FDA Grants Breakthrough Status to Teclistamab for Relapsed/Refractory Multiple Myeloma

FDA

The FDA has granted a breakthrough therapy designation to teclistamab for the treatment of patients with relapsed/refractory multiple myeloma, according to Janssen, the developer of the bispecific antibody.¹

The designation was based on data from a phase 1 study (NCT03145181), an open-label, multicenter trial evaluating the safety and efficacy of teclistamab in adults with relapsed/refractory disease.

Primary data from the phase 1 study, which were presented at the 2020 ASCO Virtual Scientific Program, showed that teclistamab led to a 67% objective response rate (ORR) and a very good partial response rate (VGPR) or better of 50% in patients with relapsed/refractory myeloma at a dose of 270 µg/kg.²

Updated results from the study showed that at the recommended phase 2 dose (RP2D), which was 1500 μg/kg given subcutaneously (SC), the ORR with teclistamab was 73% and the VGPR or better was 55%; the complete response (CR) rate or better was 23%.³

The agent was also well tolerated at the RP2D; the maximum-tolerated dose (MTD) was not identified, and all reports of cytokine release syndrome were of grades 1/2 and were mostly a result of step-up doses and the first full doses of treatment.

“We are pleased to have received Breakthrough Therapy and PRIME Designations for our novel bispecific antibody, teclistamab,” said Peter Lebowitz, MD, PhD, Global Therapeutic Area Head of Oncology at Janssen Research & Development, LLC. “This program exemplifies our commitment to advancing science for patients living with multiple myeloma, and it builds upon our robust portfolio in this disease.”

Teclistamab is an off-the-shelf, T-cell redirecting, bispecific antibody that targets BCMA and CD3. Teclistamab redirects CD3-positive T cells to BCMA-positive myeloma cells to induce malignant cell death. Preclinical data have shown that teclistamab kills myeloma cell lines and bone marrow–derived myeloma cells from heavily pretreated patients.

To be eligible for enrollment in the phase 1 study, patients had to have measurable myeloma that was relapsed/refractory to standard therapies or be intolerant to standard treatments, hemoglobin that was at least 8 g/dL, platelets that were at least 75 x 109/L, and white blood cell counts that were at least 1.0 x 109/L. Patients could not have received prior BCMA-targeted treatment.

The study comprised 2 cohorts: intravenous (IV; n = 84) and SC (n = 65) administration. The dosing schedule in each cohort comprised 1 to 3 step-up doses prior to week 1, followed by full doses in weeks 1 to 3. In the IV cohort, doses increased following 0.3 to 19.2 μg/kg with a maximum dose of 720 μg/kg; the SC cohort started at 80 μg/kg and increased up to 3000 μg/kg. The initial every-2-week IV dose was switched to weekly IV or SC plus or minus step-up dosing.

Premedication with dexamethasone were limited to the step-up doses and the first full dose, and there was no steroid requirement following the first full dose.

In the overall study population (n = 149), the median age is 63 years (range, 24-84), and 22% of patients were 70 years and older; 54% of patients were male. Twenty-five percent of patients had at least 60% of bone marrow plasma cells, 12% had at least 1 extramedullary plasmacytomas, and the median years since diagnosis was 7 years. A total 32% of patients had high-risk cytogenetics, and 85% had prior transplantation.

The median number of prior lines of therapy was 6 (range, 2-14); most patients (96%) were exposed to 3 classes of therapy, and 69% were penta-refractory. Patients were refractory to carfilzomib (Kyprolis; 66%), pomalidomide (Pomalyst; 77%), and anti-CD38 antibodies (93%), and 91% of patients were refractory to their last line of therapy.

The primary end point in part 1 of the trial was the RP2D; in part 2, the key objective was safety and probability at the RP2D, as well as antitumor activity, pharmacokinetics, and pharmacodynamics.

The updated findings also showed that at the RP2D, the median time to first confirmed response was 1 month (range, 0.3-3); 70% of patients who were triple-class refractory responded to treatment, and 75% of patients who were penta-refractory responded.

Most of the active doses were reported to be between 270 to 720 μg/kg given IV and 720 to 3000 μg/kg given SC. At these doses, the ORR was 69%, 59% of patients had a VGPR or greater, and a CR or better occurred in 26% of these patients. In the IV cohort (n = 27) and SC cohort (n = 41), the ORRs were 67% and 71%, respectively.

