Janssen's First-in-Class GPRC5D/CD3 Bispecific Antibody Talquetamab Granted CDE Breakthrough Therapy Designation for Relapsed/Refractory Multiple Myeloma

On March 31, Johnson & Johnson's GPRC5D/CD3 bispecific antibody Talquetamab was granted Breakthrough Therapy Designation by the CDE for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

Talquetamab is an investigational first-in-class off-the-shelf bispecific T-cell engager antibody that can simultaneously target GPRC5D on MM cells and CD3 on T cells. GPRC5D, known as a G protein-coupled orphan receptor, is a novel drug target that is overexpressed on malignant plasma cells, with its expression limited to the skin (hair follicles and eccrine sweat glands) and testes (seminiferous tubules) in normal tissues. Its expression level is relatively independent of the BCMA target. Talquetamab activates CD3-positive T cells, inducing T-cell-mediated killing of GPRC5D-positive MM cells.

Previously, Johnson & Johnson had submitted a marketing application to the FDA based on the results of the Phase I/II MonumenTAL-1 study. This study aims to evaluate the efficacy of subcutaneous injection of Talquetamab in treating R/R MM patients who have previously received more than three lines of therapy. The results of the Phase II portion of this study were also presented at the ASH conference held on December 10.

The study results showed that, in patients receiving 0.4mg/kg QW (once weekly) treatment, the median follow-up time was 14.9 months (range 0.5–29.0), ORR was 74.1%, 59.4% of patients achieved very good partial response (VGPR) or better, 33.6% achieved complete response (CR) or better, and 23.8% achieved stringent complete response (sCR). The median duration of response (mDoR) was 9.3 months (95% CI, 6.6–20.2). The median progression-free survival (mPFS) was 7.5 months (95% CI 5.7–9.2).

The ORR was similar between the two dose groups of Talquetamab. In the 0.8 mg/kg Q2W (once every two weeks) dose group, with a median follow-up of 8.6 months (range 0.2-22.5), the ORR was 73.1% (≥VGPR: 57.2%, ≥CR: 32.4%, sCR: 20%). Due to the shorter follow-up time in the 0.8 mg/kg Q2W dose group, the median PFS has not yet matured. In subgroup analyses, there were no significant differences in ORR, including prior treatment regimens, refractoriness to prior treatments, and cytogenetic risk.

Another cohort evaluated the efficacy of two doses of Talquetamab following prior T-cell redirection therapy (CAR-T or CD3 bispecific antibodies). With a median follow-up of 11.8 months (range 1-25.4), 62.7% of patients who had previously received T-cell redirection therapy achieved a response. The ORR for patients previously treated with CAR-T cells was 72.2% (95% CI, 54.8-85.8), and the ORR for those previously treated with bispecific antibodies was 44.4% (95% CI, 21.5-69.2). The safety profile was similar between patients who did and did not receive prior T-cell redirection therapy.

In terms of safety, the most common adverse events (AEs) at the 0.4mg/kg QW dose were cytokine release syndrome (CRS) (79%; Grade 3/4: 2.1%), skin-related AEs (55.9%; all Grade 1/2), and nail-related AEs (51.7%; all Grade 1/2).

The most common adverse events at the 0.8mg/kg Q2W dose were CRS (72.4%; 3/4 grade: 0.7%), skin-related AES (67.6%; 3/4 grade: 0.7%), and psychiatric disorders (46.2%; not applicable). CRS events were mostly grade 1/2, primarily limited to the dose-escalation phase and the first full dose.

Talquetamab was granted Breakthrough Therapy Designation by the U.S. FDA in June 2022 for the treatment of adult patients with R/R MM who have previously received at least four prior lines of therapy, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies. In May 2021 and August 2021, Talquetamab was designated as an orphan drug for the treatment of multiple myeloma by the U.S. FDA and the European Commission, respectively. In January 2021, Talquetamab received PRIME designation from the European Commission.

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