Talquetamab Shines Bright: Impressive Overall Response Rates Achieved Across All Cohorts

Talquetamab is an innovative antibody that is currently being studied as a potential treatment for multiple myeloma. It is unique in that it targets two specific proteins: GPRC5D, found in high levels on multiple myeloma cells, and CD3, a key component of the T-cell receptor responsible for activating T cells. By binding to both GPRC5D and CD3, talquetamab aims to enhance the immune response against multiple myeloma cells.

Recently, the updated findings from the pivotal MonumenTAL-1 clinical trial were presented at the ASCO 2023 conference. The trial included two phases with different criteria for patient eligibility. In Phase I, patients who were either intolerant to or had shown progression on established therapies were included. In Phase II, patients who had received three or more prior lines of therapy, including at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody, were eligible.

During the trial, the patients were administered talquetamab subcutaneously at recommended Phase II dose (RP2D) levels. These levels were either 0.4 mg/kg once a week or 0.8 mg/kg once every two weeks, with step-up doses as required. The severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was evaluated using the criteria established by the American Society for Transplantation and Cellular Therapy (ASTCT).

As of January 2023, the overall response rate (ORR) of talquetamab treatment was observed to be 74.1% when administered once a week (QW), 71.7% when administered once every two weeks (Q2W), and 64.7% in patients who had previously received T-cell redirection therapy (TCR). Among patients who had received TCR prior to talquetamab treatment, the ORR was 75% in patients who had previously undergone CAR-T therapy, and in those who had received bispecific antibody (BsAb) therapy before, the ORR was 44.4%. These results demonstrate the potential effectiveness of talquetamab in patients who have received different types of prior therapies, including TCR, CAR-T, and BsAb.

The overall response rate (ORR) observed in the talquetamab clinical trial remained consistent across various subgroups, including patients with advanced ISS stage III disease, different cytogenetic risk profiles, varying numbers of prior lines of therapy (LOT), and exposure to the drug belantamab.

Among patients with baseline plasmacytomas, the ORR was found to be 49% in both pivotal cohorts of the trial. In the cohort of patients who had previously undergone T-cell redirection therapy, the ORR was 63%, with 53% achieving a very good partial response (VGPR) or better. The median follow-up period for this subgroup was 11.8 months.

The median progression-free survival (PFS) for patients receiving talquetamab once a week (QW) was 7.5 months, while it was 11.9 months in the Q2W cohort, with 61% of patients having their progression censored. In the subgroup of patients who had previously undergone T-cell redirection therapy, the median PFS was 5.1 months.

Common adverse events (AEs) observed during the talquetamab clinical trial included cytokine release syndrome (CRS), skin-related AEs, nail-related AEs, and dysgeusia (altered sense of taste). These AEs resulted in dose reductions in 14.7% of patients receiving talquetamab once a week (QW), 8.3% of patients receiving it once every two weeks (Q2W), and 9.8% of patients in the prior T-cell redirection (TCR) cohort. Furthermore, 4.9% of patients in the QW cohort, 8.3% in the Q2W cohort, and 7.8% in the prior TCR cohort discontinued the treatment due to AEs.

Most adverse events (AEs) observed during the talquetamab clinical trial were Grade 1 or 2 and clinically manageable. Infections occurred in 58% of patients receiving talquetamab once a week (QW), 65% of patients receiving it once every two weeks (Q2W), and 71% of patients in the prior T-cell redirection (TCR) cohort. Among these infections, Grade 3 or 4 infections were reported in 22% of patients in the QW cohort, 16% in the Q2W cohort, and 26% in the prior TCR cohort, with low rates of opportunistic infections.

AEs resulted in dose reductions in 15% of patients in the QW cohort, 8% in the Q2W cohort, and 10% in the prior TCR cohort. Additionally, 5% of patients in the QW cohort, 8% in the Q2W cohort, and 6% in the prior TCR cohort discontinued the treatment due to AEs. Importantly, there were no deaths related to talquetamab reported in the trial.

Overall, the observed AEs were generally manageable, with the majority being mild or moderate in severity. Infections were relatively common, but the rates of severe infections were relatively low, and there were no deaths directly attributed to talquetamab treatment.

KOL insights

“Through our discovery and development of talquetamab, a novel GPRC5DxCD3 bispecific antibody, we remain relentlessly committed to the investigation of innovative therapies for patients and oncologists. We look forward to working closely with the FDA in their review of the talquetamab submission.” –Expert Opinion.

Conclusion

With a median follow-up ranging from 13 to 19 months, talquetamab has consistently shown significant and long-lasting responses in patients, including those who had previously undergone T-cell redirection therapy (TCR). The drug's impact on severe infections and neutropenia were relatively modest, indicating a distinct adverse event profile compared to other novel immune therapies. These findings support the need for further investigation of talquetamab, including exploring its potential in combination with other treatments.

Exciting developments surround talquetamab as it progresses toward potential approval for the treatment of relapsed or refractory multiple myeloma. Janssen has submitted a Biologics License Application (BLA) based on the promising results from the MonumenTAL-1 study. The momentum continues for talquetamab, as it has received Breakthrough Therapy designation from the US Food and Drug Administration (FDA) targeting adult patients who have already received a remarkable four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Additionally, talquetamab has received PRIME (PRIority MEdicines) designation from the European Commission, highlighting its potential as a significant therapeutic advance. 

These designations and submissions reflect the growing recognition of talquetamab's potential as a groundbreaking therapy in the field of multiple myeloma. They demonstrate a commitment to advancing innovative treatments and offer hope to patients and healthcare professionals alike