Early promise seen with lisaftoclax in relapsed / refractory CLL and other hematologic malignancies
Lisaftoclax (APG-2575), a new inhibitor of BCL-2, has demonstrated encouraging responses with acceptable safety in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and other hematologic cancers that have been processed in a Phase 1 human trial (NCT03537482), according to data presented at the ASCO 2021 annual meeting.1
Twelve of 15 evaluable patients with relapsed / refractory CLL / SLL experienced a partial response (PR) to treatment with lisaftoclax, resulting in an objective response rate (ORR) of 80%. In this population, the median number of treatment cycles was 9 (range, 5-24) and the median response time was 2 cycles (range, 2-8).
In addition, the BCL-2 inhibitor has also been administered to 21 patients with non-CLL / SLL malignancies, including those with non-Hodgkin lymphoma (NHL; n = 12), multiple myeloma (n = 6) , myeloid tumors (n = 2), and hairy cell leukemia (n = 1). The median duration of treatment in these patients was 3 cycles (range, 1-22). None of these patients achieved PR or better with lisaftoclax, although one patient with multiple myeloma and t (11; 14) had a minor response to treatment.
It is important to note that no dose limiting toxicity (DLT) was observed with the agent, even when administered at the highest dose of 1200 mg.
“[Lisaftoclax] is a very well tolerated agent, even up to doses of 1200 mg and has uncommon Grade 3 or 4 treatment-related adverse reactions [TRAEs]. No tumor lysis syndrome [TLS] or DLT has been observed and the maximum tolerated dose [MTD] was not achieved, ”said Sikander Ailawadhi, MD, lead study author, consultant and professor of medicine, Department of Medicine, Division of Hematology / Oncology, at the Mayo Clinic, during a presentation on the data. “Our preliminary data suggest proof of concept, with an ORR of 80% in patients with relapsed / refractory CLL or SLL. “
Lisaftoclax is a novel, potent, orally active selective BCL-2 inhibitor currently in development. By targeting the BCL-2 family of anti-apoptotic proteins, the agent serves to prevent cancer cells from bypassing apoptosis, which would allow prolonged survival. In particular, many malignant hemopathies are characterized by high levels of BCL-2.
Although another BCL-2 inhibitor, venetoclax (Venclexta), has been approved by the FDA in this space, the agent has been linked to TLS; thus, the agent needs a ramp-up of 5 weeks. In addition, venetoclax has been shown to be associated with other AEs, such as thrombocytopenia and severe neutropenia.2
Previously, in preclinical models of malignant B cell tumors, lisaftoclax was shown to be able to selectively target BCL-2 and demonstrate antitumor activity. When the cell-free kinetics of the agent were compared to venetoclax, the agents appeared to exhibit a similar profile, according to Ailawadhi. In an acute lymphoblastic leukemia cell line, which is induced by BCL-2, selectivity for BCL-2 was again demonstrated by lisaftoclax. Other models have shown that the agent’s mechanism of action allows it to disrupt the BCL-2: BIM complex, which mediates the induction of apoptosis.
In the Phase 1 study, investigators set out to evaluate oral lisaftoclax at daily doses ranging from 20 mg to 1200 mg over a 28-day treatment cycle. The clinical trial initially included an accelerated dose escalation with one or more patients per dose level.
However, once the dose level reached 400 mg DLT was observed, any biological or clinical SLT was observed, any hypersensitivity reaction was suspected, 2 drug-related toxicities of grade 2, or 1 or several grade 3 drug-related toxicities were reported the standard 3 + 3 dose escalation design would begin.
At this point, the patients were then divided into 1 of 2 cohorts. Patients included in cohort A had non-CLL hematologic malignancies and low risk of TLS, while those included in cohort B had CLL or other hematologic malignancy with intermediate / high risk of TLS. Three to 6 patients were treated per dose level.
Once the MTD or the recommended phase 2 dose (RP2D) has been reached, the dose extension phase of the study would begin. Patients received treatment until disease progression or intolerable toxicity.
The objectives of the early phase trial are to examine safety in the form of DLT, MTD and RP2D, as well as to characterize the pharmacokinetic (PK) profile of the agent and its efficacy. The main measures of effectiveness include ORR, progression-free survival, duration of response, overall survival, and minimal residual disease status.
To be eligible for enrollment, patients had to have histologically confirmed relapsed / refractory CLL / SLL, multiple myeloma, Waldenström macroglobulinemia, myeloid malignancies, and NHL, which included diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. The patients were also required to have acceptable hematologic and renal function.
Whether the patients had previously received treatment with a BCL-2 inhibitor; had undergone an allogeneic hematopoietic stem cell transplant within one year; had Burkitt’s lymphoma, Burkitt-type lymphoma, or lymphoma / lymphoblastic leukemia; or required concomitant central nervous system treatment, they were excluded.
