The bispecific antibody REGN5459 achieved a 90.5% overall response rate when given at the two highest doses in patients with relapsed or refractory multiple myeloma, according to the results of a phase I/II clinical trial.1 Although preliminary, the results of this first-in-human trial for the bispecific antibody were presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting.
REGN5459 is designed to target both the B-cell maturation antigen (BCMA), which is found mainly on malignant plasma B cells, and CD3 on T cells, allowing the latter to attack the former. The new findings with this agent come on the heels of U.S. Food and Drug Administration approval of the first bispecific antibody targeting BCMA and CD3—teclistamab-cqyv—for persistent multiple myeloma after four prior lines of therapy.
“These initial data show that REGN5459 has acceptable safety and tolerability in relapsed/refractory multiple myeloma, with most cytokine-release syndrome of low grade and a low incidence of neurologic toxicity. This approach of modulating CD3 affinity on bispecific antibodies to maximize tumor killing and mitigate cytokine-release syndrome and T-cell exhaustion warrants further research. The efficacy approaching 100% response at the two highest doses was encouraging in this heavily pretreated cohort, and the severity of cytokine-release syndrome did not increase. Responses were deep and durable,” said lead author Attaya Suvannasankha, MD, a physician-scientist at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis.
“This approach of modulating CD3 affinity on bispecific antibodies to maximize tumor killing and mitigate cytokine-release syndrome and T-cell exhaustion warrants further research.”— Attaya Suvannasankha, MD
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A unique advantage of REGN5459 is that it has low-affinity binding to CD3 on T cells, which theoretically can mitigate the potentially life-threatening side effect of cytokine-release syndrome. “Dialing down the strength of binding CD3 to T cells might sound contradictory. Why would we not want the therapy to grab the T cells very hard? Preclinical data suggested that decreasing the binding affinity to T cells might reduce cytokine-release syndrome, which may enable us to more safely deliver treatment to patients, particularly those who are older and more frail,” Dr. Suvannasankha explained.
The study sponsor, Regeneron, is also -developing a bispecific antibody targeting BCMA with normal affinity-binding to CD3 known as REGN5458. In preliminary studies, the normal-affinity binder performed as well as REGN5459, the low-affinity binder.
Study Details
The phase I/II study used fixed-step dosing to mitigate the risk of cytokine-release syndrome. Phase I was conducted to determine the safety, tolerability, and dose-limiting toxicities and to determine the phase II dose. Doses ranging from 3 to 900 mg were studied. The phase II study looked at objective response rates using the recommended phase II dose of 480 mg. The maximum tolerated dose was not reached.
The study enrolled 43 patients with multiple myeloma that had stopped responding to more than three prior lines of therapy, including anti-CD28 antibodies, proteasome inhibitors, and immunomodulatory drugs. These patients were heavily pretreated and had exhausted all treatment options for disease control. Baseline characteristics included a median patient age of 67 years, with almost 40% aged 70 and older, and about 80% were White. Approximately 86% had undergone autologous stem cell transplantation; 95% were exposed to at least triplet therapy; 93%, to at least quadruplet therapy; and 72%, to five or more prior therapies. In about 86% of patients, disease was considered refractory to the last line of therapy.
Adverse Events
The most common treatment-related adverse events of any grade were cytokine-release syndrome (53.5%), cough (39.5%), diarrhea (39.5%), fatigue (39.5%), neutropenia (39.5%), and anemia (34.9%). Infections occurred in 62.8% of patients. Grade 3 or 4 infections were reported in 30.2%, with the most common being pneumonia (9.3%), COVID-19 (7%), sepsis (7%), and urinary tract infection (4.7%). Treatment discontinuation because of treatment-related adverse events was reported in 16.3% of patients. Grade 5 adverse events occurred in two patients, one from pneumonia and from COVID-19. One patient developed grade 2 immune effector cell–associated neurotoxicity syndrome.
Among patients who developed cytokine-release syndrome, 81% occurred at the highest dose levels (480 mg and 900 mg). All but one of these cases were grade 1, and one was grade 2. “These patients developed no significant changes in cytokine levels. They had fever, and about 10% were treated with steroids and tocilizumab at the discretion of the treating physician,” Dr. -Suvannasankha said.
At a median follow-up of 9 months, 90.5% of patients responded at the highest dose levels. At that level, 76.2% had a very good partial response, and 61.9% had a complete response or better. Among patients who achieved a complete response and had measurable residual disease (MRD) data available, 79% (15 of 19 patients) achieved MRD negativity at a sensitivity of 10-5.
“Responses occurred early, were durable, and deepened with time,” Dr. Suvannasankha said. The median duration of response was not reached at 9 months. “The probability of maintaining a response at 12 months is 78.1%. The longest ongoing response is 26-plus months at the latest data cutoff, she noted.
DISCLOSURE: The study was sponsored by Regeneron. Dr. Suvannasankha has received research support from Bristol Myers Squibb, Genentech, GSK, Janssen, Regeneron, and Sutro Biopharma; and is on the advisory board of Bristol Myers Squibb, GSK, Janssen, and Regeneron.
REFERENCE
1. Suvannasankha A, Kapoor P, Pianko M, et al: Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA x CD3 bispecific antibody with low CD3 affinity in patients with relapsed/refractory multiple myeloma. AACR Annual Meeting 2023. Abstract CT013. Presented April 17, 2023.
