Final Thoughts on On-Body Injectors

Dr Paul Richardson reflects on discussions surrounding the use of on-body injectors in multiple myeloma treatment. 

To learn more, view the full series: Subcutaneous Solutions: The Evolving Landscape of Drug Administration in Multiple Myeloma Care. 

Hello everyone. My name's Dr Paul Richardson, and I'm the Director of Clinical Research and the Clinical Program Leader here at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts. I also serve as the R.J. Corman Professor of Medicine at Harvard Medical School. It's my real pleasure to be with you today to take a deep dive on some of the data emerging around on-body injecting devices versus traditional subcutaneous administration for monoclonal antibody therapy with a particular focus on isatuximab. So, as part of this wonderful series of subcutaneous solutions, the evolving landscape of drug administration in multiple myeloma care—and my remit is to really discuss with you some of the data from the IZALCO phase 2 study, which is a randomized, sequential, open-label study evaluating the efficacy and safety of isatuximab subcutaneously administered via a manual push compared to an on-body device really aiming to improve patient's convenience. 

This particular antibody approach was, of course, combined with carfilzomib and dexamethasone in adult patients with relapsed/refractory myeloma, again, reflecting the standard of care. These patients had to have received at least one to 2 prior lines of therapy. Now, in terms of the study design, a few key takeaways. All the patients had received isatuximab subcutaneously with Kd, carfilzomib/dex. The design was sequential, so initial patients received the manual subcutaneous administration. Then, the on-body delivery method was applied in the next cohort of patients. Now currently, the data with follow-up estimated at over 10 months. The efficacy results are very reassuring, very consistent with what we know from the really striking results of the IKEMA study. Isatuximab subcutaneously combined with carfilzomib/dexamethasone engendered a response rate of 80%. This obviously was consistent with what we would've expected and certainly served the purposes of showing that this approach was as active in terms of response rate as we would see with intravenous administration. 

The VGPR rate was actually also encouraging and in excess of 60%. When we looked at the complete response rate in our patients, this was actually 22%. So, an exciting result. Now, what about the safety results for this trial? Well, I think in this context we were pleased to see that the overall safety profile of isatuximab combined with carfilzomib and dexamethasone was very consistent with the established safety profile seen in the IKEMA trial. There were no new safety concerns observed. Interestingly enough, only 2 patients—and that would be 3% of the total—experienced a grade 2 infusion-related event with the manual injection. So, really, minimal infusion reactions just at 3%. Interestingly—and this, I think, is critical—is that with the on-body administration device or the on-body infusion administration, so-called OBI, basically, this was actually fascinating because actually no infusional reactions occurred. 

So, in that context, these were very encouraging results. I think what's also worth mentioning is that in only 1% of injections administered was there a local reaction. Now, with the on-body device or the on-body injection, as it's called, or OBI, what did we see in terms of efficacy, recognizing we'd seen such impressive efficacy with the subcutaneous injection method that I just described a moment ago? Well, what we saw here was that actually the overall response rate was very similar and very consistent with everything that we've seen with the subQ administration. So, there was really no issue there. One of the most interesting questions, however, was what about the patients? What did the patients think about the 2 approaches? Well, I think this is a very interesting question. What we saw here was that in terms of looking at both methods, patient preference after treatment, interesting enough, the preference rate for those patients receiving the OBI method was 75%. Only 17% preferred manual injection, and 8.5% had no preference. 

So, this essentially generated, I think, an important observation that from a patient preference point of view, the on-body device clearly was preferred. Now, what about the healthcare providers? I mean, we're obviously talking here with our nursing colleagues and physicians who are part of the study, and about 20 of these folks provided data in the questionnaire. Most of the questionnaires were completed by nursing staff. What was very interesting here—and I think this is important—was 76 preferred the on-body infusion device, the OBI, and only 20% had no preference. So, I think the impressions from this study—recognizing its limitations, but nonetheless the importance of it because it's very patient-focused—responses, obviously very equivalent to what would've expected from IV infusion, and no questions about safety, exactly the same. But, clearly, the design, the efficacy and safety results, and the patient outcomes, I think, are very encouraging. 

