Teclistamab Demonstrates High Response Rate and Good Tolerability in Multiple Myeloma

Investigators reported an objective response rate (ORR) of 73% for the anti–B-cell maturation antigen (BCMA) teclistamab (formerly JNJ-64007957) in patients with relapsed/ refractorymultiple myeloma, according to results from an ongoing study (NCT03145181) presented during the 2nd European Myeloma Network Meeting.1 Findings also demonstrated a tolerable safety profile.

In addition, results from the phase 1 study showed that the agent had a very good partial response rate (VGPR) or better at 55%, which includes the complete response (CR) rate (23%) and the VGPR rate (32%).

The agent was also found to be well tolerated at the recommended phase 2 dose (RP2D), which was 1500 μg/kg given subcutaneously (SC); the maximum-tolerated dose was not identified, and all reports of cytokine release syndrome (CRS) were grades 1/2 and generally confined to step-up doses and the first full doses of treatment.

“Teclistamab is an off-the-shelf therapy targeting BCMA, [and it] showed promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma,” said lead study author Alfred L. Garfall, MD, an assistant professor of medicine at the Hospital of the University of Pennsylvania, in a virtual presentation of the data.

There continues to be an unmet need for patients with relapsed/refractory multiple myeloma, he explained; for those who progress on available therapies, the ORR is approximately 30%, the median progression-free survival is estimated at 3 months, and the median overall survival ranges from 6 to 11 months.

Teclistamab is a bispecific humanized IgG4 antibody targeting both BCMA and CD3. The agent induces the T-cell–mediated killing of myeloma cells from both preclinical models and heavily pretreated patients.

Prior data of the phase 1 study, which were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program, showed that teclistamab was found to be safe and effective in this patient population.²

In the updated results of the study, Garfall presented additional data of teclistamab administered intravenously (IV) or SC in patients with relapsed/refractory multiple myeloma. To be eligible for enrollment, patients had to have measurable myeloma that was relapsed/refractory or intolerant to established treatment, a hemoglobin level of at least 8 g/dL, a platelet count of at least 75 × 10⁹ /L, and white blood cell counts of at least 1.0 × 10⁹ /L.

The study included 2 cohorts: 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 from weeks 1 to 3. In the IV cohort, doses increased from 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. Investigators selected 1500 μg/kg as the RP2D.

Premedication with dexamethasone was 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 was 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. 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.

Baseline characteristics were similar overall and in the cohort of patients on the RP2D (n = 33), except there were fewer patients with bone marrow plasma cells at 60% or more (10%) in this cohort.

The primary end point in part 1 of the trial was the RP2D; in part 2, the key objective was safety and tolerability 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 ug/kg given IV and 720 to 3000 μg/kg given SC. At these doses, the ORR was 69% and 59% of patients had a VGPR or greater, with a CR or better occurring in 26% of these patients. In the IV cohort (n=27) and SC cohort (n=41), the ORRs were 67% and 71%, respectively.

Responses in the SC Cohort 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 (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 (MRD)–negative CR at 10-6 and 1 patient experienced this at 10-5 sensitivity.

Responses were found to be durable and deepen over time. Among responders who received the RP2D (n=16), at a median follow-up of 3.9 months, 94% of patients were alive and progression free. Of those in the SC cohorts (n=35), 91% of patients were on treatment with ongoing responses at the median follow-up of 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 data supported the RP2D. Regarding the SC dosing, exposure was dose proportional following the first treatment dose (80 μg/kg to 3000 μg/kg SC), and 1500 μg/kg SC was found to have low peak/trough ratio and maintained exposure over the max EC90. This leads to the opportunity for less frequent SC dosing, Garfall added. Two of 107 patients (2%) had antidrug antibodies of low titer, and soluble BCMA was not found to impact teclistamab exposure, as seen in the preliminary population pharmacokinetic analysis. Pharmacodynamics also supported the RP2D.

Safety Profile 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 events (AEs) were neutropenia (57% and 46%, respectively), anemia (55% and 32%), thrombocytopenia (40% and 22%), and leukopenia (28% and 14%). Nonhematologic allgrade 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).

In the RP2D cohort, hematologic AEs were neutropenia (all-grade, 52%; grade≥3, 33%), anemia (39% and 21%, respectively), thrombocytopenia (33% and 22%), and leukopenia (33% and 18%). Nonhematologic AEs were CRS (64%), pyrexia (18%), diarrhea (12%), nausea (18%), fatigue (24%), headache (12%), and cough (3%). There was 1 nonhematologic AE that was grade 3 or higher, which was fatigue (3%).

There were 2 dose-limiting toxicities (DLTs) across all doses but none at the RP2D. The DLTs 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% of these patients had grade 3 or higher infections across all doses, and 6% had grade 3 or higher infections at the RP2D.

Neurotoxicity events occurred in 7 patients (5%), with 1 (3%) occurring at the RP2D. Two grade 3 or higher neurotoxicity occurred at the IV dose, and none were reported with SC dosing. 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 measures to treat CRS: tocilizumab (Actemra; 23%), steroids (13%), low-flow oxygen (6%), and single low-dose vasopressor (1%).

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

The phase 1 study remains ongoing, and a phase 2 expanded study has been initiated, Garfall concluded.

_Reference:

_{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.}