Novel ABL1 Kinase Inhibitor Active in Heavily Pretreated CML

Michael Mauro, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses results from a phase 1 trial which evaluated asciminib, an ABL1 kinase inhibitor, in patients with heavily pretreated chronic myeloid leukemia (CML). 



Hello, my name is Michael Mauro from the Myeloproliferative Neoplasms Program within the Leukemia Service at Memorial Sloan Kettering Cancer Center.

On behalf of a number of international investigators and the sponsor, we recently were able to publish the phase 1 study of asciminib, or previously known as ABL001, for chronic myeloid leukemia after other ABL kinase inhibitor failures.

The purpose and the rationale for the study was still an unmet need in Ph‑positive leukemia, particularly chronic phase CML, in where patients can have either resistance, intolerance, or both to available therapies. In addition, we continue to seek better therapies for patients with select mutations in that ABL kinase domain, including the T315I mutation.

Given that the family of medications currently available all target the ATP binding pocket of ABL1 and resistance is known via mutations in the ATP binding site, and while some drugs are effective against T315I, we have only one, and there's some still‑unmet need.

Asciminib was a new type of ABL1 kinase inhibitor preclinically in that it's an allosteric inhibitor. The currently available drugs bind the ATP binding pocket in different ways. Some more in inactive or an active conformation, some with less or more steric inhibition difficulties, with a varying degree of penetrance for different mutations.

Asciminib binds or occupies the myristoylation pocket of the ABL kinase, which is a distinct region from the ATP binding pocket. The myristoylation site of ABL is usually inhibited, and this leads to a more inactive conformation of the BCR‑ABL kinase.

With BCR‑ABL fusion or translocation, we lose this autoinhibition, due to the altered BCR‑ABL kinase. Asciminib was developed to help reconfigure and re‑regulate this autoinhibition, which, again, preferentially moves BCR‑ABL into an inactive conformation.

This would be favorable, obviously, to downregulate the kinase and to treat BCR‑ABL‑driven leukemias. Again, this was a phase 1 study, a first in human study in patients with chronic phase CML.

The purpose of a phase 1 study, of course, is safety and tolerability. Overall, the conclusions, which we published on, were in a fairly large number of patients in the phase 1 study, a total of 141 in chronic phase and 9 with accelerated phase CML. We found the drug to be quite well‑tolerated and quite active.

Much has been the case for other targeted drugs. No real dose‑limiting toxicity was observed, and the study examined a variety of different doses and schedules. Once‑daily, twice‑daily dosing, and dose ranges from 10 milligrams to 200 milligrams once or twice daily.

This was a heavily pretreated population. Two‑thirds or more of patients had had multiple lines of therapy. There were patients at various stages of response loss or degree of response, and we saw response improvements across the board, patients without hematologic response achieving hematologic remission, the overwhelming majority.

A majority of patients who didn't have cytogenetic response moved into cytogenetic response, and near half the patients achieved molecular response amongst those who were able to be assessed, including some with resistance to previous lines of therapy, including ponatinib.

What was most remarkable, I think, was the durability of response. We had very little dropout with patients needing to exit the study for tolerability issues with asciminib or loss of response. In some of the details of the paper, we cover the fact that mutations against the myristoylation site in the cases that have been examined have been fairly limited.

The overall conclusions are that this medication may offer significant benefit and shows very good safety for patients with chronic phase CML as a single agent. From this study, and from this safety, we've been able to see further efforts continue to further explore the drug.

For example, in patients with T315I mutation who have had, or perhaps have not had, ponatinib, but who may benefit. Some of these data have been presented preliminarily and look promising. Further study of the drug in combination, importantly with the available ABL kinase inhibitors, has continued.

When asciminib was first conceptualized or developed, that was one of the premises that, could a myristoylation site inhibitor or an allosteric inhibitor be combined with ATP binding pocket inhibitors, given the distinct sites that these different medications bind?

This is unprecedented in Ph‑positive leukemias, because dual‑targeted therapy against the ABL kinase wasn't feasible, given the commonality of the targets of the currently available drugs. We do have some preliminary data on the combination of asciminib with, for example, imatinib, nilotinib, and dasatinib from this study also presented preliminarily so far.

These efforts continue to further look at the efficacy and the proper dosing of asciminib in combination with available TKIs. Lastly, there is interest and concepts are being developed that move forward to move asciminib into earlier lines of therapy, potentially after limited failure of available kinase inhibitors, even potentially as an early or front-line treatment.

Also, as a means to improve chances of treatment‑free remission or treatment cessation, perhaps by coadministration with available TKIs for patients who have failed to achieve a treatment‑free remission for the first time around, having gained remission from one of the conventional TKIs.

There's a lot of excitement about asciminib as probably one of the biggest advances in Ph‑positive leukemias, particularly chronic phase CML. There was a lot of effort, and this is a very large phase 1 trial.

We all eagerly awaited these results, so I think it's excited to be able to see them published in the New England Journal and to allow us to continue to move forward to examine better the safety and efficacy in larger populations, select populations, such as the highly resistant CML patients, and in combination with available therapies.

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