FDA Gives Talquetamab Accelerated Approval for R/R Multiple Myeloma

The approval is based on results from the phase 1/2 MonumenTAL-1 trial (NCT03399799; NCT0463452), which assessed talquetamab, a first-in-class, off-the-shelf T-cell redirecting bispecific antibody against the GPRC5D and CD3 receptors.

The FDA has granted accelerated approval to talquetamab-tgvs (Talvey) for patients with relapsed/refractory multiple myeloma who have undergone at least 4 previous lines of therapy including a proteosome inhibitor, immunomodulatory agent, and anti-CD38 antibody, according to a press release from The Janssen Pharmaceutical Companies.¹

“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, MD, director of Multiple Myeloma Program and a professor of Clinical Medicine at the University of California, San Francisco. “Patients at this stage of the 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 approval is based on results from the phase 1/2 MonumenTAL-1 trial (NCT03399799; NCT0463452), which assessed talquetamab, a first-in-class, off-the-shelf T-cell redirecting bispecific antibody against the GPRC5D and CD3 receptors. The 0.8 mg/kg subcutaneous dose of the agent resulted in an overall response rate (ORR) of 73.6% (95% CI, 63.0%-82.4%). After a median follow-up of 6 months, the very good partial response rate (VGPR) was 58% and the complete response (CR) rate or better was 33%. Additionally, the corresponding ORR at the subcutaneous 0.4 mg/kg dose was 73.0% (95% CI, 63.2%-81.4%); the VGPR was 57% and the CR or better rate was 35% at a median follow-up of 14 months.

Responses were long lasting, with investigators reporting that the median duration of response was not reached at the 0.8 mg/kg dose level and 9.5 months with 0.4 mg/kg. A total of 85% of patients in the 0.8 mg/kg group continued to respond for a minimum of 9 months.

Eligibility criteria for the phase 1 portion of the study included patients who had progressed on or were intolerant to all available therapies. An ECOG performance status of 0 to 2 was also required. In the study’s second phase, patients needed to have received 3 or more prior therapies, and have an ECOG performance status of 0 to 2.²

Patients were given either talquetamab (n = 143) at 0.4 mg/kg or 0.8 mg/kg (n = 145). Additionally, there was a third cohort (n = 51) of patients—who were able to have previously received previous T-cell redirection therapy—who could receive either dose level.

In a previous publication of the study,² between the 0.4 mg/kg and 0.8 mg/kg cohorts, the median patient age was 67 years, with 31.1% vs 28.9% having high-risk cytogenetics, respectively. Additionally, 93.0% of patients in the 0.4 mg/kg arm and 92.4% in the 0.8 mg/kg arms were previously exposed to an anti-CD38 monoclonal antibody, with 74.1% vs 69.0% being refractory to 3 classes of drug, respectively.

Investigators reported an objective response rate (ORR) of 74.1% in the 0.4 mg/kg group and the 0.8 mg/kg group of 73.1%. In the 0.4 mg/kg group. A total of 23.8% of patients achieved a stringent complete response (sCR), 9.8% had a CR, 25.9% had a very good partial response (VGPR), and 14.7% had a partial response (PR). Corresponding rates in the 0.8 mg/kg group were 20.0%, 12.4%, 24.8%, and 15.9%. The median duration of response (DOR) had not been reached at the time of the data read out.

Additionally, 70.6% of the population received prior CAR T-cell therapy, 35.3% had a prior bispecific antibody, and 7.8% were belantamab (Blenrep) refractory. Of those who received prior T-cell redirection, the ORR was 62.7%. This included a sCR rate of 17.6%, a CR rate of 5.9%, a VGPR rate of 29.4%, and a PR rate of 9.8%. The median DOR was 12.7 months.

In the 0.4 mg/kg arm, the median progression-free survival was 7.5 months (95% CI, 5.7-9.4), and it was 11.9 months (95% CI, 8.4-not estimable) in the 0.8 mg/kg arm.

The most common hematologic adverse effects (AEs) overall were cytopenia. Regarding grade 3/4 AEs, the most common were anemia (31.5% vs 24.8%), neutropenia (30.8% vs 22.1%), lymphopenia (25.9% vs 25.5%), and thrombocytopenia (20.3% vs 16.6%) in the 0.4 mg/kg and 0.8 mg/kg groups, respectively.

A total of 57.3% of patients in the 0.4 mg/kg group and 50.3% in the 0.8 mg/kg group experienced infections, 16.8% and 11.7% of which were high-grade, respectively. In each respective treatment arm, 13 patients and 16 patients contracted COVID-19, and 2 patients died.

While there was a low rate of discontinuation, the majority of patients discontinued because of cytokine release syndrome (CRS), with most events being grade 1/2. Investigators noted that the incidence of grade 3/4 skin, nail, and rash toxicities was low.

Immune-effector cell-associated neurotoxicity syndrome occurred in 10% of patients in the 0.4 kg/mg group and 11% in the 0.8 mg/kg group, with most events being low-grade.

Additionally, common any-grade AEs in the 0.4 mg/kg arm included CRS (79.0%) and skin AEs (55.9%); grade 3/4 AEs included fatigue (3.5%) and pyrexia (2.8%). In the 0.8 kg/mg group, any-grade AEs were CRS (72.4%), skin AEs (67.6%), and dysgeusia (46.2%), and grade 3/4 AEs were rash (5.5%) and dysphagia (2.1%).

References

1. U.S. FDA approved TALVEY (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. The Janssen Pharmaceuticals. August 10, 2023. Accessed August 10, 2023. https://prn.to/3KwnjyD
2. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Blood. 2022; 140(suppl 1):384-387. doi.10.1182/blood-2022-159707