On May 25, 2023 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported updated data from two Phase 2 expansion dose cohorts evaluating investigational linvoseltamab (formerly REGN5458) in patients with heavily pre-treated, relapsed/refractory (R/R) multiple myeloma (Press release, Regeneron, MAY 25, 2023, View Source [SID1234632072]). The results will be shared in an oral session at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the LINKER-MM1 trial will form the basis of planned submissions to regulatory authorities, including to the U.S. Food and Drug Administration (FDA) later this year. Linvoseltamab is an investigational BCMAxCD3 bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells to facilitate T-cell activation and cancer-cell killing.

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"Despite advances, new treatments are needed that drive meaningful and durable responses to help patients with relapsed and/or refractory multiple myeloma," said Hans Lee, M.D., Associate Professor and Director, Multiple Myeloma Clinical Research at The University of Texas MD Anderson Cancer Center. "Treatment with linvoseltamab at the recommended 200 mg dose in the LINKER-MM1 trial demonstrated impressive efficacy, with rapid, deep and durable responses in patients with multiple myeloma that’s highly refractory to standard therapies. Moreover, less than half of patients experienced any grade cytokine release syndrome, which was mostly Grade 1, with some Grade 2 and a single Grade 3 case. This reinforces the potential of linvoseltamab as a promising treatment option."

The new data to be presented at ASCO (Free ASCO Whitepaper) 2023 are from patients treated in the 50 mg (n=104) and 200 mg (n=117) cohorts of the Phase 1/2 trial. Initial results were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in December 2022. Among the 200 mg cohort, the median soluble BCMA (sBCMA) was 377 ng/mL, 22% had bone marrow plasma cells ≥50% and 36% had high-risk cytogenetics, representing a patient population with a high disease burden and poor prognosis. The primary endpoint was objective response rate (ORR) assessed by independent review committee, which will be available when the data are more mature. The secondary endpoints included ORR and other efficacy measures assessed by local investigator. With a median follow-up of 6 months, patients receiving the recommended 200 mg dose showed:

71% ORR, per local investigator.
59% achieved a very good partial response (VGPR) or better, with 30% achieving a complete response (CR) or stringent complete response (sCR), per local investigator. Based on earlier results, responses may deepen with longer follow-up.
Median time to onset of response was less than 1 month.
84% and 79% probability of maintaining a response at 6 and 12 months, respectively, per Kaplan-Meier estimates.
Median progression-free survival was not reached.
Strong efficacy per ORR was consistently observed in the 200 mg cohort across multiple subgroups, even in high risk patients such as adults ≥75 years of age (n=31; 68%), patients with International Staging System (ISS) stage II and III disease (n=44 and 22; 73% and 59% respectively), patients with extramedullary plasmacytomas (defined as disease without bone association, n=16; 56%) as well as patients with baseline sBCMA ≥400 ng/mL (n=51; 55%). Additionally, among patients treated with 50 mg and 200 mg that achieved CR or sCR with available minimal residual disease (MRD) data, 54% were MRD negative at 10-5.

No new safety signals were identified with longer follow-up in the Phase 1 or Phase 2 portions of the trial. Among all patients in the 200 mg cohort, 79% experienced Grade ≥3 adverse events (AE). Most commonly occurring AEs (in ≥20% of patients) were cytokine release syndrome (CRS; 45%), neutropenia, cough, fatigue and diarrhea (33% each), anemia (27%), arthralgia (26%), and headache (23%). Discontinuations due to an AE occurred in 16% of patients. Deaths due to treatment-emergent AEs, on-treatment or within 30 days post last dose, in the 200 mg cohort were reported in 6 patients. None of the deaths were considered related to treatment per the treating physician. Among the 200 mg cohort, the majority of CRS cases were mild or moderate, there was a single case of Grade 3 CRS, and no cases of ≥Grade 4 CRS. The median time to first CRS onset was 15 hours (range: 0-177 hours), with the median time to resolution within 1 day (17 hours; range: 1-144 hours). Among the 50 mg and 200 mg dose cohorts (n=221), there were 14 immune effector cell-associated neurotoxicity syndrome events (ICANS, 6% all Grades; 2% Grades 3-4).

"With these latest pivotal results, linvoseltamab demonstrated notable response rates, providing encouraging evidence for this bispecific antibody," said L. Andres Sirulnik, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Hematology at Regeneron. "We designed linvoseltamab with patient needs at the center and are proud that it has provided benefit across the spectrum of relapsed refractory multiple myeloma patients, even those with hard-to-treat disease. We look forward to sharing these data with regulatory authorities with the goal of bringing this medicine to patients with heavily pre-treated multiple myeloma as soon as possible."

Based on these data, the Phase 3 development program investigating linvoseltamab in earlier stages of the disease has been initiated. In the U.S., linvoseltamab has been granted Fast Track Designation for multiple myeloma by the FDA. Linvoseltamab is currently under clinical development, and its safety and efficacy have not been fully evaluated by any regulatory authority.

About the Phase 1/2 Trial
The ongoing, open-label, multicenter Phase 1/2 dose-escalation and dose-expansion trial is investigating linvoseltamab in patients with R/R multiple myeloma. Among the 282 patients enrolled, all have received at least three prior lines of therapy or are triple refractory. Patients were administered linvoseltamab utilizing a step-up dosing regimen that was designed to help mitigate CRS.

The Phase 1 dose-escalation portion of the trial, which is now complete, primarily assessed safety, tolerability and dose-limiting toxicities across 9 dose levels of linvoseltamab exploring different administration regimens. The fully-enrolled Phase 2 dose expansion portion of the trial is further assessing the safety and anti-tumor activity of linvoseltamab, with a primary objective of ORR. Key secondary objectives include duration of response, progression free survival, rate of minimal residual disease negative status and overall survival.

About Multiple Myeloma
Multiple myeloma is the second most common blood cancer. Globally, there were 176,404 new diagnoses in 2020 and 35,730 new diagnoses estimated for 2023 in the U.S. It is characterized by the proliferation of cancerous plasma cells (multiple myeloma cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Multiple myeloma is not curable despite treatment advances, and while current treatments are able to slow the progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies. In addition, patients are at increased risk of frequent infections, bone fracture and pain, reduced kidney function, and anemia.