Bispecific Antibody Shows Promise in Phase I/II MM Trial

REGN5459, a bispecific antibody targeting BCMA and CD3, yielded “early, durable, and deep responses” in heavily pretreated relapsed or refractory multiple myeloma (MM), according to results from a phase I/II clinical trial.

Attaya Suvannasankha, MD, of the Indiana University School of Medicine and Indiana University Melvin and Bren Simon Comprehensive Cancer Center, and colleagues presented the study during the American Association for Cancer Research (AACR) Annual Meeting 2023, in Orlando, Florida.¹

“Despite the increased effectiveness of combination therapy in myeloma, myeloma continues to be incurable and most patients end up succumbing to drug-resistant relapse,” Dr. Suvannasankha said during an AACR press briefing. ² “So, new therapies are highly needed.”

The design of the bispecific antibody aims to overcome challenges with cytokine release syndrome (CRS), she said.

“The uniqueness of this molecule is its different affinity to CD3 on the T cells,” Dr. Suvannasankha said. ² “The binding triggers T-cell activation, which causes plasma cell clearance. In the preclinical model, this molecule showed lower rates of cytokine release, which is the problem with bispecific antibodies as a whole class of drugs.”

The study included 43 patients, with 33 in the phase I portion, and 10 in the phase II portion. Eligible patients had active MM per the International Myeloma Working Group criteria and had relapsed or refractory disease, or intolerance, to at least three lines of therapy, including anti-CD38 antibodies, proteasome inhibitors, and immunomodulatory imide drugs.

“These are our main classes of drugs currently available. Patients also have to have exhausted all available treatment options,” she said. ²

The median patient age was 67 years and 51% were female. Of these patients, 95.3% were at least triple-class-exposed, with 86% progressing on their last line of therapy. Nearly all (86%) patients previously received an autologous hematopoietic stem cell transplant.

The primary objectives of the phase I study were to assess the safety, tolerability, dose limiting toxicities, and to determine the recommended phase II dose of REGN5459. The primary objective of the phase II portion of the study was to evaluate the overall response rate (ORR).

In the phase I portion of the trial, patients received doses of REGN5459 ranging from 3 mg to 900 mg. One dose-limiting toxicity—grade 3 hypoxia—occurred at the 900 mg dose.

“This patient was later found to have primary lung cancer in the setting of [chronic obstructive pulmonary disease] and it was declared that that side of was not related to the study drug,” Dr. Suvannasankha said. ²

The maximum tolerated dose was not reached. The study’s investigators selected 480 mg weekly as the recommended phase II dose.

CRS occurred in 23 (53.5%) patients across dose levels, with 81% of the patients receiving 480 mg or 900 mg experiencing CRS, but there were no grade 3 or higher events.

“While we were seeing increases in response, we saw that there is increasing incidence of [CRS], but not an increase in severity, because [the] majority of [CRS] was grade 1 and there was only one grade 2 event at that highest-dose cohort,” Dr. Suvannasankha said. ²

Other common treatment-emergent adverse events of any grade included cough in 39.5% of patients, diarrhea in 39.5%, fatigue in 39.5%, neutropenia in 39.5%, and anemia in 34.9%.

“The side effect profile appears to be acceptable, and safety data—which is our primary concern—seem to be manageable in this case,” she said. ²

Infections of any grade occurred in 27 (62.8%) patients, with grade 3 or 4 infections reported in 13 (30.2%) patients. The most common infections were pneumonia, COVID-19, sepsis, and urinary tract infections. Treatment discontinuation due to treatment-emergent adverse events occurred in seven patients (16.3%).

The ORR across dose levels was 65.1%, with 51.8% of patients achieving a very good partial response or better, and 51.2% achieving a complete response (CR) or better across dose levels. In the 21 patients who received 480 mg or 900 mg—the two highest dose levels— the ORR was 90.5%. Of those patients, 76.2% had a very good partial response or better, and 61.9% had a CR or better, including 38.1% who had a stringent CR.

Among the 19 patients with a CR or better who had available minimal residual disease (MRD) data, 15 (79%) patients were MRD negative at the 10⁻⁵ threshold.

The median time to response was less than one month (0.8 months). At a median follow-up of nine months, the median duration of response was not reached. The longest responses are ongoing at more than 26 months at the latest data cutoff, Dr. Suvannasankha said. ² The probability of maintaining a response at 12 months was 78.1%.

Overall, REGN5459 was able to “yield early, deep, and durable responses in patients with relapsed refractory [MM]  who were heavily pretreated and had received at least prior lines of therapy,” she said. ²

Dr. Suvannasankha concluded by outlining the next steps for investigating the bispecific antibody.

“Further development of this agent, as well as a strategy to modify the CD3 binding affinity as a way to mitigate [CRS] in bispecific antibody therapy in myeloma, are promising areas,” she said, adding that “development of this agent is under consideration by the sponsor.” ²

Funding for this study was provided by Regeneron Pharmaceuticals.

Referenced

1. Suvannasankha A, Kapoor P, Pianko MJ, et al. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma. Abstract CT013. Presented at the American Association of Cancer Research; April 14-19, 2023; Orlando, Florida.
2. American Association of Cancer Research press briefing, April 17, 2023