IMS 2026 | Phase III CERVINO trial: etentamig efficacy and safety in relapsed/refractory multiple myeloma

The CERVINO trial is a phase 3 trial that evaluated the efficacy of etentamig, a BCMA-targeted bispecific antibody in patients with relapsed disease. Now, etentamig is a uniquely designed bispecific antibody. We know there are several bispecific antibodies in the clinic today that are targeting BCMA. The etentamig stands out in terms of its design for several reasons. One, it has a bivalent BCMA binding domain with high affinity that promotes the T cell mediated killing and it also at the same time have a low affinity CD3 binding domain, which we hypothesize will reduce the risk of CRS and also hopefully decrease the risk of infection by avoiding some of the tonic signaling that happens. And then finally, it also has an optimized EF-CRN binding that allows it to be dosed every four weeks, unlike the bispecifics that we currently have in the clinic, which have to be given once a week or once every other week to start with. The initial studies with etentamig in the phase one and the phase two studies clearly demonstrated a high efficacy of about 60 to 70 percent in patients with relapsed disease in line with what we have seen with other BCMA-targeted bispecifics. However, the overall cytokine release syndrome rates appear to be lower than what was historically seen with others, as was the case with infection. So this led to the design of the CERVINO trial, which is a phase 3 trial that randomized patients with at least two prior lines of therapy with relapsed myeloma who have been exposed to an IMID, a anti-CD38 monoclonal antibody and a proteasome inhibitor, but with no prior BCMA targeted agent exposure. And these patients were then randomized to receive either etentamig as a single agent given once every four weeks or an investigator’s choice of one of three regimens of either carfilzomib and dexamethasone, elotuzumab, pomalidomide and dexamethasone, or selinexor or bortezomib and dexamethasone, allowing a wide variety of standard of care choices for the clinical trial. The etentamig was given with one step-up dosing, and then the patients would get a full dose. And the primary endpoint for the study was overall response rate and the progression-free survival. Overall, 393 patients were enrolled on this clinical trial and randomized to the two groups. As expected, the median number of lines of therapy was three, with nearly half of the patients having received two lines and about 55% having received three or more lines of therapy. As per the inclusion criteria, all these patients were triple-class exposed, and they were also triple-class refractory. Almost half of those patients were. So it clearly reflects a set of patients that we typically see in the clinic having received two lines of therapy. And these patients were then randomized to either of these two therapies. And what we found was the overall response rate was about 74%, including a VGPR rate of 63% and a 40% rate of CR for those getting etentamig compared to about 46% overall response rate with about 20% VGPR rate and relatively low complete response rate of 7% in patients getting any of those three standard of care arms. And these responses then translated to a significant improvement in the progression-free survival. The median PFS was not reached for the etentamig compared to a six-month PFS for the standard of care. And at 12 months, 62% of these patients were free of progression compared to 28% for the standard of care, suggesting a significant benefit with the use of etentamig as a single agent. And importantly, the responses and the impact on PFS were similar across all the patient subgroups, irrespective of the age, gender, as well as whether they were treated at an academic site versus a non-academic site, and the number of lines of prior therapy. And the median duration of response wasn’t reached either, and it was 10.2 months for those patients receiving standard of care. Now, of course, we look at MRD negativity nowadays as an important metric, and 90% of those patients who are in complete response were MRD negative with etentamig compared to only 25% amongst those patients getting the standard of care arm. And this kind of a difference existed when we looked at the minus six cutoff as well. Now the overall survival there seemed to be a trend in favor of etentamig though we don’t really have mature data at this point with a median follow-up of only 11.4 months. Now another important characteristic that really stood out with the etentamig was its toxicity profile. Now, we did see hematological adverse events of grade three or higher in about a third of the patients, primarily neutropenia. What was important was that we did not see any grade three or higher cytokine release syndrome. Most of these were grade one or two and seen in about a quarter of the patients. And there was only one patient with ICANs. Now CRS, of course, we have gotten much better at managing. One of the toxicity of concern with bispecific antibody are the infections. In the setting of etentamig, actually only a quarter of the patients actually had a grade 3 or 4 infection. And when you look at the standard of care arm, there were about 20% of the patients who got grade 3 or 4 infection. So only about an 8% increase compared to the standard of care arm, again, highlighting the relative safety of etentamig compared to the current standards that we use outside of the BCMA targeted by specific antibodies. And particularly one of the interesting findings was among the 113 patients who got a single step-up dosing, the CRS rate was only about 28%, and in about a handful of patients, 22, who got prophylactic tocilizumab, the cytokine release syndrome rate was 0%. So clearly demonstrating the ability to use this in the community settings and scale up the application of this BCMA-targeted therapy across different patient population. Overall, what we found with the etentamig data from the CERVINO Phase III trial is that it retains the efficacy that we have seen and have come to expect across the BCMA-targeted bispecific antibody in this patient population. Importantly, this has been achieved without a significant CRS burden. In fact, less CRS than what we have historically seen with bispecific antibodies and very easily manageable and almost no CRS with the prophylactic tocilizumab and an infection rate that didn’t seem to be much higher than what we have seen in the standard of care arm. And importantly, there were more discontinuations for infection-related toxicity among the standard of care arm than the case with etentamig. So it certainly, you know, places this in a unique position as a BCMA targeted by specific antibody with a very good safety profile. And of course, you know, this trial was for patients with two prior lines of therapy and ongoing trials are looking at early lines of therapy, including patients with newly diagnosed multiple myeloma. Yeah, based on the CERVINO data, we know that it is very effective and more effective than the standard therapies in patients who have at least two prior lines of therapy. Now, we have data from early lines of therapy in the smaller phase, one phase, as well as the dose escalation studies that have been done. And the phase three trials are ongoing for the earlier population. So at least for the population studied in the CERVINO trial, clearly this is an excellent choice in terms of BCMA targeted by specific antibody. How does it compare with the other BCMA targeted by specific antibody? You know, certainly the safety profile appears to be quite good, and the schedule appears to be quite convenient with once every four week dosing. So I think any patient today with relapsed myeloma whom we are considering for a BCMA targeted by a specific antibody, etentamig can safely be considered for that patient with the expectation that the toxicity profile is quite manageable and you’re going to see good efficacy when used as a single agent.

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