Regeneron’s multiple myeloma medicine linvoseltamab, which was accepted for priority review at the FDA in February, is showing durability in the latest data drop from a phase 1/2 test.
Regeneron presented 12-month data from the LINKER-MM1 study with a cutoff date of Sept. 8, 2023 at the American Association for Cancer Research meeting April 7. Patients with multiple myeloma who had progressed after at least three lines of therapy or those who had refractory disease received a 200-mg dose every week, then twice weekly. The trial includes 117 total patients of which 83 are white, 20 are Black or African American and 10 are Asian.
The primary endpoint in the phase 1 portion is safety and the secondary is overall response. For the phase 2 portion, the primary is overall response and the secondary is safety, duration of response, progression-free survival and overall response.
Regeneron already presented data in December 2023 showing a 71% objective response rate and a 46% rate of complete responses or better.
Now, the company is reporting that 92% of evaluable patients with complete response were minimal residual disease (MRD) negative—which is an endpoint that is coming into focus as a major predictor of efficacy in multiple myeloma.
The endpoint provides an evaluation of a patient’s response to treatment and can signal future prognosis. MRD is assessed by measuring the absence of tumor plasma cells in total cells.
“There are multiple studies and even meta-analysis of MRD in relapsed/refractory and newly diagnosed multiple myeloma that shows correlation of MRD negativity with overall survival and PFS,” Karen Rodriguez-Lorenc, vice president and global program head for hematology and translational sciences at Regeneron, told Fierce Biotech in an interview.
“So, we are very happy with the observations that we have with linvoseltamab and this is giving us a better understanding of the depth of the response that is possible with the agent.”
A conclusion on median duration of response, progression-free survival and overall survival still has not been reached, Rodriguez-Lorenc said.
Regeneron was also keen to understand whether an adaptive response regimen that spaced dosing out to every four weeks would provide better responses, according to Rodriguez-Lorenc.
A total of 62 patients received the study drug for at least 24 weeks in the phase 2 portion of the trial. Out of these, 56 patients (90%) were considered to have a very good partial response by the investigators and were able to transition over to once every four weeks dosing.
Once in the lower dosing regimen, 50% of the 29 patients who had not yet achieved a complete response got there.
“We think that that is really compelling information—that the response regimen is not putting at risk efficacy,” Rodriguez-Lorenc said. “On the contrary, it is maintaining the efficacy or is even deepening the response rate.”
Regeneron also did some sub-group analysis, but Rodriguez-Lorenc said the patients in the LINKER-MM1 study are pretty representative of the multiple myeloma population. The analysis showed a consistent response across all the groups examined, including those who are difficult to treat, according to Regeneron’s Andres Sirulnik, senior vice president of translational and clinical sciences for hematology.
“Patients that have high burden of disease are still benefiting significantly from the drug. And we're very encouraged by that,” Sirulnik said.
As for safety, Regeneron had already reported that 100% of patients experienced some sort of adverse events, with 85% reporting a grade 3 or worse event. The most common adverse event was cytokine release syndrome, with most of those cases being grade 1. There were also 14 patient deaths "due to treatment-emergent" adverse events, of which 11 were due to infections, the company reported in December.
Rodriguez-Lorenc said the company did not observe any new safety signals. However, a deeper analysis of the infection risk showed a decrease over time after initial treatment near the six-month mark.
“So our interpretation is that this could be related with the regimen in one way but also with the depth of the response that the patients are reaching at that point,” Rodriguez-Lorenc said.
Sirulnik stressed that infections are a common event with multiple myeloma and if providers are treating until the disease progresses, patients are likely to experience an infection.
“But the data that we are showing—what we observed, actually—is that we have a peak of infections in the first three months and a higher rate of infections initially, but actually the rate doesn't increase or remains constant. In fact, there is a major decrease in the rate of infections after six months and this is significant, not a small decrease in the rate,” Sirulnik said.
That means that patients can stay on treatment without impacting safety, according to the executives. The regimen is already calling for the lesser dose at the 24-week mark. Patients who achieve complete response also seem to have a drop-off in infections.
“This suggests that potentially, patients have a recovery or reconstitution of the immune system, which we still need to demonstrate and prove,” he added.
As for the deaths, Rodriguez-Lorenc said they are fairly consistent with the disease progression of multiple myeloma.
She added that the benefit-risk profile is “very compelling.”
Regeneron expects more data from the trial to be presented mid-year at future medical meetings such as the American Society of Clinical Oncology in late May and early June.
Linvoseltamab was accepted for FDA review in February to treat patients with relapsed/refractory multiple myeloma that has progressed after at least three prior therapies. The application was accepted under a priority review, with an action date of Aug. 22.