Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center and the Dana-Farber Cancer Institute, Boston, Massachusetts, shares results from the phase 3 ICARIA-MM trial, showing promising efficacy and safety for isatuximab in combination with pomalidomide and low-dose dexamethasone in relapsed/refractory MM, which were presented at the 2019 ASCO Annual Meeting.

Transcript

My name is Dr. Paul Richardson. I'm the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center and the Dana-Farber Cancer Institute in Boston, Massachusetts.

The rationale behind the ICARIA trial was built out of the success, on the 1 hand, of pomalidomide and dexamethasone as a salvage regimen in relapsed/refractory myeloma, and at the same time, the very promising data that is emerged with isatuximab, which is a CD38 targeting antibody.

It's importantly different to daratumumab, because it has a different isotope for binding, and it triggers different signals preclinically, that may set aside certain quality differences between the two antibodies.

There was a strong rationale preclinically for the development of isatuximab. Moreover, early phase studies with isatuximab as both monotherapy, and then when we combined it with pomalidomide, was very promising.

Specifically, with isatuximab as a monotherapy, response rates were very comparable to what we see with daratumumab. In fact, one of the advantages of isatuximab, given its properties, is that it requires a short infusion time and relatively limited pre-med.

It can also be administered to patients who have histories of asthma and chronic obstructive pulmonary disease, which is because it activates compliment to a lesser degree. As a result of that it has, obviously, a tolerability profile that's very favorable. The rates of infusion reactions are actually quite low.

Putting that all together, it was then combined rationally within it, in various settings, but the relevant ones to ICARIA were the combination trials that we did with isatuximab combined with pomalidomide. What we showed there, was a very impressive response rate in relapsed/refractory patients.

Most encouraging, when we saw remarkable PFS in these phase 1/2 experiences, and the median PFS was actually over 17 months for our patients with this platform. That, in this setting, with relapsed/refractory disease is really quite encouraging.

With that as a background, we sought to validate this in a randomized phase 3 setting, which was to compare pomalidomide and dexamethasone to pomalidomide, dexamethasone, and isatuximab in relapsed/refractory patients.

In terms of the study design, this was sought to be a 1:1 randomization between the 2-drug standard, and that of course is pomalidomide and dexamethasone given in the classical fashion, compared to the 3-drug platform.

Just to remind people that isatuximab is given typically weekly for the first month, and then can be converted quickly onto every 2 weeks thereafter. Essentially, this was partnered with the pomalidomide which was given 3 weeks on and 1 week off, which was exactly, of course, how it was administered to the patients in the standard of care arm.

Also, what's important to note is, that if patients were assigned to the standard of care arm, should they unfortunately progress, then they were able to go on and receive CD38 targeting therapy in the form of daratumumab, off protocol. That was an important design consideration.

Suffice to say that we enrolled approximately 150 patients per arm. This was done relatively quickly, because we were very fortunate in having over 90 sites involved, and the study was conducted in over 20 countries.

We've sought to make the study as real world is possible. By that, I mean we were able to enroll patients with a broad-age range, including some much older patients in their 80s, as well as frailer patients, patients with histories of chronic obstructive pulmonary disease and asthma.

Also, we allowed patients with significant renal dysfunction to participate. Most importantly, patients entering the study had to have been exposed to proteasome inhibitors and the immunomodulatory drugs.

A critical point was that they had to be refractory to lenalidomide. Therefore, we were very encouraged that the patient population reflected this, but over 90% of the patients ultimately enrolled, randomized and treated, were truly refractory to lenalidomide.

This constitutes a very important population of patients. In many ways, what we would consider an unmet medical need. With that in mind that the study was conducted relatively fast. The end point was reached quickly, with demonstration of a significant PFS advantage in favor of the 3 drugs over the 2.

This was essentially a doubling of PFS. We saw approximately a 12-month median PFS for the 3 drugs, and we saw approximately a six-month PFS for the 2 drugs. Obviously, the statistical significance to that was very substantial, and the hazard ratio was very encouraging.

The responses reflected that, as well, and there was effectively a doubling of response rate from around 35%, to approximately 60% to 70% in the 3-drug combination. Importantly, there was a very high-quality response difference as well, in favor of the 3 drugs versus the 2.

Interestingly, we did an exploratory analysis of MRD testing in this highly refractory population. We were struck to find that with next-generation sequencing, we were able to achieve MRD negativity in 5% of patients with the 3 drugs, whereas zero for the control group, which was an interesting and important signal.

In terms of the results of the study, we were encouraged by the efficacy signal. We're also very pleased by the safety. In that regard, there were no new signals that were unusual or unexpected seen. Whilst there were higher rates of neutropenia and also, by that same token, higher rates of upper respiratory tract infection, non-hematologic toxicities were very uncommon.

Infusion reactions were low in terms of incidents, just around 35%. The vast majority were grade 1 and 2, with only a couple of patients experiencing grade 3 or 4 reactions only. As a result of that, the overall tolerability profile of the isatuximab, we felt it was very favorable.

Reflecting that, as well, was the quality of life data that we generated. I think, in that regard, the ICARIA trial was very proactive. We were able to, in fact, present our randomized comparative quality of life data in our presentations both at ASCO and EHA.

What we showed there was that there was no difference in quality of life between the 2 arms, such that the 3 drugs did not impact adversely on QoL compared to the 2. That was a very important signal to share.

The implications of the study are very encouraging and broad. The first one to share is that in terms of real-world practice, we were struck that whilst the data are relatively immature, we were still seeing a trend in favor of overall survival advantage to 3 drugs over the 2.

That, to see so early in the course of the trial, was quite striking. That's despite the fact that over half the patients in the control group received daratumumab at relapse. That would suggest that keeping CD38 targeting antibody therapy in reserve for patients in the relapsed/refractory setting is not entirely our best strategy, but in fact moving the antibody earlier makes sense.

That's an important message from the study, that clearly the use of isatuximab early in the relapsed/refractory course conferred trend favoring survival, despite CD38 salvage for the control group.

Another real-world implication was that the time to mix therapy for the 3 drugs versus the 2 was strikingly different in favor of the 3 drugs versus the2, which is another real-world implication.

When you looked specifically at subgroups in the trial, and this was an Apriori analysis. It's preplanned Apriori analysis. If you look at the patients with lenalidomide refractory, signal was very robust in that group to the 3 over the 2.

Then most importantly, when you looked at high risk, be it cytogenetics, renal dysfunction, other features, we were able to see clear advantage to 3 drugs. Finally, in the context of real world, older patients did well. That's a very important signal, because often these patients are not well represented in large clinical phase 3 trials.

Because of that, the signal that clinicians can derive from studies, that they can bring to their clinics, can be a little bit more difficult to extrapolate. In our study, we've did a preplanned analysis of all the patients, and were able to show clearly that the benefit there was as big as it was for the median overall. Lots of real-world data.

The question then becomes, "How does this align, given that daratumumab, which has been so successful, is now upfront in the treatment of myeloma, and rightly so?" What it tells us is that as you have exciting new regiments being used upfront, you have to have highly successful regimens for salvage.

In combination certainly, there would be, in my mind, a rationale for the use of isatuximab in relapse, and indeed, after patients already received daratumumab, and for example, daratumumab treatment had ultimately failed them.

This would seem, to me anyway, to suggest that combination strategies incorporating isatuximab have a strong rationale, given the data that we have so far.

With that in mind, studies are now going forward with isatuximab earlier in myeloma, and in combination with other platforms, such as for example, combination of isatuximab with lenalidomide, bortezomib, and dexamethasone, as well as other platforms including carfilzomib, and other novel agents.