Oncology

Linvoseltamab, intravenous (IV)

Regeneron Pharmaceuticals

Proposed indications

Relapsed/refractory multiple myeloma (RRMM)

United States (U.S.) Food and Drug Administration (FDA) approval timeline

Aug. 22, 2024

• Fast track
• Priority review

Place in therapy

Linvoseltamab is a bispecific T-cell-engaging antibody that links B-cell maturation antigen (BCMA), which is highly expressed on multiple myeloma (MM) cells, with cluster of differentiation 3 (CD3)-expressing T cells. This mechanism promotes T-cell activation and subsequent cancer cell death.

• In the clinical trial studying linvoseltamab for RRMM, patients receiving linvoseltamab 200 mg transitioned to every-four-week dosing if they reached a very good partial response (VGPR) or higher and had received at least 24 weeks of treatment.
• If approved, linvoseltamab will enter a treatment landscape in which similar treatment options exist: Talquetamab-tgvs (Talvey), teclistamab-cqyv (Tecvayli) and elranatamab-bcmm (Elrexfio) are FDA approved bispecific T-cell engagers (BiTEs) for the treatment of RRMM after at least four lines of therapy and are given via subcutaneous (SC) injection. Talquetamab-tgvs (Talvey), teclistamab-cqyv (Tecvayli) and elranatamab-bcmm (Elrexfio) all have options for up to every-two-week dosing. If approved with the option of up to every-four-week dosing, linvoseltamab could potentially be dosed less frequently than the other BiTEs. Additionally, the chimeric antigen receptor (CAR)-T therapies ciltacabtagene autoleucel (Carvykti) and idecabtagene vicleucel (Abecma) are approved for RRMM after at least one and two lines of therapy, respectively.
• In the clinical trial, treatment with linvoseltamab 200 mg resulted in high rates of durable responses, which included select high-risk and high disease burden patient subpopulations. Although an indirect comparison, the overall response rate (ORR) for linvoseltamab was 71%, which differs from the 74%, 62%, 58%, 85% and 71% ORR seen in the RRMM trials for talquetamab-tgvs (Talvey) (biweekly), teclistamab-cqyv (Tecvayli), elranatamab-bcmm (Elrexfio), ciltacabtagene autoleucel (Carvykti) (at least one prior line of therapy) and idecabtagene vicleucel (Abecma) (at least two prior lines of therapy), respectively.
• The rate of cytokine release syndrome (CRS) was 46% in the linvoseltamab 200 mg group, and it occurred in 76%, 72%, 58%, 78% and 91% of patients in the talquetamab-tgvs (Talvey), teclistamab-cqyv (Tecvayli), and elranatamab-bcmm (Elrexfio), ciltacabtagene autoleucel (Carvykti) and idecabtagene vicleucel (Abecma) trials, respectively — although no head-to-head trials were completed.
• A phase III confirmatory trial studying linvoseltamab in RRMM is ongoing (LINKER-MM3).
• Current and future trials involving linvoseltamab include use in the following settings: first-line for MM, high-risk smoldering MM, combination therapy for MM, monoclonal gammopathy of undetermined significance, relapsed or refractory systemic light chain amyloidosis, immunoglobulin E (IgE)-mediated food allergy in combination with dupilumab (Dupixent) and monotherapy in patients with chronic kidney disease who need kidney transplantation and are highly sensitized to human leukocyte antigen (HLA).

Understanding your data

Linvoseltamab is an anti-BCMA x anti-CD3 bispecific antibody (BCMAxCD3 bsAb). It functions by binding to both BCMA located on plasma cells as well as CD3 located on T-cells, resulting in T-cell activation and subsequent myeloma cell death. The following are clinical trials evaluating linvoseltamab in MM:

• NCT03761108: Phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients with Relapsed or Refractory Multiple Myeloma
• NCT05730036: An Open-label, Randomized, Phase 3 Study of Linvoseltamab (REGN5458; Anti-BCMA x Anti-CD3 Bispecific Antibody) Versus the Combination of Elotuzumab, Pomalidomide, and Dexamethasone (EPd), in Patients with Relapsed/Refractory Multiple Myeloma (LINKER-MM3)
• NCT05137054: Phase Ib Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) Plus Other Cancer Treatments for Patients with Relapsed/Refractory Multiple Myeloma

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

• Patients aged ≥ 18 years old
• Diagnosis of MM
• History of use of at least one of each of the following drug categories:
  • Proteasome inhibitor (PI)
  • Immunomodulatory agent (IMiD)
  • Anti-CD38 antibody

Common measurable exclusion criteria:

• Diagnosis of any of the following:
  • Plasma cell leukemia
  • Primary systemic light-chain amyloidosis (excluding myeloma-associated amyloidosis)
  • Waldenström macroglobulinemia (lymphoplasmacytic lymphoma)
• History of allogenic stem cell transplant at any time
• History of autologous stem cell transplantation within 12 weeks of the start of treatment
• History of CAR-T therapy within 60 days of linvoseltamab treatment

