ICARIA results: Treating RRMM patients with isatuximab, pomalidomide and low-dose dexamethasone

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Published: 20 Jun 2019
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Prof Paul Richardson - Dana-Farber Cancer Institute, Boston, USA

Prof Paul Richardson speaks to ecancer at the 2019 European Hematology Association (EHA) Annual Meeting about the results of the ICARIA trial.

The phase III trial used isatuximab, pomalidomide and low-dose dexamethasone vs pomalidomide and low-dose dexamethasone to treat relapsed and refractory multiple myeloma.

Prof Richardson explains that the trial found an improvement in PFS and response rate from the three drug combination, as well as a manageable side effect profile.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

 

It’s my pleasure to present at this meeting on behalf of my co-investigators the result of the ICARIA trial which is the first phase III of its kind to report on the treatment of patients with relapsed refractory multiple myeloma where we used the novel CD38 targeting drug isatuximab with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone alone. The rationale for this study was built on the success of isatuximab, both as a monotherapy and then in combination with pomalidomide and dexamethasone where we had shown that in relapsed/refractory patients it could generate a progression free survival approaching 18 months, which was quite promising, with an excellent tolerability profile.

Now isatuximab obviously is in the same class as daratumumab in that it targets CD38. But it’s important to note that it has differences, perhaps the most important biologically is that it targets a key different epitope and that results in it having less compliment activation as part of its profile. But at the same time, whilst it preserves the same immunological effects and arguably has even more striking effects on the immune suppressive microenvironment, it has critically a stronger apoptotic and ectoenzymic signal which means it has more of a direct effect on the tumour. Now, in that context, whilst these are preclinical observations we obviously have to validate those clinically but when you think of combination strategies this particular trial would suggest that by virtue of what I’m going to share with you in terms of the clinical efficacy seen.
The other advantage of those properties is because it’s less complement activating its infusion time is shorter and it doesn’t require the same amount of premedication. Most importantly, you can safely give it to patients with chronic obstructive pulmonary disease and asthma. So in that setting it’s a very real world monoclonal antibody to have available if at all possible.

With that in mind, the phase III trial was launched, ICARIA, across over twenty countries and involving over a hundred centres. What we were able to do was enrol patients with a median age of around 70 but our oldest patient in the trial was, in fact, 86. At the same time patients had to have had prior bortezomib, lenalidomide and be refractory and relapsed in that setting. This means that we had 100% of patients exposed to lenalidomide and, in fact, over 90% were lenalidomide refractory. So that’s very important because, again, that’s a first in the phase III setting. Again, what we showed here was that whilst the control group, the current standard – pomalidomide and dexamethasone, did well with a progression free survival of around 6 months and a response rate of around 35%, we were very pleased to see that the three drug platform generated a progression free survival of a median of almost 12 months, twice that of the control, and very importantly almost twice the response rate with a response rate in excess of 60% with high quality responses seen as well, including actually MRD negativity by intent to treat using next generation sequencing where we showed MRD negativity in this population, remembering how heavily pre-treated they are, of around 5% versus 0% for control. So this suggests this has real benefit in terms of quality of response.

What was particularly exciting as well was to look at subgroups by pre-specified analysis. What we showed there was that patients with renal dysfunction, patients with high risk cytogenetics, patients who had had multiple lines of therapy versus fewer, all of these important subgroups derived substantial clinical benefit going forward. Then I think what was particularly exciting was to see that in the context of other parameters of clinical benefit there was actually a survival signal, a trend at the moment, but nonetheless a clear trend in favour of the three drugs. When we looked at time to next therapy we were able to show that in fact it was about 9 months for pomalidomide and dexamethasone but we’re nowhere near being reached for the three drug arm. So that actually also suggests substantial clinical benefit.

When we looked at the patients who had unfortunately progressed on the control group most of them had received daratumumab, in fact over 50%. So with that in mind the fact that we’re seeing a survival signal in favour of the early use of the three drugs versus keeping the CD38 targeting in reserve suggests that another message of this study is that keeping CD38 therapy in the relapsed/refractory population in reserve doesn’t make sense, so bringing it earlier makes sense. So lots of information from this trial.

In terms of safety, short infusion time, very few infusion reactions that were severe, in fact just one or two, the vast majority grade 1 or 2. In fact, the overall rate was around 38%. To give the audience a context there, if you look at the infusion reaction rate seen with daratumumab combined with pomalidomide and dexamethasone in this same group of patients it’s actually more like 50% based upon published data. So that suggests, although you have to be careful about cross trial comparisons, that this construct that the less complement activation is important is very real in terms of what it means for patients. However, what we have to say, though, is with daratumumab moving into the subcutaneous setting, and doing so remarkably well, that obviously that’s changing for the better anyway. Nonetheless, the fact is that giving this by the intravenous route is relatively quick and requires minimal premedication. There doesn’t have to be a prolonged period of observation after infusion and the fact that it’s otherwise so well tolerated is very encouraging.

So in terms of long-term side effect profile obviously no long-term side effects were unexpected. In the short to medium term infection risks from all of the antibodies is real and in that context it’s important to note that chest infections, community-acquired pneumonia, these were higher for the three drugs versus the two but, again, manageable. So the message for clinicians is be proactive about managing chest infections with any antibody and in particular with the CD38 targeting class. At the same time there was more neutropenia with isatuximab, something also seen, of course, with daratumumab, but the fact of the matter is that with use of growth factor this was manageable. So, again, overall side effect profile clearly manageable. The best reflection of that was in the quality of life measurement which showed no difference in quality of life between the two arms. So, in fact, good quality of life for both groups so clearly then the two drugs versus the three performing well with a side effect profile that was manageable and a quality of life measurement that showed a relatively steady and consistent signal for both groups.

Where are we going with this? Well, obviously this represents a new treatment option for relapsed/refractory patients. Clearly three drug combinations are becoming the new standard of care and this is another one. But in particular, in my view, for lenalidomide refractory patients this is a very important one. Other studies of isatuximab are being pursued and at this meeting we’re showing that even shorter infusion can be given safely. Furthermore, subcutaneous delivery mechanisms are already developed and current trials are about to open. Finally, moving in to the randomised setting in combination with other platform drugs there are studies ongoing with isatuximab in the up-front setting and in the earlier relapse. So I think the outlook is very good.
As we think about broader context it’s reasonable to assume because daratumumab has been so successful and so effective and has moved forward into the front line setting remarkably quickly that this is great news for patients. What it means is if you’re getting daratumumab early and then, of course, in the relapsed setting you may need something subtly different, perhaps isatuximab is an excellent choice to think about in that setting. Of course, beyond that as well, there are lots of things that we need to learn about both antibodies and their patterns of response and relapse and so forth that position it, it would be fair to say, that this is always a matter of more is better in terms of treatment options for our patients. So I’m very pleased with these results today.