At the time of the April 15, 2021 data cutoff, a total of 36 patients had been enrolled in the trial. The median age of study participants was 70.0 years (range, 39-89), with 52.8% of patients aged 70 or older. The majority of patients were men (72.2%) and had a median number of 2 prior treatments (range, 1-13).
Additionally, 58.3% (n = 21) of patients discontinued treatment, and the most frequently cited reason was disease progression (61.9%; n = 13). Other reasons for discontinuation included toxicity (9.5%), patient withdrawal (14.3%), or physician decision (14.3%). One patient was transferred to standard care regimen due to symptomatic anemia, 1 was transferred to another option due to hepatitis B reactivation, and 1 was transferred to another option due to a lack of response to treatment.
“The swimmer’s plot also showed some important elements. First, there is a significant proportion of patients who are on treatment, ”noted Ailawadhi. “In addition, you will particularly notice in [patients with] CLL, very early, the presence of PR. A significant number of patients at various dose levels achieved RA even at the 2 cycle mark. It was something quite important and [says something] on the effectiveness of the drug.
When looking specifically at patients with non-CLL / SLL malignancies, the clinical benefit rate (CBR) obtained with lisaftoclax was 50.0% (n = 10). Specifically, in people with NHL, multiple myeloma, myeloid malignancy, and hairy cell leukemia, these rates were 63.6% (n = 7), 40.0% (n = 2), 0%, respectively. and 100% (n = 1). .
“Five of those 21 patients were treated at a dose of less than 600 mg,” Ailawadhi said. “Even in these patients, with the monotherapy treatment, half of the patients had stable disease. This is, in fact, encouraging and justifying more focused development in these areas of the disease. “
When looking at patients in the CLL / SLL group (n = 15), 14 patients had CLL and 1 patient had SLL. In addition, in this subset, 53.3% of patients had stage I to II disease, while 46.7% had stage III or IV disease. Looking at the International Prognostic Index for CLL, 20% of patients were poor, 33.3% were intermediate, 40% were high, and 6.7% were very high.
In addition, 2 patients had del (17p) /TP53 mutation, 1 had del (11q), 3 had CD38 positivity, and 9 patients had unmutated IgVH. All patients have previously received CD20 antibody therapy, 2 received fludarabine, and 4 had previous BTK inhibition. Four patients had voluminous disease.
“Focus only on efficiency within the [patients with] CLL / SLL, we can see a little more clearly that many patients are still on treatment, especially at higher doses, ”said Ailawadhi. “Several patients have achieved PR even at the start of their treatment. “
Overall, the safety profile of lisaftoclax was found to be favorable. Treatment-related AEs (TRAs) of all grades were reported in 75% of patients, including fatigue (27.8%), neutropenia (22.2%), diarrhea (19.4%), anemia (16.7%), constipation (11.1%), and nausea (11.1%). Grade 3 or greater ERTs, occurring in 5% or more of patients, were observed in 25% of patients and included neutropenia (13.9%), nausea (5.6%), and decreased count platelet (5.6%).
Only 1 patient discontinued lisaftoclax treatment due to TRAE, which was grade 2 pruritus and skin tenderness. In particular, no grade 5 TRAE was observed.
“MTD has not been reached and no laboratory or clinical TLS has been reported. This is a fairly significant finding that no TLS was noted in any of the patients in any of the cohorts during the study, at any of these dose levels, ”Ailawadhi said. “In cohort B, which is the high-risk TLS group, 600 mg of [lisaftoclax] was selected as RP2D on the basis of clinical results and PK / pharmacodynamic profile. In cohort A, there is still 1 window to enroll at the dose of 1200 mg after which the RP2D will be determined.
The preliminary pharmacokinetic profile of the agent demonstrated that exposures increased with doses of 20 mg to 1200 mg, with a mean half-life ranging from 4 to 8 hours. “So there was also some activity at lower doses,” Ailawadhi noted.
Additionally, on BH3 profiling, the drug was found to rapidly trigger complex changes in BCL-2 proteins among samples taken from patients with CLL / SLL; these changes were consistent with rapid clinical reductions in absolute lymphocyte count.
1. Ailawadhi S, Chanan-Khan AAA, Chen Z, et al. First human study of lisaftoclax (APG-2575), a new inhibitor of BCL-2 (BCL-2i), in patients (pts) with relapsed / refractory CLL (R / R) and other blood diseases malignant (HM). J Clin Oncol. 2021; 39 (suppl 15): 7502. doi: 10.1200 / JCO.2021.39.15_suppl.7502
2. Davids MS, Hallek M, Wierda W, et al. Comprehensive Safety Review of Venetoclax Monotherapy in Patients with Relapsed / Refractory Chronic Lymphocytic Leukemia. Clin Cancer Res. 2018; 24 (18): 4371-4379. doi: 10.1158 / 1078-0432.CCR-17-3761