With both of the newer BCL-2 inhibitors that are currently in development, the goal is a faster ramp-up, but the monitoring is still intensive. Perhaps we may have an effective BCL-2 inhibitor that does not cause TLS. However, given the mechanism of action of BCL-2 inhibitors and the mechanisms of TLS, BCL-2 inhibition might always carry some risk of TLS. Although the efficacy of both of these investigational drugs is quite high, I am not sure that they are offering any additional major advantages over venetoclax.
Ailawadhi S, Chanan-Khan AAA, Chen Z, et al. First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs). J Clin Oncol. 2021;39(suppl 15):7502. doi:10.1200/JCO.2021.39.15_suppl.7502
Cheah CY, Tam CS, Lasica M, et al. A phase 1 study with the novel B-cell lymphoma 2 (Bcl-2) inhibitor BGB-11417 as monotherapy or in combination with zanubrutinib (ZANU) in patients (pts) with CLL/SLL: preliminary data [abstract 962]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
ClinicalTrials.gov. Study of APG-2575 as a single agent or in combination with other therapeutic agents for CLL/SLL. Updated March 2, 2022. Accessed March 8, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04215809
Davids MS, Chanan-Khan A, 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 [abstract 964]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Deng J, Paulus A, Fang DD, et al. Lisaftoclax (APG-2575) is a novel BCL-2 inhibitor with robust antitumor activity in preclinical models of hematologic malignancy. Clin Cancer Res. 2022;28(24):5455-5468. doi:10.1158/1078-0432.CCR-21-4037