So, this particular approach, I think, bodes very well as it moves towards approval and availability for our patients and provides the convenience of the ease of administration, the speed of administration, without any compromise on efficacy. So, I personally see these data particularly as being particularly encouraging, and we look forward to further experience with the on-body injectable device. It's a real pleasure to have listened to the innovations in administration with a spotlight on the on-body injectors moderated by my outstanding colleague Joe McHale. I think really my comments to this would echo everything that's been said by Joe and Sikander and Beth as part of the discussion. I think obviously the convenience of subcutaneous delivery, the ability to deliver a high volume subcutaneous administration with minimal inconvenience and minimal discomfort to the patient really is exciting. I think the use of a wearable injector where we can see that this has been done in other settings, for example, with long-acting GCSF or so-called pegfilgrastim. I think this provides real advantages to workflow and to tolerability for patients, which without loss of efficacy is particularly encouraging. 

Again, building on this theme of a deep dive on on-body injectors and understanding their role compared to the classic, already approved IV administration of isatuximab, I think the session moderated by Sikander looking really at the IRAKLIA data are particularly interesting because, remember, this was a global randomized, open-label, pivotal phase 3 non-inferiority study comparing isatuximab administered either by an on-body device subcutaneously or by infusion combined with pomalidomide and dexamethasone. So, this built on our own ICARIA experience, which it was my privilege to have co-led with my partner Dr Michel Attal some years ago. What we showed in that study clearly was efficacy and superiority over pomalidomide and dexamethasone alone, which led to its FDA and EMA approval. The IRAKLIA design, I think, was particularly important because it sought to demonstrate equivalence in terms of activity and hopefully obviously address the issue of improved patient preferences and tolerability and convenience of the subcu approach. 

What I think is very exciting from the data that Sikander discussed is that the response rates were exactly the same essentially. It's 71% for the subcutaneous device and 70.5% for the infusional approach. This established non-inferiority very convincingly with a P value of 0.0006 no less, which I think is very impressive. I think what was also impressive was dosing was very equivalent. In fact, actually subcutaneous dosing was superior for the subcutaneous administration. So, clearly, the non-inferiority was established. Then, I think what's really exciting about this study is that the secondary endpoints—including very good partial response and also some of the pharmacokinetic and pharmacodynamic effects—were particularly exciting. On the one hand, we saw VGPR rates of around almost 50% from both, which I think is great to see. The pharmacokinetic data by assessing mean trough levels at C troughs at 4 weeks were very reassuring, in fact, superior for subcu, which I think is really interesting. Then, progression-free survival was really equivalent for both, which I think is a very important point. This was a PFS estimate at 12 months. Here, the subcutaneous PFS estimate at 12 months was very impressive at 66% and just marginally lower, but essentially the same at 65% for the intravenous approach. I think what's really interesting then is to think about the safety profile. Because this is really from a patient and provider point of view what matters, now that we've established that there's no difference in efficacy in terms of activity or PFS. What I think was really interesting was that the systemic infusion reactions were significantly lower with the subQ preparation and on-body device. I think this is really very, very important. Essentially, it was striking. It was just 1.5% versus 25% for intravenous, which I think is really, really encouraging. 

Basically, all of the reactions to the curve were very low grade—grade 1 or 2—resolving within a day. Then, in terms of the patient outcome, I think a very important PRO question was how satisfied or how very satisfied were you with your treatment? What was really interesting here was that with the on-body device administered subcutaneously, the satisfaction rate was actually 70%, whereas for the IV satisfaction rate, it was actually lower and significantly lower at 53.4%. So, this was by using, I think, a very nice tool statistically to demonstrate positive impact of the on-body administration on the patient experience. The P value for that was a remarkable 0.0001. So, all things considered, an excellent outcome. The questionnaires were actually quite impressively done because there was essentially a 97% rate of patients being satisfied or very satisfied with subQ compared to just 71% being satisfied or very satisfied with the IV administration. 

