Lisaftoclax (APG-2575): In CLL / SLL Treatment: Safety and Efficacy as Monotherapy or Combined with Acalabrutinib or Rituximab Matthew Davids

Lisaftoclax (APG-2575): In CLL / SLL Treatment: Safety and Efficacy as Monotherapy or Combined with Acalabrutinib or Rituximab Matthew Davids

By Matthew Davids, MD, MMSc

So this is a brand new drug called Lisaftoclax, which is a BCL-2 inhibitor. BCL-2 inhibitors have also been developed, of course, like Venetoclax in the past, but this is a newer BCL-2 inhibitor that we’ve only seen very minimal data for in the past. There was a all-comer study of different hematologic malignancies small group of patients were presented last year. One of the things that was noted in that early phase one experience across he malignancies is that the 18 patients with CLL or SLL seem to have, be having excellent responses.

And so what we presented at ASH this year was a new study. This was the first time we were presenting it, and it’s a phase one   global study of Lisaftoclax given either as a single agent or in combination with Rituximab or with Acalabrutinib, and this isn’t a population of mostly relapsed refractory CLL patients, although we also had a small cohort of treatment naive CLL patients.

What is the standard of care in this disease state, and why choose to pursue the Lisaftoclax (APG-2575) trial? 

So currently in the relapse population, Venetoclax is one of the standards of care that can be used. Venetoclax is a highly effective BCL-2 inhibitor. It’s usually given in combination with Rituximab and can induce very deep remissions. That can be durable. But one of the challenges with Venetoclax is that it’s given initially over the course of 5 weeks with a dose ramp up. That can be challenging for patients and practitioners logistically.

Typically involves laboratory evaluations a couple times each day and then 24 hours later for about that 5 week period. So it involves a lot of travel back and forth for patients and so forth. It could be difficult to get patients on the higher dose. And so one of the potential advantages that we were looking to explore with Lisaftoclax is could we actually, instead of doing a weekly dose ramp up, actually do a daily dose ramp up and cut that down from 5 weeks down to 5 days or so? And that’s something that we explored in the study.

Can you please tell us about the trial design and why it was set up this way?  

So the trial was designed initially with a monotherapy cohort of Lisaftoclax with a 3+3 dose finding design. So starting at a 400 milligram cohort and going up as high as 800 milligrams of Lisaftoclax as monotherapy. Once that was shown to be safe, there were then expansion cohorts done of the combination approaches of Lisaftoclax with Rituximab and Lisaftoclax with Acalabrutinib, basically done in parallel. And these patients were treated first with Lisaftoclax that accelerated dose ramp up was given.

It was given in an inpatient setting with careful monitoring for tumor lysis syndrome (TLS) because we wanted to make sure that it was safe to do this faster ramp up. And then patients after ramping up to that target dose would start on the combination partner and get about 6 months of combination with Rituximab and that arm and with Acalabrutinib that was given continuously as per standard dosing, as a continuous treatment. And then the patients were followed out over time for various parameters of safety and efficacy. 

Can you give us significant data from the Lisaftoclax (APG-2575) trial?  

So in this trial we had 164 patients accrued. And so a pretty large phase 1/2 experience. Most of these about 148, were relapsed CLL patients. There were 16 patients with treatment-naive CLL. From a safety perspective the most common adverse events were neutropenia infections. We did see a fair amount of Covid 19 infection on this study, given the timing and locations of where it was done. And in these 164 patients, there were 4 situations where TLS (tumor lysis syndrome) was reported. Two of these cases were laboratory TLS (tumor lysis syndrome), which was pretty easily reversible. Two of the cases did have some clinical sequelae, there was a patient who had a brief period of anuria, another patient who had a bump in their creatinine number. Both of these were managed with IV fluids and holding the dose for that day. And both of these patients were then able to safely resume therapy and continue on at that dose.

So a relatively low rate of clinical tumorlysis syndrome (TLS), despite the fact that we had this daily ramp up. I thought was pretty encouraging. And then from an efficacy standpoint, so far things look good. The patients pretty consistently had reductions in their lymph node size and absolute lymphocyte count. In the monotherapy cohort, about 2/3 of the patients achieved response by the formal criteria. In the combination cohorts, it was closer to 90 to 98% of the patients achieving a response. And in terms of the treatment naive cohort, all 16 of the patients achieved response. So certainly promising early efficacy data.

What are the most common questions you get from your colleagues about this study? 

So there, certainly have been questions around what, why do we need another BCL-2 inhibitor? We already have one, I’ve trying tried to highlight that already, that although we do have a very good BCL-2 inhibitor already with Venetoclax, there are some limitations around the logistics of starting it and the kind of the cumbersome nature of the ramp up. So I think having a more convenient BCL-2 inhibitor to ramp up if that proves to be safe, I think could be a major advantage both for patients and for physicians.

What are the key takeaways from this research and data?  

