Lisaftoclax Elicits Responses With a Tolerable Safety Profile in Relapsed/Refractory CLL

Sikander Ailawadhi, MD

Lisaftoclax (APG-2575), a BCL-2 inhibitor, demonstrated impressive response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and other hematologic malignancies, without the typical adverse effects (AEs) typically seen in the treatment of these patients, according to Sikander Ailawadhi, MD.

Preliminary data from an early, first-in-human phase 1 study (NCT03537482) demonstrated clinical proof of concept with lisaftoclax with an overall response rate of 80% in a cohort of patients with relapsed/refractory CLL. Notably, investigators did not observe any incidence of tumor lysis syndrome (TLS), a common AE with BCL-2 inhibitors, and the maximum tolerated dose (MTD) was not reached. Moreover, the drug induced a benefit across a range of hematologic malignancies.

“Despite it being very heavily pretreated 36-patient cohort, with median prior lines of therapy being anywhere from 1 to 13, patients saw clinical benefit across the board,” Ailawadhi said. “The patients were able to stay on treatment for a long period of time and even have stable disease. In fact, in [a patient with] multiple myeloma, we saw a minor response.”

In an interview with OncLive^®, Ailawadhi, professor of medicine, consultant, Division of Hematology/Oncology, Department of Internal Medicine; consultant, Department of Cancer Biology; and lead, International Cancer Center, Mayo Clinic, discussed the unique pharmacodynamic profile of lisaftoclax, the similar responses seen across cohorts, and the favorable tolerability of the drug.

OncLive^®: Could you discuss the rationale for this study with lisaftoclax in patients with CLL and other hematologic malignancies?

Ailawadhi: BCL-2 inhibitors are a very important mechanism for hematologic malignancies in general. The first-generation BCL-2 inhibitor, venetoclax [Venclexta], is FDA approved for treatment in quite a few different malignancies, such as chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], non-Hodgkin lymphoma, multiple myeloma, myeloid malignancies, and hairy cell leukemia.

The rationale for this trial was to continue utilizing a BCL-2 inhibitor but [develop] an agent that would be more refined in the sense that it could work the same or hopefully even better and importantly, have a much more tolerated safety profile.

With that in mind, lisaftoclax (APG-2575), was devised. Lisaftoclax is a BCL-2 inhibitor, but has a very distinct pharmacokinetic and pharmacodynamic profile, [defined by its ability] to affect the BCL-2 but not bind irreversibly to [the gene which can cause] prolonged AEs. Hopefully [it is] a safer alternative which will continue to show similar or, more importantly, better efficacy.

What was the design of the study and what patients were included in the population?

The study included patients with a wide variety of hematologic malignancies because the concept of BCL-2 inhibition is active in a lot of different cancer diagnoses. Since this [study] was first-in-human, the patients first started on a very small dose, only 20 mg, but then increased up to 1200 mg. [The trial followed] an accelerated dose level design. Initially, there was 1 patient enrolled at a particular dose level. If they did fine without any AEs in the first month, the next patient was enrolled at the next higher [dose] level. This was followed from 20 mg up to 400 mg as an accelerated design, [including] patients with any of the malignancies.

If the dose was safe at 400 mg] was safe, which it was, then the patient population was divided into 2 arms. In 1 arm was patients who had a low risk of TLS…for example, multiple myeloma, Waldenström macroglobulinemia, and certain kinds of low-grade lymphomas. The other cohort [included] patients who had a high risk of TLS, such as [patients with] CLL, AML, and certain kinds of aggressive lymphomas. That's when the more traditional 3 plus 3 phase 1 trial design was followed.

The other very important thing to keep in mind is that the drug was set up as a daily ramp-up. When a patient with CLL has to be started on venetoclax, it's typically a 5-week ramp up of the dose because of this risk of TLS. With lisaftoclax, on the other hand, the ramp-up was done on a daily basis, so the patients typically reached their target dose around the 1-week mark. As you can imagine, 5 to 7 days compared with 5 weeks was a big difference in the design. When the 2 cohorts with the 3 plus 3 design reached their MTD or recommended phase 2 dose, then [the trial] will be expanded to enroll more patients.

