FDA Grants Breakthrough Therapy Designation to Talquetamab for R/R Myeloma

The FDA has granted breakthrough therapy designation to talquetamab for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, according toa press release by The Janssen Pharmaceutical Companies of Johnson & Johnson.¹

"This Breakthrough Therapy Designation marks an important step in the continued development of talquetamab, a first-in-class bispecific antibody T-cell engager using GPRC5D, a novel target for the treatment of patients with relapsed or refractory multiple myeloma," said Sen Zhuang, MD, PhD, vice president, Clinical Research and Development, Janssen Research & Development, LLC, the press release.

Talquetamab is an investigational, off-the-shelf, T-cell redirecting bispecific antibody. The agent targeted the novel biomarker GPRC5D on multiple myeloma cells and CD3 on T-cells. In preclinical models, T-cell mediated killing of GPRC5D-expressing multiple myeloma cells was induced with talquetamab treatment by way of recruiting and activating CD3-positive T-cells and inhibiting tumor formation and growth.

Data from the phase 1/2 first-inhuman, dose-escalation MonumenTAL-1 study of talquetamab in patients with heavily pretreated r/r multiple myeloma support the breakthrough therapy designation (NCT04634552). The study showed that talquetamab was well-tolerated and highly effective at recommended phase 2 doses.

Out of 95 patients, 30 received 405 µg/kg of talquetamab, and 23 received 800 µg/kg of talquetamab. At a median follow-up of 7.5 months (range, 0.9-15.2), the overall response rate (ORR) was 70%, and 57% of the responses observed were very good partial response. Of the patients who were administered 800 µg/kg of talquetamab, 17 were response evaluable. The higher-dose cohort had an ORR of 71% with VGPRs in 53% of patients. The median duration of response was not reached at either dose level. At 6 months, the DOR rate was 67% (95% CI, 41%-84%) in the 405 µg/kg-dose cohort.

MonumenTAL-1 is ongoing and actively recruiting patients. The study aims to enroll 320 patients with r/r multiple myeloma. Cohort A will include patients who have previously received or more prior lines of therapy and have not been exposed to T cell redirection therapies. In cohort B, the study will enroll patients who have previously received 3 or more prior lines of therapy and have been exposed to T cell redirection therapies. In the final cohort (cohort C), the study will enroll patient with who have previously received 3 or more prior lines of therapy and have not been exposed to T cell redirection therapies. In all cohorts, patients with received a subcutaneous dose of talquetamab until disease progression.²

The primary end point of the study is ORR, and the secondary end points include, DOR, VGPR, complete response (CR) or better rate, stringent CR rate, time to response, progression-free survival, overall survival, minimal residual disease negative rate, the number of patients with adverse events or serious AEs, the number of patients with labortatory abnormalities. Serum concentration of talquetamab, the number of patients with talquetamab antibodies, and health-related quality of life. The study will also assessed ORR in the subgroup of patients with high-risk molecular features.

To be eligible for conclusion, patients are required to have documented diagnosed of multiple myeloma according to the International Myeloma Working Group diagnostic criteria. Patients must also have measurable disease and an ECOG performance status of 0 to 2. Women must have a negative pregnancy test to enroll in the study.

The study excludes patients who have been vaccinated with a live, attenuated vaccine within 4 weeks, as well as patients with Toxicities from previous anticancer therapies that have not be resolved to grade 1, who received a cumulative dose of corticosteroids equivalent to 140 mg of prednisone within the 14 days of starting treatment in MonumenTAL-1, and those who have had a stroke or seizure withing 6 months prior to signing consent to join the study.

MonumenTAL-1 is being conducted at 83 locations in the United States, Europe, Asia, and the Middle East.

"Despite the therapies available for patients with relapsed or refractory multiple myeloma, new targets and treatments are needed because of the heterogeneity of the disease, which can impact a patient's response to treatment. We are resolute in our commitment to advance science and develop new therapies and regimens for patients with the goal of delivering the best possible outcomes while driving toward cures, Zhuang stated.¹

_REFERENCES:

_{1. Janssen announces US FDA breakthrough therapy designation granted for talquetamab for the treatment of relapsed or refractory multiple myeloma. News release. Janssen Pharmaceutical. June 29, 2022. Accessed June 29, 2022. https://prn.to/3a5597V}

_{2. A study of talquetamab in participants with relapsed or refractory multiple myeloma. Clincaltrials.gov. Updated June 21, 2022. Accessed June 29, 2022. https://bit.ly/3NtKeJE}