Phase 2 Recommended Dose of Teclistamab Shows Promising Safety, Efficacy in R/R MM

Treatment with teclistamab (JNJ-64007957) at the recommended phase 2 dose (RP2D) demonstrated encouraging safety and efficacy among patients with relapsed/refractory multiple myeloma (MM), according to updated results from the first-in-human phase 1 trial of the agent presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Our results with longer follow-up support the recommended phase 2 dose of teclistamab,” Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center, Duarte, California, said during a presentation of the data. “We show that teclistamab was well tolerated. No new safety signals were identified. … The response rates to teclistamab were high, with deep, durable responses that deepened over time.”

In the 2-part, open-label, first-in-human phase 1 MajesTEC-1 trial (NCT03145181), teclistamab was administered across 4 dosing cohorts, of which subcutaneous teclistamab 1500 µg/kg once weekly was identified as the recommended dose (RP2D), with step-up doses of 60 µg/kg and 300 µg/kg used to mitigate the risk for severe cytokine release syndrome (CRS).

“Despite the improvements in survival with many of these new therapies, we have myeloma patients who eventually relapse and require additional treatments,” Krishnan explained. “The most promising therapies for these patients are often those that have new mechanisms of action. That includes BCMA-targeted immunotherapies.”

Teclistamab is an off-the-shelf, full-size bi-specific antibody that redirects T cells to BCMA-expressing MM cells, considered a novel, steroid-sparing treatment approach for relapsed/refractory MM.

At the 2021 ASCO Annual Meeting, Krishnan reported on RP2D results, with additional patients and longer follow-up, for evaluation of safety and tolerability of the agent, as well as antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD).

Data cut-off for the updated analyses was March 29, 2021.

To be eligible, patients needed to have documented multiple myeloma per International Myeloma Working Group criteria; were required to have measurable disease; and to be relapsed, refractory, or intolerant to established multiple myeloma therapies. However, of note, patients were not allowed to have prior BCMA-targeted therapies.

In total, 157 patients were enrolled in the trial, with 40 receiving RP2D.

Patients treated with RP2D were a median age of 62.5 (range, 39-84). The majority were male (65%); triple-class refractory (83%) and refractory to their last line of therapy (88%), with a median of 5 lines of prior therapy received (range, 2-11). Median time since diagnosis to treatment on the RP2D arm was 5.7 years (range, 0.8-17.4).

Teclistamab appeared well tolerated. The most common grade 3/4 hematologic adverse events (AEs) for the RP2D arm were neutropenia (40%), anemia (28%), thrombocytopenia (20%), and leukopenia (18%). Other grade 3/4 AEs were diarrhea (5%) and fatigue (3%).

The first onset of grade 3/4 cytopenias was generally confined to step-up dosing and cycles 1 and 2 of treatment. Infections were reported in 51% of SC-treated patients, including 21% that were grade 3/4, and 45% in those in the RP2D arm, including 23% that were grade 3/4. Neurotoxicity occurred in 1 patient treated in the SC arm; however, the patient was treated with RP2D, the AE was grade 1, resolved without intervention and the patient remains on therapy. Injection site reactions were reported in 42% of the SC treatment arm, including 50% of those treated with RP2D. Of note, all events were mild and manageable, Krishnan said.

Two deaths were reported across the SC arms; however, none were in the RP2D arm and were not related to treatment with teclistamab.

In total, 28 patients (70%) experienced CRS with the RP2D dose, but all events were grade 1/2 and generally confined to the step-up in the first full dose, she added. CRS occurred at a median onset of 2 days (range, 1-6) in the RP2D arm, lasting for a median of 2 days (range, 1-8).

Median duration of follow-up for efficacy was 6.1 months (range, 1.2-12.2).

The overall response rate (ORR) was 65% with RP2D, with 58% of patients achieving a very good partial response or better, and more than 40% experiencing a complete response (CR) or better. The median time to first confirmed response was 1 month (range, 0.2-3.1). ORR in those who were triple-class refractory was 61%.

Six patients, as of data cut-off, in the RP2D cohort had minimal residual disease (MRD)-negative CRs or stringent CRs at 10-5 (n = 1) and 10-6 (n = 6). Two patients who demonstrated a CR or better for more than 1 year had sustained MRD negativity.

At the recommended dose, responses were durable and deepened over time, Krishnan said, adding that the median duration of response (DOR) was not reached. Of the 26 responders, 22 (85%) were alive and continued on treatment with teclistama, after a medina follow-up of 7.1 months (range, 3.0-12.2).

DOR was consistent for those in the SC arms, as well as across all 4 treatment dose arms, with 36 of 45 and 19 of 32, respectively, alive and continuing treatment at median follow-ups of 9.3 months (range, 3.0-19.4) and 15.6 months (range, 5.4-2.6).

In regards to pharmacokinetics and pharmacodynamics, the RP2D group had low peak/trough ratios. “Importantly, the mean trough level was above target exposure level. Immunogenicity was low and did not impact the pharmacokinetics. Only 1 patient treated with SC teclistama had low titer anti-drug antibodies, and this patient was not treated at the recommended dose,” Krishnan explained.

“We look forward to seeing the results of the open-label, phase 2 expansion study, which was met at this recommended phase 2 dose and is currently underway,” she concluded. “Future studies will evaluate teclistama in earlier lines of therapy and also in combination with other agents.”

Reference:

Krishnan AY, 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; abstr 8007). doi:10.1200/JCO.2021.39.15_suppl.8007.