Early Efficacy, Safety Noted With Lisaftoclax in First-in-Human CLL Trial

Promising antitumor activity coupled with a tolerable safety profile in patients with with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) and other hematologic cancers was noted with the use of lisaftoclax (APG-2575), a novel BCL2 inhibitor, in a first-in-human phase 1 trial (NCT03537482).¹

Twelve of 15 evaluable patients with relapsed/refractory CLL/SLL experienced a partial response (PR) to treatment with lisaftoclax, which translated to an objective response rate (ORR) of 80%. In this population, the median number of treatment cycles was 9 (range, 5-24) and the median time to response was 2 cycles (range, 2-8).

Moreover, the BCL-2 inhibitor was also administered to 21 patients with non–CLL/SLL malignancies, which included those with non-Hodgkin lymphoma (NHL; n = 12), multiple myeloma (n = 6), myeloid malignancies (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 were found to achieve a PR or better with lisaftoclax, although 1 patient with multiple myeloma and t(11;14) experienced a minor response to treatment.

Importantly, no dose-limiting toxicities (DLTs) were 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 infrequent grade 3 or 4 treatment-related adverse effects [TRAEs]. No tumor lysis syndrome [TLS] or DLT was observed and the maximum-tolerated dose [MTD] has not been reached,” Sikander Ailawadhi, MD, lead study author as well as consultant and professor of medicine in the Department of Medicine of the Division of Hematology/Oncology at the Mayo Clinic, said during a presentation on the data at the recent 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. “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 that is currently under development. By targeting the antiapoptotic BCL-2 family of proteins, the agent serves to prevent cancer cells from circumventing apoptosis, which would allow for extended survival. Notably, many hematologic malignancies are characterized by having high levels of BCL-2.

Although another BCL-2 inhibitor, venetoclax (Venclexta), has been FDA approved in this space, the agent has been linked with TLS; thus, the agent requires a 5-week ramp-up. Moreover, venetoclax has been found to be associated with other AEs, such as thrombocytopenia and severe neutropenia.²

Previously, in preclinical models of B-cell malignancies, lisaftoclax has proven to be able to selectively target BCL-2 and to demonstrate antitumor activity. When the cell-free kinetics of the agent was compared with venetoclax, the agents appeared to showcase a similar profile, according to Ailawadhi. In a cell line of acute lymphoblastic leukemia, which is BCL-2 driven, selectivity for BCL-2 was again demonstrated by lisaftoclax. Other models have demonstrated that the mechanism of action of the agent 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 in a 28-day treatment cycle. The clinical trial initially included an accelerated dose escalation with 1 or more patients per dose level.

However, once the dose level reached 400 mg, a DLT was observed, any laboratory or clinical TLS was observed, any hypersensitivity reaction was suspected, 2 grade 2 drug-related toxicities, or 1 or more grade 3 drug-related toxicities were reported, the standard 3+3 dose-escalation design would begin.

At that time, patients were then divided into 1 of 2 cohorts. Patients enrolled to cohort A had non-CLL hematologic malignancies and low risk of TLS, while those enrolled to cohort B had CLL or another hematologic malignancy with intermediate/high risk of TLS. Three to 6 patients were treated per dose level.

Once the MTD was reached or the recommended phase 2 dose (RP2D) was determined, then the dose-expansion phase of the study would begin. Patients received treatment until either progressive disease or intolerable toxicity.

The objectives of the early-phase trial are to examine safety in the form of DLTs, MTD, and RP2D, as well as to characterize the pharmacokinetic (PK) profile of the agent and its efficacy. Key efficacy end points include ORR, progression-free survival, duration of response, overall survival, and minimal residual disease status.

To be eligible for enrollment, patients needed 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. Patients also needed to have acceptable hematologic and renal function.

If patients had previously 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/leukemia; or required concurrent central nervous system therapy, they were excluded.

At the time of the April 15, 2021, data cutoff, a total of 36 patients had been enrolled to the trial. The median age of study participants was 70.0 years (range, 39-89), with 52.8% of patients aged 70 years or older. The majority of patients were male (72.2%) and had a median number of 2 prior therapies (range, 1-13).

