This study evaluated a new immunotherapy: REGN5459 is a bispecific antibody that has one binding site to BCMA on the surface of myeloma cells, on the other hand it grabs onto CD3 on T-cells. The uniqueness of the molecule in the lower affinity to the T-cells, in preclinical models this lower affinity linked to less cytokine release syndrome which is a main problem with the bispecific antibodies in the myeloma space currently. So we are taking this molecule to explore the safety and efficacy in a phase I/II clinical trial in patients with relapsed or refractory multiple myeloma.
What was the study design?
Patients in this study were all with active myeloma who had failed at least three prior lines of therapy and that includes an immunomodulatory agent, a proteasome inhibitor and a CD38 antibody and have to have exhausted other therapies. There are two portions of this study: the phase I looked at dose escalation, safety profile, dose limiting toxicity and recommended phase II dosing; for the phase II portion we evaluated efficacy based on response rates. In the phase I we tested a total dose level. The agent is administered intravenously weekly and before patients get to the full dose they went through step-up dosing which occurred for the first four cohorts low dose, medium dose for week 1 and week 2 and then patients get full dose from week 3 onwards. Based on the pattern of the cytokine release there is a little bit of an adjustment in the step-up dosing for those cohorts five through eight which made it a bit more tolerable with more manageable cytokine release syndrome.
The recommended phase II dose was declared at 480mg; the maximum tolerated dose was not reached and there was one patient who had hypoxia that wasn’t related to cytokine release syndrome and was declared later to probably be related to COPD and occurrence of primary lung cancer. So ultimately we expanded that 480mg dose to look at efficacy in the phase II portion. So far we have 43 patients enrolled totally and the response rate in the higher dose cohort, the 480mg and the 900mg, was 90.5% and that includes 100% response rate we saw in the 880mg which is the phase II dose.
What were the key findings?
The cytokine release syndrome, which was the primary reason why this molecule was brought to the clinical trial, we wanted to decrease the cytokine release syndrome, we continued to see cytokine release syndrome in this study. At that top dose level the incidence of grade 1 cytokine release syndrome is about 81%; all of them are grade 1 except for one grade 2. That means that everyone has some fever but only one patient had a change in their vital signs, in this case a decline in blood pressure. The majority of patients were just treated with antipyretics; about 16% had tocilizumab which is a medication that is used to dial down the inflammatory response that could occur with this particular treatment, and about 9% of patients had the steroid therapy, these are a standard of care, and the use of actively supported care on this study was just done at the discretion of the treating physician.
We were pretty impressed that even though there continues to be fever, it seemed to be relatively manageable, it did not lead to significant delay in the step-up dosing and the majority of patients actually escalated up to full dose despite occurrence of their cytokine release syndrome.
What’s next for the study?
The sponsor is evaluating the future development of the compound. Ultimately it is my wish to see that we continue to try to deliver this kind of treatment as safely as possible to our patients by making it accessible as well. Cytokine release syndrome is at the forefront of the problem because right now patients are getting bispecific antibodies, they usually get admitted and they receive step-up dosing as in-patients which means that they have to go to a centre. Cytokine release syndrome also could potentially be more difficult to tolerate when patients are more frail or elderly. So perhaps dulling the CD3 affinity is one of the ways to explore the strategy to mitigate the CRS.
So, whether this particular compound is going to pan out in a larger clinical trial is yet to be seen. The preclinical data that led to moving this particular compound forward to the clinical trial was also explored with the bispecific antibody against other tumour targets in other cancers. So if it turned out that CD3 lower affinity reduces the CRS it may benefit other cancers outside of myeloma. To me, we’re featuring the technology in a relatively small cohort of patients and our ability to deliver treatment safely and quite efficiently is what was impressive. We certainly had concerns whether by lowering the CD3 binding we were going to lose the efficacy – the bispecific technology requires T-cell recognition of the tumour cells to activate the T-cells and clear the cancer cells. So if you don’t activate the T-cells very strongly are you going to lose the efficacy? In this case it doesn’t appear to be. It appears that, yes, we continue to see the cytokine release when you were escalating the dose but the grading of the cytokine release syndrome actually did not increase. On the other hand, the response rate actually went up with the dose and we didn’t see the MTD which was a success of the story.
I probably should point out that there are other side effects outside of the cytokine release that we experience with this agent. So there are certainly some challenges of toxicity, including some dropping in the blood counts. That’s not necessarily out of expectation for patients with relapsed/refractory myeloma; infection continues to be an issue, particularly in those already immunocompromised patients. 60% or so of patients continue to have some infection; the majority were lower grade but the primary organs that were affected the most tend to be the respiratory tract, there’s some pneumonia, sinusitis, bronchitis; there is some urinary tract infection. There were two patients who died from infection, including one from pneumonia and another one from COVID.
So, as we are exploring the bispecific technology, of course there is a concern about T-cell exhaustion. As you activate the T-cells continually, these T-cells actually lose their fitness and that leads to perhaps not only inability to continue to kill off the cancer but also inability to prevent infection. So in this study we now have an amendment coming out to decrease the frequency of the agent. Currently this REGN5459 is given weekly for sixteen weeks and then it goes down to every other week until progression or intolerable toxicity. But in the amendment we would go down after 24 weeks for patients who achieve vgPR or better to be just monthly, recognising that perhaps we don’t have to be as aggressive because in these patients with very deep response they are likely to do very well. How do we know that? We know that patients in the study who have responded are projected to maintain their response passing twelve months in almost 80% of them. So not only they get a response quickly, the response rate is high, but also it’s quite durable. So perhaps we can balance the convenience and decrease the longer-term side effects and still continue to maintain response.
The whole idea whether using less frequent treatment and also using this lower affinity to the T-cell, activating and expanding T-cells in a more controlled way, whether that would also, due to cell exhaustion and decreasing function, is yet to be seen. Our study has a median follow-up of about nine months so there is still data coming in and there are about 12 patients who are still on treatment right now with some actually passing the 26-month mark. So we’re pretty encouraged about that.