ASCO 2022: MagnetisMM-3 Trial Updates

Pfizer Presents First Data from Planned Interim Analysis of Pivotal Phase II MagnetisMM-3 Trial of BCMA-CD3 Bispecific Antibody elranatamab (PF-06863135)

Mechanism of Action: Binds BCMA on myeloma cells and CD3 T cells, thereby bringing together T cells and activating them in the vicinity of the myeloma cell resulting in cell kill.

Main Content- Elranatamab is a BCMA x CD3-targeted investigational therapy currently being developed to treat multiple myeloma. The agent has been granted fast track designation by the United States Food and Drug Administration (FDA). Pfizer presented findings of Elranatamab’s Phase II MagnetisMM-3 study (NCT04649359) at ASCO 2022. MagnetisMM-3 is a Phase II open-label, multicenter, single-arm trial examining the safety and efficacy of elranatamab monotherapy in patients with relapsed/refractory multiple myeloma.

Initial efficacy findings of elranatamab showed a 60.6% objective response rate after a median follow-up of 3.71 months. At the time of the data cut-off, 89.5% of objective responders were ongoing with no evidence of progression or death.

The safety and effectiveness of 94 patients who had received at least one dose of elranatamab (Cohort A – BCMA- naïve) as of the data cutoff on March 23, 2022, were studied in this interim analysis. In patients with triple-class refractory Multiple Myeloma, the data revealed that 76 mg of elranatamab weekly (QW) might have a tolerable safety profile. Hematologic adverse events such as anemia, neutropenia, thrombocytopenia, lymphopenia, and cytokine release syndrome (CRS) were the most prevalent treatment-emergent adverse events. All CRS were Grade I (40.0%) or II (40.0%) in the 90 individuals who underwent the 2-step-up priming regimen (18.9%). In addition, ICANS (immune effector cell-associated neurotoxicity syndrome) affected 2.2% of patients, all of whom were in Grade 2 or below.

“Bispecific antibodies hold promise as the next breakthrough in treating multiple myeloma. These data represent an important step forward as we look to bring elranatamab as a potential innovative new treatment to people living with relapsed or refractory multiple myeloma, where there is a high need”-Expert Opinion.

“We are encouraged by these early efficacy and safety results, which suggest elranatamab may have a manageable safety profile coupled with early promising clinical responses. We look forward to the final analysis from MagnetisMM-3, which is expected later this year.” -Expert Opinion.

Conclusion: The antibody-drug conjugate (Blenrep) and the FDA-approved CAR T-cell therapies (Abecma and Carvykti) are the current BCMA-directed choices for heavily pretreated Multiple Myeloma patients. In the registrational directed Phase II MagnetisMM-3 trial, Pfizer's BCMA x CD3 bispecific antibody elranatamab demonstrated encouraging preliminary effectiveness and tolerability. Before this, the company disclosed results from the phase I MagnetisMM-1 study (NCT03269136), which demonstrated that when elranatamab was administered in dosages up to 1000 µg/kg, the drug had a tolerable safety profile with no dose-limiting toxicities (DLT’s) when presented at the 2021 ASCO Annual Meeting. It is worth noting that the FDA slapped a partial clinical hold on the drug last year owing to peripheral neuropathy cases. But now, the hold has been lifted.

Along with Pfizer, many companies, including J&J, Roche, Regeneron Pharmaceuticals, and others, are investigating bispecific antibodies in Multiple Myeloma. Some of the companies are investigating non-BCMA targets, including FcRH5 and GPRC5D. J&J holds the lead among many bispecific antibodies being explored for Multiple Myeloma. Janssen's teclistamab is the first BCMA x CD3 bispecific to be filed to the FDA (filing in December 2021) and EMA (filing in January 2022) for approval in Multiple Myeloma. While teclistamab appears to be on track to become the first BCMA-targeting bispecific antibody to hit the market, Pfizer's elranatamab is closely following J&J's footsteps. In the registration MagnetisMM-3 trial, elranatamab was linked with an ORR of 60.6 percent after a median follow-up of just under four months; on the other hand, teclistamab's MajesTEC-1 study gave an ORR of 63%. Pfizer’s therapy has a competitive edge in terms of safety profile. The MagnetisMM-3 data show a 60% rate of CRS, compared to roughly 72% in the teclistamab trial. Because bispecific antibodies are off-the-shelf, readily available medicines, they are anticipated to become widely employed in the relapsed/refractory arena. In this area, ADC and CAR T-cell therapies are already available, but the inclusion of bispecific antibodies may provide patients with more options (different treatments will be appropriate for different patients). 

Companies- Oncopeptides, GlaxoSmithKline, Bluebird Bio, Janssen Pharmaceutical, Legend Biotech, AbbVie, Roche (Genentech), Bristol Myers Squibb, Regeneron Pharmaceuticals, Pfizer, Takeda, Amgen, SpringWorks Therapeutics, Arcellx, Gracell Biotechnologies, Oricell, Poseida Therapeutics, Precision Biosciences, CRISPR Therapeutics AG, Collectis SA, Allogene Therapeutics, Fortis Therapeutics, Novartis, I-Mab/MorphoSys, Cartesian Therapeutics, CASI Pharmaceuticals, LAVA Therapeutics, and others