The novel BCL-2 inhibitor, lisaftoclax (APG-2575), elicited encouraging responses and acceptable tolerability in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and other hematologic malignancies, according to results of a phase 1 study presented at the American Society of Clinical Oncology 2021 virtual annual meeting.
“APG-2575 is well-tolerated in doses up to 1200-mg per day, with infrequent grade 3 to 4 treatment-related adverse events [AEs]. No tumor lysis syndrome [TLS] or dose-limiting toxicity has been observed in this trial, and the maximal tolerated dose has not been reached. This preliminary data from the trial suggests proof of concept, with an objective response rate of 80% in relapsed or refractory CLL and activity in other hematologic malignancies,” said Sikander Ailawadhi, MD, Lead, International Cancer Center, Hematology/Oncology, Mayo Clinic, Jacksonville, FL, during the presentation.
“This new drug is a potential alternative for patients with relapsed or refractory CLL and other hematologic malignancies where BCL-2 is a driver. It has a shorter daily ramp-up schedule [than venetoclax] that may be more patient-centric and convenient, as well as a preliminary favorable safety profile,” he added.
Although another BCL-2 inhibitor, venetoclax (Venclexta), is approved by the FDA for the treatment of patients with CLL, this drug has been associated with TLS, thrombocytopenia, and severe neutropenia, and is given at a 5-week ramp-up schedule.
To be eligible for enrollment, patients needed to have histologically confirmed CLL/SLL, multiple myeloma, Waldenström’s macroglobulinemia, myeloid malignancies, or non-Hodgkin lymphoma, which included diffuse large B-cell lymphoma, follicular lymphoma, and mantle-cell lymphoma. If patients had received treatment with a BCL-2 inhibitor; had undergone allogeneic hematopoietic stem-cell transplant within 1 year; had Burkitt lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma or leukemia; or required concurrent central nervous system therapy, they were ineligible for enrollment. At the time of the April 15, 2021, data cutoff, a total of 36 patients had been enrolled in the trial. Median age of patients was 70 years (52.8% were aged ≥70), and 72.2% were male. Median number of previous lines of therapy was 2 (range, 1-13).
Among the CLL group (N = 16), 8 patients had stage I-II disease and 8 had stage III-IV disease. The International Prognostic Index score was 20% for low-risk, 33% for intermediate-risk, 40% for high-risk, and 6.7% for very high-risk.
Prognostic features included 13.3% with 17p deletion/TP53 mutation, 6.7% with 11q deletion, 20% with CD38-positive, and 60% with unmutated IGVH.
Patients were treated with oral lisaftoclax at doses ranging from 20 to 1200 mg/day in a 28-day cycle. Cohort A included patients with non-CLL hematologic malignancies who were at low risk for TLS. Lisaftoclax was given without a ramp-up to 3 to 6 patients at each dose level up to 1200 mg/day. Cohort B included patients with CLL who were at intermediate and high risk for TLS. Lisaftoclax was given with a 5-day ramp-up with 3 to 6 patients enrolled per dose level up to 1200 mg/day. Treatment was given daily in 28 cycles until disease progression or toxicity. The dose-expansion phase includes 9 to 12 patients in each cohort.
The objective response rate in patients with relapsed/refractory CLL/SLL was 80%, and the median time to response was 2 cycles.
Treatment-related AEs of any grade (≥10%) included fatigue, neutropenia, diarrhea, and anemia. Grade ≥3 AEs (5%) included neutropenia, nausea, and decreased platelet count.
“Safety was favorable. Only 1 patient discontinued due to treatment-related adverse events, and no grade 5 treatment-related adverse events were reported,” Dr Ailawadhi said.
No dose-limiting toxicities were observed at any dose level up to 1200 mg/day (the highest level tested) and no laboratory or clinical TLS was reported. Median treatment duration is 6 cycles (range, 1-24 cycles).
In cohort B (the CLL and high-risk TLS group), 600 mg/day is the recommended phase 2 dose going forward.
“Cohort A still has 1 slot to be enrolled, and then the maximal tolerated dose will be determined,” he noted.
“APG-2575 is a promising new agent for CLL and has clinical activity in other hematologic malignancies, with a rapid response and shorter daily ramp-up schedule time. Its favorable safety profile is another advantage,” said invited discussant Jacqueline C. Barrientos, MD, MS, Associate Professor, The Karches Center for Oncology Research, Feinstein Institutes for Medical Research, Hofstra Northwell Cancer Center, Long Island, NY.