ASH 2023 – Regeneron defends its bispecifics

Regeneron’s presence at this year’s ASH meeting focused on two T-cell engagers, odronextamab and linvoseltamab. While response rates continue to look competitive, there were also high numbers of infection-related deaths with both agents.

The company told ApexOnco that it had a few potential explanations for this. Firstly, the studies in question were uncontrolled, noted Andres Sirulnik, senior vice-president of translational and clinical sciences for Regeneron’s haematology division. Secondly, the trials were carried out at the height of the Covid pandemic, when the risk of infection was particularly high.

The uncontrolled nature of the studies could be relevant because “patients with myeloma are profoundly immune suppressed and are at risk of infection”, said Sirulnik. He added that it was “very likely” that infections were down to underlying disease.

“Until we have head-to-head comparisons versus standard of care, it’s going to be very difficult to tease out what is myeloma, and what is not.”

With various controlled trials ongoing, this should eventually become clearer. In the meantime, regulators are set to rule on both assets.

BCMA

The first data to emerge involved linvoseltamab, a BCMA x CD3 bispecific, from the phase 1/2 Linker-MM1 trial in relapsed/refractory multiple myeloma. Regeneron put out a press release on Thursday, and this had longer follow-up than results presented in an ASH poster on Monday.

In the most recent cut, with 11 months’ follow-up, the overall and complete response rates were 71% and 46% respectively. Patients had a median of five prior lines of therapy and received the recommended 200mg dose of linvoseltamab.

On a cross-trial basis, responses look better than those seen with Johnson & Johnson’s BCMA-directed T-cell engager Tecvayli, which showed respective overall and complete response rates of 62% and 28% in the late-line MajesTEC-1 study.

However, in Linker-MM1 there were 14 deaths due to treatment-emergent adverse events, representing 12% of patients; 11 (9%) of these were due to infections.

Still, infection is also a risk with Tecvayli, and there were five treatment-related deaths in MajesTEC-1, representing 3% of patients. Two of these were caused by Covid and one by pneumonia.

Regeneron plans to submit linvoseltamab to regulators this year.

CD20

Meanwhile, there was a similar story with odronextamab, a CD20 x CD3 bispecific. Final analysis from the DLBCL cohort of the registrational Elm-2 trial, presented at ASH on Sunday, showed an ORR of 52% and a complete response rate of 32%, in 127 patients who had received a median of two prior therapies. These data are in line with an earlier cut presented at ASH last year.

Genmab and AbbVie’s Epkinly is the product to beat in this class: in the analogous Epcore NHL-1 trial, this drug showed overall and complete response rates of 61% and 38% respectively. Meanwhile, Roche’s Columvi produced overall and complete response rates of 56% and 43% respectively in Study NP30179, which also included some follicular lymphoma patients. 

Moving to adverse events in Elm-2, there were five treatment-related deaths, all due to infection.

By way of comparison, in a recent cut of data from Epcore NHL-1 there were two treatment-related deaths, one due to Covid and the other due to neurotoxicity. 

Odronextamab is filed for third-line DLBCL and FL, with a Pdufa date in March 2024.

One Regeneron project that isn’t moving forward in blood cancers is REGN5459; the company had hoped that this anti-BCMA x CD3 bispecific would be associated with lower rates of cytokine release syndrome, binding more loosely to CD3 than linvoseltamab. 

However, this did not come to pass, and Regeneron is now focused REGN5459 in non non-malignant conditions: a trial in kidney transplantation is ongoing, and the group is also interested in allergy and lupus, Sirulnik said.

Controlled phase 3 trials of linvoseltamab and odronextamab

Source: OncologyPipeline.