First-in-class STAMP inhibitor asciminib in patients with CML harbouring the T315I mutation

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Published: 8 Dec 2020
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Dr Jorge Cortes - Augusta University, Augusta, USA

Dr Jorge Cortes speaks to ecancer about a study he presented at the virtual ASH 2020 meeting on the use of the first-in-class STAMP inhibitor asciminib in patients with CML harbouring the T315I mutation.

He reports the 52 patients treated had an MMR rate of 47%, with patients previously treated with ponatinib fairing worse than those that had not been.

Dr Cortes believes that the results show a very active drug in this context with good responses even in ponatinib treated patients.

This program is funded in part via an independent grant from AbbVie. ecancer is editorially independent and there is no influence over content.

 

First-in-class STAMP inhibitor asciminib in patients with CML harbouring the T315I mutation

Dr Jorge Cortes - Augusta University, Augusta, USA


The study is about asciminib in patients with T315I mutation. First to remind you that asciminib is a tyrosine kinase inhibitor but it has a novel mechanism of action. It’s what we call a STAMP inhibitor, specifically targeting the ABL myristoyl pocket. So this is a pocket, this myristoyl site serves as an autoregulator of the activity of ABL; when ABL binds to BCR that autoregulation is lost and asciminib restores that ability to inhibit the kinase activity. It’s a completely different binding site from all of the other TKIs which makes it important because it’s not affected then by the usual mutations that we see affect the other TKIs and that includes, of course, the T315I which is why we wanted to test this in the clinic. Of course in vitro we had seen that.

This is an arm of a larger study where patients also without T315I were investigated and combinations etc. but we were focussing specifically on the patients with the T315I. One other thing that I will mention in terms of the design, it was part of a phase I study, but here we are focusing on patients that received the actual dose that was found to be effective for the T315I.

What methods did you use in this study?

For this study we included adult patients only in chronic or in accelerated phase and they had to have a T315I mutation confirmed in a central laboratory. They should have received a prior TKI. Very importantly, the dose that was used here for this study was 200mg twice a day. This is a higher dose than what is used for other studies and in patients without this mutation it’s 40mg twice a day. So this is a higher dose. Now, in the phase I study it was found to be safe at doses even higher than that so we didn’t have concerns going into this study but it is important to recognise that difference. The drug is given orally and it was continued indefinitely until progression or intolerance.

What were the results?

We treated 52 patients, their median age was in their mid-50s and of course, by definition, everybody had the T315I. A few patients, just a handful of them, had additional mutations besides the T315I but most of them had the T315I alone. Most of the patients had more than 1% transcripts at the start of the therapy, there were a few patients that had less than 1% but all of them had more than 0.1%. So, again, these were 52 patients and importantly some of these patients had received ponatinib already which is the only other drug that’s available today that works against T315I. So 31 of these patients had received prior ponatinib, so more than half.

So if the overall MMR rate was 47% it was somewhat better for the patients who had not been previously treated with ponatinib than in the patients who had received prior ponatinib. So if we take the accumulated 24 week mark, the response rate was 57.8% for those who had not received prior ponatinib and 29%, 28.6%, for the patients with prior ponatinib. So a respectable rate, very good but certainly lower than if they had not been treated with ponatinib.

Importantly, we are also seeing deeper responses. We are seeing MR4 in 26.5% of the patients, MR4.5 in 20% of the patients. Of course the treatment continues for the majority of patients, two-thirds of the patients continue on therapy so it is possible that these rates will continue to improve over time. Again, there’s a little bit of a difference between ponatinib treated and ponatinib naïve patients.

Overall the treatment has been very well tolerated, very few adverse events that we saw in this study, grade 3 or 4. Perhaps the most common ones were elevation of lipase, it was about 15% of patients who had this, it was usually transient, very manageable with brief treatment interruptions and dose adjustments. Then thrombocytopenia was the only other grade 3 or 4 that reaches more than 10%.

There were a few patients that had some arterial occlusive events. There were three patients that had such events: one had a cerebral vascular event; another patient had both an ischemic stroke and a cerebral ischemia and then a third patient had a peripheral vascular disorder. So these events had happened, now these are patients that have been heavily pre-treated so we need to keep an eye on this. But those are the results that we had on this study.

What are you concluding from these results?

These results show a very active drug in this context. We see a very high response rate, certainly in ponatinib naïve patients, but encouragingly even in ponatinib treated patients. And with a toxicity profile that, so far, and granted follow-up is still relatively short, but the toxicity profile seems to be very, very acceptable. So this promises to be a very good drug to our armamentarium, particularly when we consider that we have only one drug available for T315I. So the drug is not yet approved, we hope that the drug will be approved in the near future but it will be a very welcome addition.

The one thing that I would conclude with is just to emphasise that this is a tyrosine kinase inhibitor but it is one with a completely different mechanism of action. So even though we have a lot of tyrosine kinase inhibitors, we still have some patients with need and having a drug, a first in class of what we call the STAMP inhibitors, is very valuable when we consider those patients that go from one inhibitor to another and have no response and even more for patients with T315I where we just have one drug and some patients end up having to change, either because of efficacy or because of safety. So this is a completely novel agent that is very, very welcome in the clinic.