EHA 2019 | ICARIA study: Isatuximab and pom/dex for multiple myeloma

I think what’s most exciting for us at this meeting is to present the pivotal data from the ICARIA trial. The ICARIA trial is a large, multi-center international phase III trial which we compare pomalidomide, dexamethasone combined with

I think what’s most exciting for us at this meeting is to present the pivotal data from the ICARIA trial. The ICARIA trial is a large, multi-center international phase III trial which we compare pomalidomide, dexamethasone combined with isatuximab, a CD38 targeting antibody, versus the pomalidomide and dexamethasone current standard of care. I think what’s important to share with the audience is that isatuximab is a CD38 targeting antibody which has some very important differences to the current breakthrough monoclonal antibody, daratumumab.

Isatuximab has a different epitope of binding and so it’s signaling in terms of its affect on the tumor cell involves primarily targeting the ectoenzymic portion of the cell surface and triggering a primarily an apoptotic signal in terms of what it does to the tumor cell.

Very importantly though, it would be a mistake to say that they’re different. It would simply be important to note that they have the same target but subtle differences in their quality of core properties which may have an impact clinically. Probably the most important one is there is less compliment activation from isatuximab. Meaning that its infusion characteristics are somewhat easier. There’s less premedication involved and the infusion time is shorter.

But the difference in apoptotic signaling is fascinating because that’s a very potent part of the way the antibody works. In myeloma that may additionally augment what we’ve seen so remarkably from the success of daratumumab which is this remarkable immune effect which is clearly apparent from numerous clinical trials.

All that being said, the ICARIA study was basically designed in the relapsed refractory population to evaluate the impact of isatuximab combined with pomalidomide and dexamethasone, compared to the two drugs alone. In a relapsed refractory population, had a median of three prior lines of therapy.

We treated approximately 300 patients, about 150 per arm. The patients had very real world characteristics, significant renal dysfunction, high risk features. All of what you might expect in a group of patients in whom not only had proteasome inhibition failed them but also lenalidomide had failed them. In fact, over 90% were lenalidomide refractory which is a very important population and an area of unmet medical need.

We were very pleased to see the primary outcomes met. These included progression free survival as the primary endpoint in which the control group did relatively well with a PFS of approximately six months, but what was remarkable was that the three drug combination almost doubled that, with a PFS approaching 12 months. And at the same time, this was reflected by an approximate doubling of response rate as well. Not only the overall response but the quality of response substantially improved in favor of the three drugs.

I think what’s particularly important for clinicians is that the safety profile didn’t reveal any unexpected new signals. There is neutropenia, there are a higher rate of infections, particularly chest infections with antibody use generally and we saw that with isatuximab but these were manageable. In fact, the overall severe toxicity rates were actually very comparable between the two arms so I think that was an encouraging safety signal, suggesting that this platform is a very reasonable and well tolerated regimen overall.

I think this was very mostly reflected by the quality of life data and we did a quality of life prospective evaluation as part of the trial. There we were very pleased to see the QOL assessments showed to decrement for the three drugs over the two, which again is very reassuring.

I think finally the most exciting thing to me was to see subgroup analysis showing clearly clinical benefit in very particular groups, such as those patients with renal dysfunction, patients with high risk cytogenetics, patients who are truly lenalidomide refractory and last line and to see a degree of benefit whether you’d had two or more prior lines. In other words, that those groups who’d had two prior lines and those who’d had three or more because it was between two and four, to see the degree of benefit be very similar in both populations.

Many people say, “Well what about the infusion?” I think the infusion characteristics with isatuximab are quite favorable. We did see some infusional reactions but they were manageable and largely all grade one or two. There were just one or two patients who had grade three or four events which obviously led to discontinuation of the antibody but overall, the infusional reactions were very minimal and typically around the first infusion. They didn’t occur thereafter.

An important point to share with the audience is that we use relatively limited amounts of steroid with isatuximab because this compliment or this less effect on the compliment pathway manifests itself by being an easier infusional type approach to the antibody and that I think is relevant too because it meant we were able to give this antibody to patients who had COPD and asthma. In fact, 10% of the patients had concomitant COPD and asthma and these patients tolerated the infusions without difficulty. I think that’s actually an encouraging, encouraging signal. It means in the real world, this antibody may have an important place.