Moreover, 58.3% (n = 21) of patients have discontinued treatment, and the most frequently cited reason was because of 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 switched to a standard-of-care regimen because of symptomatic anemia, 1 was switched to another option because of hepatitis B reactivation, and 1 was switched to another option because of lack of response to treatment.

“The swimmer plot also showed a couple of things of prominence. One, there is a significant proportion of patients who are ongoing on treatment,” Ailawadhi noted. “Also, you’ll especially notice in [patients with] CLL, early on, the presence of PRs. A significant number of patients at various dose levels achieved a PR—even at the 2-cycle mark. This was something quite prominent and [says something] about the efficacy of the drug.”

When looking specifically at patients with non-CLL/SLL malignancies, the clinical benefit rate (CBR) achieved with lisaftoclax was 50.0% (n = 10). Specifically, in those with NHL, multiple myeloma, myeloid malignancy, and hairy cell leukemia, these rates were 63.6% (n = 7), 40.0% (n = 2), 0%, and 100% (n = 1), respectively.

“Five of these 21 patients were treated at a dose below 600 mg,” Ailawadhi said. “Even in these patients, with the single-agent treatment, half the patients had stable disease. This is, in fact, encouraging and warrants further focused development within these disease areas.”

When looking at the patients in the CLL/SLL group (n = 15), 14 patients had CLL, and 1 patient had SLL. Moreover, within this subset, 53.3% of patients had stage I to II disease, while 46.7% had stage III or IV disease. When looking at the International Prognostic Index for CLL, 20% of patients were low, 33.3% were intermediate, 40% were high, and 6.7% were very high.

Additionally, 2 patients had del(17p)/TP53 mutation, 1 had del(11q), 3 had CD38 positivity, and 9 patients had unmutated IgVH. All patients previously received CD20 antibody-based therapy, 2 received prior fludarabine, and 4 had prior BTK inhibition. Four patients had bulky disease.

“Focusing just on the efficacy within the [patients with] CLL/SLL, we can see a bit more clearly that a lot of patients are still continuing therapy—especially on higher doses,” Ailawadhi said. “Several patients achieved PR, even early on in their treatment.”

Overall, the safety profile of lisaftoclax was found to be favorable. Any-grade treatment-related AEs (TRAEs) were reported in 75% of patients, and these included fatigue (27.8%), neutropenia (22.2%), diarrhea (19.4%), anemia (16.7%), constipation (11.1%), and nausea (11.1%). Grade 3 or higher TRAEs—which occurred in 5% or more of patients—were experienced by 25% of patients and included neutropenia (13.9%), nausea (5.6%), and decreased platelet count (5.6%).

Only 1 patient discontinued treatment with lisaftoclax because of a TRAE, which was grade 2 pruritus and skin sensitivity. Notably, no grade 5 TRAEs were observed.

“The MTD was not reached, and no laboratory or clinical TLS has been reported. Itis quite a prominent finding that no TLS was noted in any of the patients on any of the cohorts during the study, at any of those dose levels,” Ailawadhi said. “In cohort B, which is the high-risk TLS group, 600 mg of [lisaftoclax] has been selected as the RP2D based on the clinical results and the PK/pharmacodynamic profile. In cohort A, there is still 1 slot to be enrolled at the 1200-mg dose after which the RP2D will be determined.”

The preliminary PK profile of the agent demonstrated that exposures increased with doses from 20 mg to 1200 mg, with an average half-life ranging from 4 to 8 hours. “So, there was some activity at lower doses, as well,” Ailawadhi noted.

Additionally, on BH3 profiling, the drug was found to rapidly trigger complex changings in BCL-2 proteins among samples collected from patients with CLL/SLL; these changes were consistent with rapid clinical reductions in absolute lymphocyte counts.

“[Lisaftoclax, based on all of these data, holds very good promise as a potential treatment alternative for patients with relapsed/refractory CLL, SLL, or other hematologic malignancies where BCL-2 may be a driver with a significantly shorter daily ramp-up schedule, as against weekly, and a very favorable safety profile based on these data,” Ailawadhi concluded.

References

1. 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
2. Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371-4379. doi:10.1158/1078-0432.CCR-17-3761