This study is investigating this new tyrosine kinase inhibitor, asciminib, which is the first of its kind which is an inhibitor of the myristoyl pocket which is a unique mechanism of action for inhibition of the kinase activity of the BCR-ABL. This drug has been investigated and approved in late lines of therapy – patients who have received two or more lines of therapy – and also in the frontline setting but the area where there is less data is in patients who have received only one prior tyrosine kinase inhibitor.

So this study investigates precisely that population and it has two elements that are novel. One is that, that it investigates the patients with only one prior therapy. The second one is that we are looking at what may be the potential benefit of escalating the doses in patients who may not be getting the response that we want. So it has a built-in element where patients who have not achieved the goals that we want at certain times, we can escalate the dose from the starting 80mg/day to 200mg once a day to 200mg twice a day. So both elements are being investigated.

What was the study design?

Yes, the study is specifically for patients in chronic phase that do not have the T359 mutation and that have received only one prior TKI. They could be either resistant or they could be intolerant and the idea was to include 100 patients. Everybody was starting at an 80mg daily dose. At six months if the patients have not reached 1% or less on the transcript levels they could escalate to 200mg daily and at 12 months if they have not reached a major molecular response, 0.1% or less, then they could escalate if they were still at 80mg to 200mg or if they were already at 200mg to 200mg twice a day. The primary endpoint for this cohort is the major molecular response at 12 months.

There’s another cohort for frontline therapy but that is being presented separately so that’s not something we are discussing in this presentation.

What were the key results?

The results look very good. As I mentioned, we included 101 patients in the study. The majority had received either dasatinib or imatinib as initial therapy. As I said, the primary endpoint was the rate of major molecular response at 12 months. This was achieved in a large percentage of patients – 59.4% of the patients achieved that primary endpoint.

We also looked at the other endpoints, for example achieving 1% or less, which is the equivalent of a complete cytogenetic response and 81% of the patients achieved that level of response. We also looked at the deeper responses and 29.7% of the patients achieved MR4 at 48 weeks and almost 15% of patients an MR4.5.

Another thing that’s important in the results is that the efficacy was similar regardless of whether the patients came into the study because of lack of efficacy to their initial TKI or because of lack of tolerability. The rate of major molecular response was 56% and 63% respectively. So overall very good results.

We did have a few patients that had a dose escalation, a total of 18 patients. We did see some improvement in the response after the dose escalation, it is too early to say whether dose escalation really made a difference. We have early indications that probably it did but that requires further study.

The other important element of the study is that the tolerability was very good, really nothing of significance in terms of grade 3 adverse events. Probably the most common was a little bit of hypertension in 12% of the patients, that was the highest of the grade 3 toxicities. So overall very well tolerated and for the patients who escalated the dose there was no significant increase of adverse events.

So, overall very good efficacy and very good tolerability is what we observed in this study.

What is the clinical significance of these results?

There’s a few important elements. Number one, at least in the United States and in a few other countries the drug is approved for all lines of therapy but we were missing these data. So this confirms the validity of the use in second line. We certainly have good data to use it as front-line therapy but the reality is that many patients are going to use other drugs as initial therapy and this shows that when that is the case if they have resistance or intolerance asciminib is a very good option.

The next step will be to see how far we can go into these deep molecular responses. Because up until now we have considered that patients that have had particularly resistance to prior TKIs maybe shouldn’t be considered for treatment discontinuation. But maybe with a new approach like this, we may feel more comfortable if the data continues to improve and we start seeing some patients become eligible, a significant number of them, maybe starting to stop therapy and see what the outcome may be. I think that that will be the next big step for this study in addition to what I mentioned to clarify better what is the potential benefit and what patients may benefit the most of a dose escalation when the initial response is not optimal.

Is there anything else that you would like to add?

The only thing that I would add is that, as I mentioned, there is a cohort for frontline therapy that will be worth for those interested to look for that report that’s going to be presented at ASH separately.