The Janssen Pharmaceutical Companies of Johnson & Johnson have announced that the U.S. Food and Drug Administration (FDA) has 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 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. Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trial(s).
TALVEY is a bispecific T-cell engaging antibody that binds to the CD3 receptor on the surface of T cells and G protein-coupled receptor class C group 5 member D (GPRC5D) expressed on the surface of multiple myeloma cells, non-malignant plasma cells and healthy tissue such as epithelial cells in keratinised tissues of the skin and tongue. TALVEY is approved as a weekly or biweekly subcutaneous (SC) injection after an initial step-up phase, offering physicians the flexibility to determine the optimal treatment regimen for patients.
“The clinically meaningful efficacy and safety profile observed with talquetamab in heavily pretreated patients in this clinical trial, which included patients treated with prior BCMA-targeted bispecific or CAR-T cell therapy, has been notable,” said Ajai Chari, M.D., Director of Multiple Myeloma Program, Professor of Clinical Medicine at the University of California, San Francisco. “Patients at this stage of disease have a poor prognosis. Talquetamab as a first-in-class therapy is a new option for patients with this difficult-to-treat blood cancer.”
The talquetamab Phase 2 MonumenTAL-1 study, which included patients who had received at least four prior lines of therapy and who were not exposed to prior T-cell redirection therapy (n=187), showed meaningful overall response rates (ORR). At the SC biweekly dose of 0.8 mg/kg, 73.6 percent of patients (95 percent Confidence Interval [CI], range, 63.0 to 82.4) achieved an ORR. With a median follow-up of nearly 6 (range, 0 to 9.5) months from first response among responders, 58 percent of patients achieved a very good partial response (VGPR) or better, including 33 percent of patients achieving a complete response (CR) or better. At the SC weekly dose of 0.4 mg/kg, 73.0 percent of patients (95 percent 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 percent of patients achieved a VGPR or better, including 35 percent 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 percent of responders maintained response for at least 9 months.
The MonumenTAL-1 study also included 32 patients who were exposed to prior bispecific antibody or CAR-T cell therapy (94 percent B-cell maturation antigen [BCMA]-directed therapy) and had received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, received TALVEY at the 0.4 mg/kg SC weekly dose. With a median duration of follow-up of 10.4 months, 72 percent of patients (95 percent CI, range, 53 to 86) achieved an ORR per an Independent Review Committee assessment, and an estimated 59 percent of responders maintained response for at least 9 months.
The Safety Profile for TALVEY includes a Boxed Warning for cytokine release syndrome (CRS) and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS); Warnings and Precautions include Oral Toxicity and Weight Loss, Infections, Cytopenias, Skin Toxicity, Hepatoxicity and Embryo-fetal toxicity. The most common adverse reactions (≥20 percent) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥30 percent) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.
"Although options for the treatment of multiple myeloma have expanded significantly in recent years, the disease remains incurable, and therefore, patients are in need of new treatment options,” said Michael Andreini, President and Chief Executive Officer, Multiple Myeloma Research Foundation. “Today’s approval of talquetamab provides patients with a new treatment approach for relapsed or refractory disease that is a welcome addition to the myeloma community.”
TALVEY is available only through a restricted program called the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy (REMS). Details of the Important Safety Information are included below.
The most common non-hematologic adverse events observed in the study were oral toxicities, which occurred in 80 percent of patients, with Grade 3 occurring in 2.1 percent of patients. The most frequent oral toxicities were dysgeusia (49 percent), dry mouth (34 percent), dysphagia (23 percent), and ageusia (18 percent). In addition, 62 percent of patients experienced weight loss, including 29 percent with Grade 2 weight loss and 2.7 percent with Grade 3 weight loss. Serious infections occurred in 16 percent of patients, with fatal infections occurring in 1.5 percent of patients. Grade 3 or 4 serious infections occurred in 17 percent of patients. Grade 3 or 4 decreased neutrophils occurred in 35 percent of patients and decreased platelets occurred in 22 percent of patients. Skin reactions occurred in 62 percent of patients, with Grade 3 skin reactions in 0.3 percent. Permanent discontinuation of TALVEY due to an adverse reaction occurred in 9 percent of patients.
About the MonumenTAL-1 Study
MonumenTAL-1 (Phase 1: NCT03399799, Phase 2: NCT04634552) is a Phase 1/2 single-arm, open-label, multicohort, multicenter dose-escalation study involving over 300 patients. Phase 1 evaluated the safety and efficacy of TALVEY in adults with relapsed or refractory multiple myeloma who received three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who experienced T-cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T-cell redirection therapy, an autologous stem cell transplant within the past 12 weeks, an allogenic stem cell transplant within the past 6 months, Eastern Cooperative Oncology Group (ECOG) performance score of 3 or higher, stroke or seizure within the past 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, and plasma cell leukemia, active or documented history of autoimmune disease (exception of vitiligo, resolved childhood atopic dermatitis or resolved Grave’s Disease that is euthyroid based on clinical and laboratory testing).
Phase 2 of the study evaluated the efficacy of TALVEY in participants with relapsed or refractory multiple myeloma at the recommended Phase 2 dose(s) (RP2Ds), established at SC 0.4 mg/kg weekly and 0.8 mg/kg every two weeks, respectively. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an Independent Review Committee using IMWG criteria.