Clinical activity and safety of cevostamab in relapsed/refractory multiple myeloma

Prof Adam Cohen - University of Pennsylvania, Philadelphia, USA

I was presenting a phase I first in human study with a novel bispecific antibody targeting FcRH5 in relapsed refractory multiple myeloma. FcRH5 is really a new target in multiple myeloma, it’s a cell surface receptor that’s expressed only in the B-cell lineage, namely B-cells and plasma cells, but the expression is highest on plasma cells, especially malignant plasma cells as in myeloma. It’s almost universally expressed in myeloma patients which makes it an attractive target for myeloma immune therapy.

The drug that was studied in this phase I study is called cevostamab and it’s a bispecific antibody. So, one end of the molecule targets FcRH5 on the myeloma cells, the other end targets CD3 which is on T-cells. Essentially this leads to activation of the endogenous T-cells within the bone marrow microenvironment, leading to T-cell mediated killing of the myeloma cells. So based on promising preclinical activity in myeloma models this phase I study was set up and we are presenting the first data.

This was an initial typical 3 3 dose escalation design. What was interesting about this study is that it entailed what’s called a step-up dose escalation. One of the risks of bispecific antibodies is cytokine release syndrome, so to try to mitigate that risk this study first gave a low dose of the antibody on cycle 1, day 1, and then if patients were tolerating this they’d get the full target dose starting on day 8. Then the drug was given once every three weeks as an IV infusion starting with cycle 2 and thereafter up to 17 cycles.

Initially the step-up dose was dose escalated from a very low dose, 0.05mg, up to 3.6mg, and then once the safety of that step-up dose was established it was fixed at 3.6mg and then we further escalated the target dose. Dose escalation is actually ongoing and we’re up to 160mg and climbing.

As mentioned, the drug is given once every three weeks as an IV infusion, patients are hospitalised for the first two doses for up to 72 hours to monitor for cytokine release syndrome and other toxicities. Then, if tolerating well, they get the rest of the doses as an outpatient. They are pre-medicated with Tylenol and Benadryl and steroids with the first couple of doses to mitigate an infusion related reaction.

What are the findings so far?

First I’ll mention that the patient population included in the study was highly relapsed/refractory myeloma. It was a median of six prior lines of therapy in these patients. All of them had had prior proteasome inhibitors and IMiDs, about 80% had prior CD38 antibody, 72% were triple class refractory and 45% were penta-drug refractory, meaning they were refractory to two proteasome inhibitors, two IMiDs and a CD38 antibody. Interestingly, 21% of the patients so far have had an anti-BCMA therapy in the past, either BCMA CAR T-cells or an antibody-drug conjugate.

The data that we presented included 53 patients who were evaluable to date in the single step-up cohort. The primary findings of the study were that the main toxicities were cytopenias, which were seen in grade 3/4 in 15-25% of patients; cytokine release syndrome was seen in 76% of patients, although all of these but one were grade 1 and grade 2 which suggests that this step-up dosing was effective at mitigating the high grade CRS. Neurologic toxicity was seen in 28% of patients, all of this was grade 1 or grade 2 and would occur in the setting of CRS and then resolve, typically within a day or two. Tocilizumab was given in 23% of patients, steroids in 17% of patients. There was very little CRS after those initial day 1 and day 8 doses and it was fairly well tolerated thereafter.

In terms of efficacy there were no responses with patients getting the lower doses of the drug, 10.8mg or below, but starting at 20mg as the target dose and moving up, which we considered the active doses, there were 34 patients who received these active doses and 18 of them, or 53%, actually had a partial response or better, including 32% with VGPR or better and, I believe, 18% CRs. This included patients who were penta refractory, it included patients who had prior BCMA therapy and maybe a hint of greater activity as we got up to the highest dose levels, 90-132mg – 61% of patients at those doses responded.

So those were the primary efficacy findings. The durability of response is still a little too soon to tell. The median follow-up, especially at the highest dose levels, is short but we have multiple patients out beyond six months, several beyond a year, with ongoing durable remissions. I think we just have to wait and see overall what the durability of response is going to be, particularly in some of the higher, more active, doses.

What are the next steps?

We’re continuing to dose escalate in a single step-up dosing cohort. There has also been a small expansion at the 90mg dose, so hopefully we’ll have some additional data to present later this year. In addition, the study is now open to a double step-up cohort where they get an even lower dose on day 1, a median dose on day 8 and then the full dose on day 15, again, trying to see if we can reduce the incidence of cytokine release syndrome. So that double step-up dose escalation is ongoing.

Ultimately once the recommended phase II dose is found and we see which of these two approaches, single or double step-up, really looks the most promising based on the bounds of toxicity and efficacy then it’s expected there will be a large phase II expansion to really get a sense of how effective the drug is going to be and a better sense of safety and tolerability and durability of response.

What can we understand from the results at this point?

I think the main takeaways so far are, one, yes it is early still so we need more time and more data, but this does establish proof of principle that FcRH5 is a viable target in multiple myeloma. This is really the first study to show that you can get responses, including deep responses, in highly refractory patients targeting this. So it validates the target, it also shows the activity of this novel bispecific antibody.

But I think it’s a little too soon to tell where this drug is going to fit in our armamentarium of multiple myeloma. Obviously we hope the phase II expansions validate and confirm the data that we’re seeing in this early dose escalation period. Then once we know a little bit more about the response rates and the populations that are more likely to respond, that will help guide us as to where we’re going to be using this going forward.

Is there anything you would like to add?

No, I don’t think so. I’d just like to really thank all of my co-investigators and all the patients who have enrolled in this study.