In the SC cohort, the ORR was 46% at the 80 μg/kg plus 240 μg/kg dose (n = 13), 60% at the 720 μg/kg dose (n = 15), and 73% at the 1500 μg/kg dose (n = 22), in which the VGPR or better was 55%.

Of 11 evaluable patients across the IV and SC doses thus far, 8 patients had a minimal residual disease–negative (MRD) CR at 10-6 and 1 patient experienced this at 10-5 sensitivity.

Responses were durable and deepened over time. Among responders who received the RP2D (n = 16), and at a median follow-up of 3.9 months, 94% of patients are alive and progression free. Of those in the SC cohorts (n = 35), 91% of patients are on treatment with ongoing responses; the median follow-up is 6.5 months.

Patients receiving the active IV and SC doses (n = 47) remained on treatment with ongoing responses (94%) at a median follow-up of 6.5 months. All 5 evaluable patients across the IV and SC cohorts showed sustained MRD negativity.

The pharmacokinetic and pharmacodynamic data supported the RP2D.

The safety profile was similar in both the overall and RP2D population. Overall, the most common (≥20%) all-grade and grade 3 or higher adverse effects (AEs) were neutropenia (57% and 46%, respectively), anemia (55% and 32%), thrombocytopenia (40% and 22%), and leukopenia (28% and 14%). Nonhematologic all-grade AEs were all-grade CRS (55%), pyrexia (30%), diarrhea (23%), nausea (22%), fatigue (22%), headache (22%), and cough (21%). Grade 3 or higher AEs were cough (2%), and diarrhea, nausea, and fatigue (1% each).

There were 2 dose-limiting toxicities across all doses, but no DLTs were at the RP2D. These were grade 4 delirium, which occurred at the 20 μg/kg IV step-up dose, and grade 4 thrombocytopenia, at the 180 μg/kg IV dose.

Infections occurred in 52% of patients, and 27% occurred at the RP2D; 15% percent of these patients had grade 3 or higher infections across all doses, and 6% had grade 3 or higher infections at the RP2D.

Neurotoxicity occurred in 7 patients (5%), 1 (3%) which occurred at the RP2D. Two events of grade 3 or higher neurotoxicity occurred at the IV dose, and none of which were reported with SC dosing. Injection-site reactions occurred in 32% of patients, 36% occurred at the RP2D, all of which were grades 1/2. One treatment-related AE, grade 5 pneumonia at 80 μg/kg after 16 cycles, led to death; no treatment-related deaths occurred at the RP2D.

CRS occurred in 55% of patients overall; the median time to CRS onset was 2 days (range, 1-5 days) and the median duration of CRS was 2 days (range, 1-8). Fifty-one percent of patients had supportive interventions to treat CRS: tocilizumab (Actemra; 23%), steroids (13%), low flow oxygen (6%), and single low-dose vasopressor (1%).

There were no treatment discontinuations because of CRS; CRS was generally confined to the step-up and first full doses. CRS occurred in 54%, 57%, and 64% of patients in the IV, SC, and RP2D groups, respectively. Step-up dosing was implemented to reduce the risk of severe CRS, and no cases of grade 3 or higher CRS.

Teclistamab is also under study in a phase 2 trial (NCT04557098) for the treatment of patients with relapsed/refractory multiple myeloma and in several combination studies (NCT04586426; NCT04108195; NCT04722146).

Updated results of the phase 1 trial will be presented at the 2021 ASCO Annual Meeting.⁴

References

1. Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma. News release. Janssen. June 1, 2021. Accessed June 1, 2021. https://bit.ly/3i9XSFO
2. Usmani SZ, Mateos M, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). Presented at: 2020 ASCO Virtual Scientific Program. May 29-31, 2020. Abstract 100.
3. Garfall AL, Usmani SZ, Mateos M-V, et al. Teclistamab, a B-cell maturation antigen (BCMA) X CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM): updated phase 1 results. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract B11.
4. Krishnan Amrita Y., Garfall AL, Mateos MV, et al. Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8007. doi:10.1200/JCO.2021.39.15_suppl.8007