CML: Asciminib Use in Later-Line Chronic Myeloid Leukemia

EP: 1.An Overview of Chronic Myeloid Leukemia (CML)

EP: 2.Chromosomal Abnormalities and Genetic Alterations in CML

EP: 3.Chronic Myeloid Leukemia: Assessing Treatment Response

EP: 4.Role of Tyrosine Kinase Inhibitors in Treatment of CML

EP: 5.Selecting Second-Line Therapy for Chronic Myeloid Leukemia

EP: 6.CML: Challenges and Unmet Needs in Later-Line Therapy

EP: 7.CML: Third-Line Treatment Options for Chronic Myeloid Leukemia

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EP: 8.CML: Asciminib Use in Later-Line Chronic Myeloid Leukemia

EP: 9.CML Management: Personal Experience With Asciminib

EP: 10.Chronic Myeloid Leukemia: Asciminib’s Toxicity Profile

EP: 11.An Overview of CML Treatment Toxicities

EP: 12.Treatment for CML: Dose Adjustment or Discontinuations

EP: 13.Monitoring Patients With Chronic Myeloid Leukemia

EP: 14.Future Management of Chronic Myeloid Leukemia

Transcript:

Daniel J. DeAngelo, MD, PhD: Asciminib, or ABL001 as it was previously known, is a newer agent. It has a different mechanism of action; I think it’s important to highlight that. Asciminib differs from all the other approved tyrosine kinase inhibitors [TKIs] in that it is not an ATP [adenosine triphosphate] mimetic agent. So all the first-, second-, and third-generation TKIs bind at the ATP domain, and therefore they’re ATP mimetic agents. Asciminib is an allosteric inhibitor. It binds at a site distant from the ATP binding or kinase activity. It’s an allosteric inhibitor and binds at a myristoylation site, which regulates the activity of the BCR-ABL kinase. It has a different toxicity pattern and a different resistance pattern. I think this really puts asciminib obviously in a class of its own.

Asciminib was compared to bosutinib in third-line chronic phase CML [chronic myeloid leukemia]. Patients needed to have been previously treated with at least 2 prior tyrosine kinase inhibitors, as well as could not have a T315I mutation, because this would have not worked based on the randomization. Patients were randomized to receive bosutinib at the standard dose or asciminib at the approved dose of 40 mg twice daily. In this study, where the primary end point was 24-week efficacy, the time to achieve a major molecular response, or a 3-log reduction, and the absolute number of patients who achieved MMR, or major molecular response, was higher in the asciminib arm. Equally, or I would argue almost more important, was the toxicity comparison. There were fewer complications or fewer adverse events in the asciminib arm. Asciminib seems to be safer and more efficacious in the third-line setting for chronic phase CML, which led to its approval.

Jorge E. Cortes, MD: This T359 mutation is what we call the gatekeeper mutation. It sits in that ATP-binding pocket, where all the other standard tyrosine kinase inhibitors that we have today, they all bind there. Ponatinib works because of the biochemical structure. It accommodates for that very bulky isoleucine residue. However, asciminib binds in a completely different place, this myristoyl pocket, very distant from the ATP-binding pocket, and therefore has activity. This mutation is not very common, initially. For example, when patients are treated with imatinib in the front line and they develop resistance, T359 probably occurs in only about 5% to 10% of all the patients. But as the patients move on to a second and a third TKI, then the frequency of T359 starts becoming much higher. This is a mutation that has a very poor prognosis, in great part because we don’t have too many treatment options. The only TKI that we had available up until recently was ponatinib. And now we do have asciminib. But if these patients are not treated, they are likely to progress and die because none of the other tyrosine kinase inhibitors work.

This [asciminib] was part of a phase 1/2 study. There was a cohort specifically of patients with T359 mutations that were included. One important aspect to note about this cohort of patients is that they were treated with a dose of 200 mg, twice daily. The dose is different than what we use for the patients who have other mutations or no mutations, where it’s 40 mg twice daily, or 80 mg once daily. That is an important consideration. In the cohort of patients with T359, there were about 50 patients who were included and they were given this dose. The response rate was actually very good; approximately 47% of patients achieved a major molecular response. That’s a very high level of response; we’re talking about a major molecular response. Again, these were patients who had T359.

Many of these patients had received multiple prior TKIs. More than 80% of patients had received at least 2 prior TKIs. And also very important, some of these patients had received ponatinib previously. Even in patients who had previously received ponatinib, the response rate was very good. It was a little bit lower than patients who had never received prior ponatinib, but it was still close to a 30% response rate. This is remarkable considering that ponatinib, aside from the safety concerns, is a very effective drug against T359. Patients who were resistant to ponatinib still had a great response rate with asciminib. The safety was also very good in this study, matching everything that we had seen with the other patients. But considering that we’re using a higher dose, there was no increase in toxicity.

Lipase elevation is one of the most common nonhematologic grade 3 adverse events, but it happened in only about 15% of patients, and very rarely, if ever, associated with true pancreatitis. The only other important grade 3 adverse event was thrombocytopenia. That’s common to all the TKIs. But in this study, it was also less than 20%, so nothing really that is too high or too different than any other treatment options, even in earlier lines of therapy. Arterial occlusive events, fortunately, were not common. We did see them in this cohort, but they were only a little over 5%. So the safety profile so far with all the data that we have from phase 1 and 2, and it matches what we’ve seen in the randomized study, which did not include T359 patients, has been very consistent and very favorable.

Transcript edited for clarity.