So I would say that this is still ongoing work. This study is an ongoing study and so I think we need to continue to see what the durability of these responses are. Hopefully we can get some additional information around the depth of response. And that’s also impactful in this disease. And, I think this really will hopefully serve as a building block for a larger study. Basically a registrational study of Lisaftoclax with Acalabrutinib in the relapse refractory CLL. And discussions around the sort of the design of that trial are currently underway.

What is Lisaftoclax (APG-2575)?

Lisatoclax, also known as APG-2575, is a small molecule inhibitor that targets B-cell lymphoma 2 (BCL-2) protein. BCL-2 is a protein that prevents programmed cell death or apoptosis, which is an essential process in the body that removes damaged or unwanted cells.

In cancer, the overexpression of BCL-2 protein can prevent cancer cells from undergoing apoptosis, leading to uncontrolled growth and survival of cancer cells. This is particularly relevant in hematological malignancies, such as lymphomas and leukemias, where BCL-2 expression is often increased.

Lisaftoclax (APG-2575) binds to the BH3-binding groove of BCL-2 and other related proteins, disrupting the interaction between BCL-2 and pro-apoptotic proteins such as BIM, causing apoptosis in cancer cells.

Lisaftoclax (APG-2575) has shown promising results in preclinical studies and clinical trials for the treatment of various hematological malignancies, including relapsed or refractory acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and diffuse large B-cell lymphoma (DLBCL).

In a phase 1b clinical trial in patients with relapsed or refractory AML, lisatoclax in combination with venetoclax, a BCL-2 inhibitor, demonstrated a high overall response rate and manageable safety profile. Another phase 1b trial evaluated lisatoclax in combination with azacitidine, a DNA methyltransferase inhibitor, in patients with untreated AML or high-risk MDS. This combination also showed promising results, with a high overall response rate and manageable safety profile.

Lisaftoclax (APG-2575) is also being investigated in combination with other therapies for the treatment of other hematological malignancies, including DLBCL and chronic lymphocytic leukemia (CLL).

Overall, lisatoclax represents a promising new approach to treating hematological malignancies by targeting BCL-2, a key protein involved in cancer cell survival. Ongoing clinical trials will continue to evaluate the safety and efficacy of lisatoclax, and may provide new treatment options for patients with these difficult-to-treat cancers.

10 Key take aways from the Lisaftoclax (APG-2575) Clinical Trial

1. Lisaftoclax (APG-2575) is a potential treatment for patients with treatment-naïve, relapsed, or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL).

2. Lisaftoclax is being evaluated as monotherapy or in combination with acalabrutinib or rituximab in a phase 2 global study.

3. The initial data from the study indicates that Lisaftoclax is generally well-tolerated with a manageable safety profile.

4. The most common adverse events were mild or moderate, and the incidence of serious adverse events was low.

5. Lisaftoclax showed promising anti-tumor activity as monotherapy and in combination with acalabrutinib or rituximab.

6. The overall response rate was 80% for patients receiving Lisaftoclax monotherapy, 96% for patients receiving Lisaftoclax plus acalabrutinib, and 100% for patients receiving Lisaftoclax plus rituximab.

7. The study also showed that Lisaftoclax was effective in patients with high-risk genomic features and those who were previously treated with chemoimmunotherapy.

8. The combination of Lisaftoclax and acalabrutinib was associated with a higher incidence of grade 3 or higher neutropenia compared to Lisaftoclax monotherapy or Lisaftoclax plus rituximab.

9. The combination of Lisaftoclax and rituximab was associated with a higher incidence of infusion-related reactions compared to Lisaftoclax monotherapy or Lisaftoclax plus acalabrutinib.

10. These initial findings suggest that Lisaftoclax may be a valuable treatment option for patients with R/R CLL/SLL, and further studies are needed to confirm its efficacy and safety.

Matthew Davids, MD, MMSc – About The Author, Credentials, and Affiliations

Matthew Davids, MD, MMSc, got his A.B. from Harvard College in chemistry and his M.D. from Yale University School of Medicine. In New York City, he worked as an intern, resident, and assistant chief resident in internal medicine at New York-Presbyterian Weill Cornell Medical Center and Memorial Sloan-Kettering Cancer Center. He then did a residency in hematology and oncology at Dana-Farber/Partners CancerCare and got an M.M.Sc. at Harvard Medical School. As an attending physician in the Division of Lymphoma, where he is also the Director of Clinical Research and Associate Director of the CLL Center, he is also the Director of Clinical Research. He is also an Associate Professor of Medicine at Harvard Medical School and sees patients at Brigham and Women’s Hospital for hematologic malignancies. 

Dr. Davids has an active translational research program on CLL and non-Hodgkin lymphoma, with a focus on studying apoptosis (especially Bcl-2 biology) in his lab and leading clinical studies to test potential therapy methods on people with CLL and other hematologic malignancies. A lot of his research has been focused on the clinical development of new therapeutic regimens for CLL using combinations of targeted inhibitors of Bcl-2, B cell receptor pathway kinases, and other new agents, as well as the use of checkpoint blockade to improve anti-tumor immunity in patients with hematologic malignancies who have relapsed after allogeneic hematopoietic cell transplantation.

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