Low-affinity bispecific antibody produces high response rates in advanced multiple myeloma
Key findings:
- The two highest doses of REGN5459 conferred a 90.5% objective response rate.
- Low-affinity binding may lead to reduced CRS and neurotoxicity.
More than 90% of patients with relapsed or refractory multiple myeloma who received the two highest doses of REGN5459 responded to treatment with the investigational bispecific antibody, results of a phase 1/phase 2 study showed.
REGN5459 (Regeneron Pharmaceuticals) — which targets the B-cell maturation antigen (BCMA) and CD3 — exhibited a manageable safety, with low incidence of severe cytokine release syndrome or neurotoxicity, according to the findings, presented at American Association for Cancer Research Annual Meeting.
The novel therapy’s use of a low-affinity binding approach has resulted in a potentially more favorable safety profile compared with currently available bispecific antibodies, the investigators suggested.
“In comparison to the average lifespan of heavily pretreated patients at this stage, which is 6 to 9 months, that the 1-year progression-free survival may be more than 70% is very promising,” Attaya Suvannasankha, MD, associate professor of clinical medicine at Indiana University School of Medicine, said in an AACR-issued press release. “Low-affinity T-cell engagers potentially result in T cells that continue killing the cancer cells but with fewer side effects.”
Background
Multiple myeloma continues to be incurable despite the effectiveness of combination therapy, according to Suvannasankha.
"Most patients succumb to disease relapse, so newer therapies are highly needed,” she said during a presentation.
Bispecific antibodies are among the more promising novel therapies for treatment of multiple myeloma. Nevertheless, CRS is a common and potentially life-threatening treatment-related toxicity with this class of agents, Suvannasankha noted.
“REGN5459 is unique in the way that it binds to CD3 on the surface of T cells,” she said.
Its low-affinity approach to binding triggers T-cell activation and plasma cell depletion with less intense CRS in preclinical models, according to Suvannasankha.
“This approach may enable us to more safely deliver treatment to patients, particularly those who are older, more frail or cannot stay within proximity of a tertiary care center for post-treatment observation,” she said.
Methodology
Suvannasankha and colleagues conducted a first-in-human phase 1/phase 2 study aimed to determine the safety, tolerability and antitumor efficacy of REGN5459 among patients with relapsed or refractory multiple myeloma.
The study included 43 patients (median age, 67 years; range, 26-85; 51% women; 79% white), all of whom had received at least three previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody. Ten patients had been enrolled as part of the phase 2 portion of the study, with 33 patients in the phase 1 trial.
Participants received a median of five (range, 2-9) previous lines of therapy, and 81.4% had at least triple-class refractory disease. They received doses of REGN5459 until disease progression or intolerable treatment-related toxicity.
Assessment of safety, tolerability and dose-limiting toxicities of REGN5459, as well as determining a recommended phase 2 dose, served as the primary objectives of the phase 1 portion of the study. The primary aim of the phase 2 portion of the study included assessment of efficacy based on objective response rate.
Median follow-up was 9 months (range, 1-32), with a data cutoff data of Dec. 8, 2022.
Key findings
One patient in the phase 1 portion had a dose-limiting toxicity (grade 3 hypoxia) after receiving a REGN5459 dose of 900 mg, the highest in the study.
Investigators identified 480 mg as the recommended dose for the phase 2 portion of the study.
All study participants experienced at least one treatment-related toxicity, with 74% having grade 3 or greater treatment-related adverse events.
Investigators identified CRS (53.5%) as the most frequently reported nonhematologic treatment-related toxicity, followed by cough (39.5%), diarrhea (39.5%), fatigue (39.5%), neutropenia (39.5%) and anemia (34.9%).
Most cases of CRS were grade 1 (46.5%), with limited reports of grade 3 CRS (4.7%). No grade 4 or higher CRS events occurred during the study, and no grade 3 CRS events occurred when patients received the recommended phase 2 dose.
Only one patient developed immune effector cell-associated neurotoxicity syndrome of grade 2 severity.
Researchers reported infections in 62.8% of patients, with approximately one-third (30.2%) being grade 3 or greater. Two infection-related deaths occurred during the study, one attributed to COVID pneumonia and the other to COVID-19 infection.
Efficacy results showed a 65.1% ORR across dose levels, including a 58.1% rate of very good partial response or better. The ORR reached 90.5% for those patients who received higher doses (480-900 mg) of REGN5459, with 61.9% achieving complete responses to therapy.
