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Elranatamab-bcmm (Elrexfio) approved for multiple myeloma

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On August 14, 2023, the Food and Drug Administration (FDA) granted accelerated approval to elranatamab-bcmm (Elrexfio, Pfizer, Inc.) for adults with relapsed or refractory multiple myeloma (r/r MM) who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The biologics license application (BLA) for elranatamab was granted priority review, breakthrough designation and orphan drug designation by FDA.

Elranatamab (PF-06863135) is a humanized IgG2a T cell-engaging bispecific antibody designed to target BCMA, which is highly expressed on tumor cells, and CD3 found on the T cell surface. Developed by Pfizer, elranatamab is formulated for subcutaneous, rather than intravenous, administration. The recommended elranatamab-bcmm dosages include the following: “step-up dose 1” of 12 mg on Day 1, “step-up dose 2” of 32 mg on Day 4, followed by the first treatment dose of 76 mg on Day 8, and then 76 mg weekly, thereafter, through week 24.

The prescribing information for elranatamab-bcmm includes a Boxed Warning for life threatening or fatal cytokine release syndrome and neurologic toxicity. Elrexfio is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the ELREXFIO REMS.

Elranatamab’s efficacy was evaluated in MagnetisMM-3 (NCT04649359), a Phase 2, open-label, single-arm, multi-center study that included patients with r/r MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody. Patients had measurable disease by International Myeloma Working Group (IMWG) criteria at enrollment. The main efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review based on IMWG criteria. The primary efficacy population consisted of 97 patients naïve to prior BCMA-directed therapy and who had previously received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The ORR in the 97 patients receiving the recommended dose was 57.7% (95% CI: 47.3%, 67.7%). With a median follow-up of 11.1 months among responders, the median DOR was not reached (95% CI: 12 months, not reached). The DOR rate at 6 months was 90.4% (95% CI: 78.4%, 95.9%) and at 9 months was 82.3% (95% CI: 67.1%, 90.9%).

FDA’s BLA review was conducted under Project Orbis, which provides a framework for concurrent submission and review of oncology drugs among international partners. The Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Swissmedic collaborated with FDA in the review process, and are continuing to review marketing applications for elranatamab.

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FDA approves TALVEY™ (talquetamab-tgvs)

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On August 9, 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval of TALVEY™ (talquetamab-tgvs), a first-in-class bispecific antibody for the treatment of adult patients with relapsed or refractory multiple myeloma (r/r MM) who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. This indication is approved under accelerated approval based on response rate and durability of response, and continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trial(s).

TALVEY™ is approved as a weekly or biweekly subcutaneous (SC) injection after an initial step-up phase. The TALVEY™ prescribing information includes a Boxed Warning for cytokine release syndrome and neurologic toxicity. The drug is available only through a restricted program called the TECVAYLI® and TALVEY™ Risk Evaluation and Mitigation Strategy

Talquetamab (JNJ-64407564) is a humanized, hinge-stabilized IgG4k/l T-cell engaging bispecific antibody with reduced effector function developed by Janssen. The antibody targets G protein-coupled receptor class C group 5 member D (GPRC5D), which is highly expressed in malignant plasma cells, and CD3 on T cells. TALVEY™ was granted Orphan Drug Designation for the treatment of MM by the U.S. FDA and the European Commission. The drug was also granted Breakthrough Therapy designation by the FDA for use in patients with r/r MM based on results of the MonumenTAL-1 study.