So, I think all of these data point in one direction—that the on-body device is preferred without loss of efficacy or safety and, in fact, improved in terms of safety. So, very exciting to me to see this. I think one thing to mention, which I think is worth sharing with our audience is that the median duration of time for the on-body injecting device was 13 minutes, and 98% of injections were all completed in less than 20 minutes. So, from a patient standpoint, this is really, I think, quite remarkable. So then, moving into the role and relevance of this, and this was chaired by my colleague Beth Faiman, who did a really nice job of providing a strategic view of the landscape that we're dealing with. I think it's important to emphasize for isatuximab some of its value as a monoclonal antibody targeting CD38. I think what's important to also understand with mechanism of action of CD38 is its complexity. 

There are differences, in my opinion, between daratumumab and isatuximab in this space, certainly preclinically. Perhaps these are being reflected by some of the differences in the clinical trials that we see, recognizing all the caveats of cross-trial comparisons. But let's just spend a minute on that because isatuximab obviously is in the same sense an IgG1-derived differentiation, anticluster of differentiation, 38 monoclonal antibody. That's so-called as a chimeric or a slightly structurally different construct to what we think about when we think about daratumumab. What's very important to note is that CD38 being expressed on the surface of myeloma cells, there is this complexity of interaction between the antibodies and the CD38 receptor. It's important to note that, as an antibody, isatuximab engages with a different epitope to daratumumab. So, there is this very direct effect on tumor cells through apoptosis, which is particularly strong through lysosomal pathway for isatuximab. 

That, I think, is important to note. There is this strong inhibition of CD38 enzymatic activity. Then, very importantly, there's this enhancement of the immune milieu with enhancement of immune cell function of activated natural killer cells and the decrease of immunosuppression. So, lots of reasons to think, I think, positively in terms of isatuximab and its potential benefits. So, as one can consider all of this—I think Beth touched very nicely on the various NCCN recommendations, and I won't go back into those in the interest of time. But I do think it is worth emphasizing some of the subtleties of this mechanism of action difference. Then, I think, finally, Beth touched on what I think was very important, which was the comparison of IRAKLIA and IZALCO in terms of the activities seen. Well, I think what's so important is that, as I just alluded to, with both isatuximab and pom/dex given subcutaneously and for the isa versus IV, there was really absolutely no difference in response rate or VGPR rate. 

Similarly, for the use of isatuximab combined with carfilzomib, the overall response rates were very encouraging as was the VGPR or better rate. The CR rate was, I think, a very promising 22% with this approach. Then, in a nutshell, what we then saw was this remarkable safety profile for both the IRAKLIA study and IZALCO study, which were, I think, really encouraging. Then, finally, the satisfaction from patients, as I just alluded to specifically for IRAKLIA, was very high. That same was for IZALCO also. So, putting it all together, I think this is a really important advance for isatuximab. It's an important advance above all for our patients and our providers. I think I'm looking forward to seeing increased utilization of the OBI strategy for our patients and improved outcome accordingly, and just thank you very much for your kind attention. 

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Paul G. Richardson, MD
Dr Paul Richardson is the RJ Corman Professor of Medicine at Harvard Medical School and serves as the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts. His work has centered on advancing the treatment of multiple myeloma. Dr Richardson has led or co-led several pivotal clinical trials, and he has played an instrumental role in the development and approval of numerous agents and supportive care strategies. Dr Richardson is a prolific author and has been honored with multiple international awards in recognition of his leadership in translational research and patient care in multiple myeloma. He has also held key leadership roles with research groups such as the Multiple Myeloma Research Consortium and has served on the editorial boards of several leading journals.