All 13 patients who received the recommended phase 2 dose had an objective response to therapy. Thirty-nine percent of these patients had a complete response to therapy, including 15% with a stringent complete response.
Median duration of response was not yet reached (95% CI, 12-not estimable), with the longest treatment response ongoing for more than 26 months as of the data cutoff date.
Researchers reported a 78.1% (95% CI, 54.9-90.3)probability of maintaining response at 12 months.
Fifteen of 19 patients (79%) with a complete or stringent complete response achieved minimal residual disease-negative status according to the investigator’s criteria.
Clinical implications
The results demonstrate that binding affinity for T-cell engaging bispecific antibodies can be reduced to address treatment-related toxicity without a loss in clinical efficacy, according to Suvannasankha.
“REGN5459 yielded early, deep, and durable responses in patients with relapsed or refractory multiple myeloma who were heavily pretreated,” she said. “Safety — which was our primary concern — appears to be manageable.”
Despite CRS still occurring with REGN5459 use, patients who received the study drug had less severe symptoms that involved mostly mild fever and rarely required intervention, Suvannasankha said.
She concluded her remarks by confirming that the study’s sponsor is considering further development of REGN5459 for patients with advanced multiple myeloma.
“The strategy of modifying CD3 binding affinity as a way to mitigate cytokine release syndrome in bispecific antibody therapy for multiple myeloma is a promising area of research,” Suvannasankha said.
References:
- New bispecific antibody demonstrates clinical activity in patients with multiple myeloma (AACR press release). Published April 17, 2023. Accessed April 17, 2023.
- Suvannasankha A, et al. Abstract CT013. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
Perspective
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REGN5459 is an extremely impressive compound. The data presented by Suvannasankha and colleagues showed not only an impressive 65% ORR in the total cohort but a 100% ORR in patients treated at the recommended phase 2 dose. Albeit small numbers, 100% response is an impressive and promising prospect. Unfortunately, this drug is not currently planned to move forward in the myeloma space. I hope this can be reconsidered in the future.
The data to date do not seem to support the role of CD3 affinity on rates of CRS. Although the CRS rate of 54% is on the lower end of the current field, it is not the lowest. Of note, the current lowest is with REGN5458/linvoseltamab (Regeneron Pharmaceuticals). It is not clear if the lack of difference is related to the true nature of the affinity, the relatively low number of patients treated or patient selection effect.
Some next-generation studies are looking at ways to augment the T-cell response. Some are starting to incorporate checkpoint inhibition. Although the CD3 affinity has so far not impacted rates of toxicity, I would love to see whether or not this has a bigger impact when the drug is given in combination therapy, specifically with checkpoint inhibitors.
Reference:
Bumma N, et al. Abstract 4555. Presented at: ASH Annual Meeting and Exposition, Dec. 10-13, 2022; New Orleans.
Icahn School of Medicine at Mount Sinai
Perspective
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BCMA-targeting T-cell based therapies have become an important tool in the treatment of patients with relapsed/refractory multiple myeloma. Currently, the two main strategies used to redirect cytotoxic T cells against myeloma cells are chimeric antigen receptors (CARs) and bispecific antibodies (BsAbs). An advantage of using BsAbs is their off-the-shelf availability. However, similarly to CARs, they can potentially have severe adverse effects, including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS).
Preclinical studies have shown that cytotoxic T-cell function can be modulated via tuning of the CD3 binding affinity of BsAbs. Thus, BsAbs able to maintain T-cell killing while triggering lower levels of cytokines can improve their safety profile. Another potential advantage of using lower-affinity agonist antibodies is their enhanced capacity for clustering their target receptors.
The preliminary results of this trial of REG5459 are in line with published data from other phase 1/phase 2 clinical trials of BCMA-BsAbs, including teclistamab-cqyv (Tecvayli, Janssen) and elranatamab (PF-06863135, Pfizer). Although the data are immature, it is noteworthy that the ORR for patients treated with the recommended phase 2 dose is 100%. Further follow-up will be needed to assess the duration of the response. In addition, correlative studies could evaluate if differences in antibody-antigen affinity can mitigate T-cell exhaustion and improve tumor control.
References:
Haber L, et al. Sci Rep. 2021;doi:10.1038/s41598-021-93842-0.
Yu X, et al. Nature. 2023;doi:10.1038/s41586-022-05673-2.
Penn Medicine
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Suvannasankha A, et al. Abstract CT013. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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