At the time of this data being submitted, the [patients with] high-risk TLS, the CLL/AML cohort, had already reached 100 mg and there was no MTD. This means that patients were able to tolerate even 1200 mg. The recommended phase 2 dose for [patients with] high-risk TMS ended up being 600 mg.

We know that from 200 mg to 1200 mg, responses were seen throughout and side effects were not bad. The whole idea was, let's take a dose that is tolerated and it's more amenable to adding other drugs rather than cross issues with AEs, so that’s why 600 mg [is the optimal dose]. Since then, even in the other cohort of [patients with] low-risk TLS…we are at the recommended phase 2 dose of 600 mg in both cohorts.

Could you expand on the results that we've seen with efficacy as well as safety?

When we look at the efficacy and safety, it's important to realize that the data on 36 patients we presented at iwCLL is a group of all malignancies put together. When we look at those different malignancies, it's a very heterogeneous group.

Going forward, let's think about CLL vs non-CLL group of [patients]. In the non-CLL group there was a median of 3 prior lines of therapy with 1 minor response seen in [a patient with] multiple myeloma, but across the other disease areas, we did have disease stabilization. [In a population that was] heavily pretreated, heterogeneous, and [received] different dose levels, [lisaftoclax] offers disease stabilization, [which is] great.

On the other hand, in the CLL cohort, 12 of 15 patients are evaluable for response. The overall response rate in the CLL group was 80%. Again, thinking about…the different heterogeneous population put together in CLL, [we had] about an 80% response rate. In the non CLL group, which was everybody else, we saw disease stabilization in the majority and some minor responses.

To understand this more, while this study is going into expansion for 2 cohorts, there are specific clinical trials that have started [enrolling only patients with] CLL, [another enrolling only patients with] Waldenström, and [another enrolling only patients with] myeloma.

In terms of clinical implications and next steps, what is exciting to you about this study?

The most exciting [aspect] is the fact that [lisaftoclax] showed clinical benefit and responses from 200 mg to 1200 mg, which is a wide range. We were able to define why [lisaftoclax] does not have [a similar] AE profile to venetoclax. Considering that we now know what the safe dose is, going forward, [we can further investigate] other drugs can be combined. Based on that, at least 3 different trials, which are all disease-focused international trials for CLL, myeloma, and Waldenström have all taken off and have started. The CLL and Waldenström trials are already accruing quite well, and the myeloma trial is on its way. That's the next wave of clinical trials out of this study.

At the same time, this phase 1 clinical trial is already [proceeding] with expansion. We are also planning to explore different areas other than the specific 3 trials [already mentioned]. For example, we are also looking at patients who have disease progression either after venetoclax and how [lisaftoclax might perform in that situation], how to combine different regimens, and so on. We are modifying this phase 1 trial while the phase 2 trials are ongoing, independently.

Is there anything else that you'd like to add regarding this study?

[Irrespective of] any amount of dose, there was absolutely no TLS seen. Diarrhea, neutropenia, thrombocytopenia, or other AEs that can be frequently seen with BCL-2 inhibitors, they were not that prominent with lisaftoclax.

This drug brings [up] a lot of other opportunities. For example, we can do a rapid ramp-up. Could we foresee a future of BCL-2 inhibitors where we can do completely outpatient [treatment with] no need for the admission of patients because there are no grave adverse effects noted? Could we eliminate the need for ramp-up? These are very provocative possibilities. Right now, to be on the safer side, I don't think we are there yet, but for the first time [with a] BCL-2 inhibitor, this drug is suddenly giving us those opportunities, making us think [that] it's not unthinkable anymore.

Reference

1. Ailawadhi S, Chanan-Khan AAA, Paulus A, et al. First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor, in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and other hematologic malignancies (HMs). Presented at: 2021 International Workshop on CLL; September 17-20, 2021; virtual.