At this year’s ASH we were able to present a follow-up from the ASCEMBL study which is a randomised phase III trial of asciminib, which is a new BCR-ABL1 inhibitor now FDA approved in the United States which is a STAMP inhibitor – a targeted drug specifically targeting the myristoyl pocket of the BCR-ABL kinase in patients with CML or Ph-positive leukaemia. Again, this was a 2:1 randomisation, patients with chronic phase CML who had failed two lines of therapy, between asciminib or bosutinib, which had been previously studied in the third line setting for chronic phase CML.
The primary endpoint was major molecular response at 24 weeks and we had previously reported on about a doubling of this response in the asciminib arm as well as decreased or a lower rate of adverse events in the asciminib arm and also lower rates of discontinuation. So at ASH this year we had a 48 week update where patients had at least one year, or 48 weeks, of follow-up or had discontinued treatment earlier. So now we show a continued and sustained improvement in major molecular response with about a 16% difference. This was, again, the primary endpoint of MMR but now looking at 48 weeks. When we looked at patients who had transcript levels less than 1% we saw, again, a fairly dramatic difference – 42% versus 19% or so for bosutinib. The results continue to be positive – again, as we follow more patients over time we see cumulative incidence of asciminib responses longer as well as now deeper molecular responses with increasing patients achieving an MR4 or an MR4.5 as we look later on treatment.
Asciminib really now, especially as it has been FDA approved in the United States, really now offers another option for CML. Many might consider that we have many options already but we clearly still have unmet needs with patients with both resistance and intolerance to prior therapy. Asciminib offers a very safe option for patients in the third line setting. The approval in the US came through for patients with two or more TKI failures or patients with a T315I mutation. This study was the ASCEMBL study which only looked at patients without those select mutations, essentially your more common grouping of patients with two or more TKIs previously but unsatisfactory response. The approval was based on data from the phase I study but I see this medication for sure now being used as a perhaps better alternative in later lines of therapy, the third line currently in the US and for patients who at any point have a T315I mutation.
The side effect profile is favourable and may compare favourably to other medications in the same space, particularly ponatinib. The adverse events for asciminib were, as we had seen in the earlier trial, mainly myelosuppression and we were able to show at the ASH presentation that the onset of myelosuppression is fairly early and doesn’t seem to accrue with increasing time on treatment. There were a few arterial occlusive events which were observed, a few more in the asciminib than the bosutinib arm and this is, of course, being scrutinised carefully. Many of these were not attributed to drug or were identified on cardiovascular screening tests but, again, this is an important question that needs to be studied further.
Not surprisingly, asciminib continues to be studied. Many are aware that this is, again, a novel BCR-ABL inhibitor which allows us to potentially combine it with the previously approved ATP binding site inhibitors, the five currently approved drugs. We have to add on combinations of asciminib with the earliest of the three drugs, imatinib, erlotinib and dasatinib. So look for more data for potential combination therapy for CML as well as earlier line use of asciminib. There are studies planned and accruing for patients in the frontline and second line. There will be a trial for patients to combine asciminib with imatinib to try to gain treatment free remission if it wasn’t successful the first time. So there’s a bright future for asciminib and this is a great advance for patients with CML.