FDA’s approval was based on the single-arm, open-label, multicenter MonumenTAL-1 study (NCT03399799, NCT04634552), which evaluated the efficacy of TALVEY monotherapy in patients with r/r MM. Patients treated with the weekly dosing schedule received step-up doses of 0.01 mg/kg and 0.06 mg/kg of TALVEY followed by TALVEY 0.4 mg/kg subcutaneously weekly thereafter. Patients treated with the biweekly dosing schedule received step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg (0.75 times the recommended step-up dose 3) of TALVEY followed by TALVEY 0.8 mg/kg subcutaneously biweekly, thereafter. Patients on both dosing schedules were treated until disease progression or unacceptable toxicity. According to the prescribing information, at the SC biweekly dose of 0.8 mg/kg, 73.6% of patients (95% Confidence Interval [CI], range, 63.0 to 82.4) achieved an overall response rate (ORR). With a median follow-up of nearly 6 (range, 0 to 9.5) months from first response among responders, 58% of patients achieved a very good partial response (VGPR) or better, including 33% of patients achieving a complete response (CR) or better. At the SC weekly dose of 0.4 mg/kg, 73.0% of patients (95% CI, range, 63.2 to 81.4) achieved an ORR. With a median follow-up of nearly 14 (range, 0.8 to 15.4) months from first response among responders, 57% of patients achieved a VGPR or better, including 35% of patients achieving a CR or better. Responses were durable with a median duration of response not reached in the 0.8 mg/kg SC biweekly dose group and 9.5 months in the 0.4 mg/kg SC weekly dose group. Among patients receiving the 0.8 mg/kg SC biweekly dose, an estimated 85% of responders maintained response for at least 9 months.

Talquetamab is being evaluated in a randomized Phase 3 study (MonumenTAL-1; NCT05455320) comparing the efficacy of talquetamab SC in combination with daratumumab SC or in combination with daratumumab and pomalidomide vs daratumumab SC in combination with pomalidomide and dexamethasone in patients with r/r MM. Initiated in October 2022, the study has an estimated enrollment of 810 and an estimated primary completion date in February 2026.

FDA approves teclistamab (Tecvayli) for relapsed or refractory multiple myeloma

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On October 25, 2022, the Food and Drug Administration granted accelerated approval to teclistamab-cqyv (Tecvayli, Janssen Biotech, Inc.) for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Teclistamab (TECVAYLI) is a T-cell redirecting IgG4λ bispecific antibody recognizing BCMA on target cells and CD3e on T cells. Generated from Ligand’s transgenic mouse (OmniAb) and Genmab’s DuoBody technology, the Fc was engineered with the stabilizing S228P mutation and L234A/L235A mutations to minimize its effector functions. Teclistamab was granted Orphan Drug designations for the treatment of MM in both the US and EU, and received the Breakthrough Therapy designation for the treatment of relapsed or refractory MM (RRMM) by the FDA, and a PRIority MEdicines (PRIME) designation by the EMA for treatment of adult patients with RRMM who previously received ≥3 prior lines of therapy. TECVAYLI (teclistamab) was granted conditional marketing authorization in the EU as monotherapy for the treatment of adult RRMM patients who previously received ≥3 prior lines of therapy in August 2022.

The authorizations for marketing were based on the results from the multicohort, open-label, Phase 1 and Phase 2 MajesTEC-1 studies (NCT03145181, NCT04557098, respectively), evaluating the safety and efficacy of teclistamab in adults with RRMM. The ongoing first-in-human dose escalation and dose expansion clinical study (NCT03145181) is assessing the efficacy of teclistamab in patients with RRMM, with the antibody administered IV (range: 0.3−19.2 μg/kg [once every 2 weeks] or 19.2−720 μg/kg [once per week]) or subcutaneously (range: 80−3000 μg/kg [once per week]) in different cohorts, with step-up dosing for 38.4 μg/kg or higher doses. Based on the dose escalation data, in the Phase 2 portion of the study patients received a weekly subcutaneous dose of teclistamab (1.5 mg/kg), after receiving step-up doses of 0.06 mg/kg and 0.3 mg/kg. Results of the MajesTEC-1 study showed that teclistamab induced durable responses that deepened over time in patients with triple-class exposed RRMM (n=165), with an overall response rate of 63%, including a complete response in 39.4% of the patients. The median duration of response and duration of progression-free survival were 18.4 months (95% confidence interval [CI], 14.9 to not estimable) and 11.3 months (95% CI, 8.8 to 17.1), respectively. Adverse events were consistent with this patient population and toxicities consistent with T-cell redirection were mostly Grade 1/2.

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