Asciminib: ASH 2022 Prof. Hughes Studies For Pts With CML

By Professor Timothy Hughes, MD, MBBS, FRACP, FRCPA

How can Asciminib help patients with CML and were there any significant side effects? Asciminib is very much a new compound with a quite a unique mechanism of action, unlike all of the other Tyrosine kinase inhibitors (TKIs) which work by inhibiting BCR-ABL by competing with ATP, Asciminib actually binds to a distinct site in BCR-ABL, called the myristate site and switches off BCR-ABL activity by that mechanism. That provides a major advantage because you do not get the inhibition of other kinases, so it's very targeted to BCR-ABL and to ABL, so the toxicity profile is much more confined, and we see that clearly expressed when we see patients who are not experiencing significant side effects and are not developing major toxicities.

What is the standard of care for patients with chronic myeloid leukemia (CML)?   

We've got great treatments now for chronic myeloid leukemia. We have the first generation drug, Imatinib, which is very safe, but not very potent. And then we have second generation drugs, several of them which are more potent and can achieve deeper responses and therefore can lead to more patients being able to stop drug eventually.

But they have quite substantial toxicities. So we have this dilemma of either safe drug with poor efficacy or great drugs in terms of efficacy with substantial toxicity. Now we have Asciminib coming into the into the scene, which has a very good safety profile, but has the potency of a second generation drug and that is a very exciting new development and it provides the potential to be used at increasingly in earlier and earlier stage of the disease. We have now very promising data in patients who have failed at least 2 Tyrosine kinase inhibitors (TKIs) where it looks to be very effective for many patients and very well tolerated, but we're now seeing some emerging data using it even in the frontline setting, which is very exciting.

The assembled data is maturing. That's a comparison of Asciminib with one of the second generation drugs bosutinib in patients who have failed or intolerant to at least two prior Tyrosine kinase inhibitors (TKIs) and the difference between the achievement of a major molecular response, which is an important target, is very substantial in favor of Asciminib compared to bosutinib.

That data was seen at six months and now we have 96 week data, which confirms that finding. So that's a very key observation. And we presented data at this meeting showing that even patients who didn't have a dramatic response over the first 6 months can have a further improvement with subsequent follow up so that overall we're achieving very good and sustained responses in many patients.

We now have the data from early data, from the ASCEND Study from Australia and New Zealand, where as Asciminib is being used frontline, and at this stage we're just analyzing the 3 month response, which is a very important milestone for patients. We know that patients who achieve a good response by 3 months tend to have a very good long-term outcome.

And we're seen with Asciminib clearly superior results than we saw with Imatinib frontline and at least as good and probably better than second generation drugs, but it's early days. The other key observation is very good safety profile and tolerance to the drug.

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What is the Tyrosine Kinase Inhibitor Asciminib?

Oral asciminib (brand names SCEMBLIX) is a therapy option for patients with chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) who have received 2 or more medications, including tyrosine-kinase inhibitors (TKIs). In addition, it is used to treat Ph+ CML in patients with CP who have the T315I mutation. Leukemia is a form of cancer in which the body produces an abnormally high number of white blood cells.

Asciminib is believed to be an antineoplastic, which is an alternative term for cancer treatments. It inhibits the growth of cancer cells, which are then eliminated by the body once the procedure has run its course.

This drug is only available with a prescription from a health care professional.

What are the most common questions for this research on Tyrosine kinase inhibitors (TKIs)?  

One of the challenges we have with the Tyrosine kinase inhibitors (TKIs) has been the development of arterial occlusive events, myocardial infarcts, cerebrovascular events, peripheral-vascular disease, and these have been a really major concern with the second generation drugs and the third generation drugs.

And of course the big question is, are we gonna see similar challenges with Asciminib? And there were some adverse events in the ASCEMBL trial. It looked to be slightly more common with the Asciminib arm compared to the Bosutinib arm. But so far we're seeing in the ASCEND trial in frontline patients out of 98 patients analyzed, with a medium follow up of 11 months. We haven't seen a single event so far, so it's looking promising, but we're following those patients very closely.

What are the key takeaways from this research and data?

One of the key takeaways from this meeting is that we now have a better choice of drugs for third line patients. We've had Ponatinib, and that's been a very major step forward for patients with resistant disease. We now have learned a lot more about how to use Ponatinib more precisely and more safely.

But furthermore, we now have another candidate, which is a Asciminib, which can be very effective and safe in that setting. So the choice for a hematologist looking after a patient with complex resistant disease now is more challenging cause we have 2 great opportunities, Ponatinib with modified dose and as Asciminib and how do you just make that decision is rather complex and it was covered in my education presentation on Sunday.

Final thoughts about the ASCEND clinical trial in progress.

So the results in the ASCEND study so far are very promising, but it's a phase 2 study, not randomized. So while we're learning a lot, it's not gonna tell us precisely how Asciminib compares to Imatinib and to the second generation drugs. For that, we're gonna need the large multinational randomized clinical trial, and that's already been started. In fact, it's now completed its accrual. That's the ask for first study which we've also now joined, and I think we're gonna be very excited to see those results emerge over the next 1 to 2 years.

Professor Timothy Hughes, MD, MBBS, FRACP, FRCPA - About The Author, Credentials, and Affiliations

Professor Hughes had a pivotal role in establishing the molecular response criteria and kinase domain mutation screening standards, which are used globally to assess response and resistance in chronic myeloid leukemia (CML). He has been the primary investigator on a number of the most influential global and Australian CML clinical trials, which have influenced the selection and sequencing of tyrosine-kinase inhibitors (TKIs). He has been a leader in the field of treatment-free remission (TFR) and was instrumental in the recent suggestions to make TFR a standard therapeutic objective. He has written over 300 publications that have been cited over 54,000 times. Currently, Professor Hughes is working at the South Australian Health and Medical Research Institute (SAHMRI).

Professor Hughes was received an L3 Investigator Grant from the NHMRC (2022-2026) for his project "A curative approach for chronic myeloid leukemia" in honor of his excellent contributions to the area.

Reference

Mayo Clinic - Asciminib (Oral Route). Mayo Clinic, November 1, 2022