Appendix

Clinical deep dive

Disease state overview

MM is a malignant B-cell neoplasm characterized by uncontrolled, harmful growth of mutated plasma cells. Plasma cells, which are located within bone marrow, are a type of white blood cell that produces antibodies (immunoglobulins) that help the immune system recognize and attack foreign substances, such as bacteria and viruses. In MM, the plasma cells overgrow and overcrowd normal blood-forming cells. This can lead to anemia, thrombocytopenia and leukopenia. The mutated plasma cells found in this disease cause a production of abnormal antibodies known as monoclonal immunoglobulin (M-protein), thus increasing risk of infection. Bone loss is a potential complication of this neoplasm that is driven by activation of osteoclasts and inhibiton of osteoblasts. Because there is breakdown of bone, patients may also experience hypercalcemia and bone pain. Additionally, patients with MM may also present with renal insufficiency due to the production of harmful immunoglobulins.

Epidemiology

The prevalence of MM in the United States was estimated to be approximately 179,063 patients in 2021. In 2024, it is projected that there will be 35,780 new cases and an estimated 12,540 deaths. In the United States, it was estimated that there were approximately 21,490 people diagnosed with MM that were treated with three or more lines of therapy in 2020. It is the second most commonly diagnosed blood cancer, is more common in men than in women and is twice as likely to occur in Black people than in white people. Although the exact cause is unknown, age is a significant risk factor. Most patients who are diagnosed with MM are 65 or older, with less than 1% of cases found in patients less than 35 years of age. Being overweight is another risk factor. The five-year survival rate for localized (one tumor growing in/outside of bone) and distant (classic MM with several tumors found inside or outside bones) disease is 79% and 57%, respectively. Most patients (96%) are diagnosed with distant classification.

Treatment

At the present time, there is no cure for MM, but there are several different treatment options to manage the disease. The goals of therapy are to decrease M-protein levels or light chains, eradicate myeloma cells from the bone marrow, improve quality of life, provide a sustained duration of response, and prolong survival. Drug therapy classes used to manage MM include: chemotherapy, corticosteroids, immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (against SLAMF7 and CD38), BiTEs, nuclear export inhibitors and CAR-T cell therapy. Autologous stem cell tranplants are also commonly performed for eligible patients. In patients with symptomatic MM, primary therapy is initially recommended with an assessment for stem cell transplant status; in transplant-eligible patients, high-dose chemotherapy with autologuous hematopoietic cell transplant (HCT) are then given followed by maintenance therapy per the National Comprehensive Cancer Network (NCCN) guidelines. Standard therapy usually includes a three-drug regimen that often is comprised of a targeted therapy (e.g., proteasome inhibitor, monoclonal antibody), an immunomodulator and a corticosteroid, but therapies vary depending on individual patient characteristics. As the disease progresses, patients may experience phases of remission and relapse. For patients with previously treated MM, therapy selection may depend upon the patient’s prior treatment and duration of response. Typically, patients will have shorter periods of remission as the cancer advances and may become refractory to three key classes of drugs used to treat MM (PIs, IMiDs, and anti-CD38 antibodies).

Drug and clinical trial overview

The open-label phase 1/2 LINKER-MM1 trial evaluated linvoseltamab in adult patients with RRMM that progressed on/after three or more lines of therapy (including a PI, IMiD and an anti-CD38 antibody) or who had triple-class refractory disease in the phase II portion of the trial (refractory to an IMiD, a PI and an anti-CD38 antibody). A step-up regimen was used prior to the first full dose to reduce the incidence and severity of CRS. In the phase II portion of the clinical trial, patients received linvoseltamab (50 or 200 mg) administerd IV once weekly through week 14 then once every two weeks thereafter. After 24 weeks, if patients in the linvoseltamab 200 mg group of the phase II portion achieved a VGPR or better, they transitioned to every four week dosing. The primary endpoint of the trial assessed ORR. The secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). For the 117 patients enrolled into the 200 mg arm, the median duration of follow-up was 14.3 months. The ORR was 71%, with 50% of patients achieving a complete response (CR) or better, and 63% of patients achieving a VGPR or better. The estimated median DOR was 29 months and estimated median overall survival was 31 months; median PFS was not reached. The estimated probability of ongoing response, progression free survival, and overall survival at twelve months were 81%, 70% and 75%, respectively. Cytokine release syndrome, neutropenia and anemia were the most common treatment-emergent adverse events (TEAEs), and 74% of patients developed infections while immune effector cell-associated neurotoxicity (ICANS) occurred in approximately 8% of patients.

Pipeline (late-stage development)