REGN5459 Demonstrates Early Promise in Heavily Pretreated Multiple Myeloma

The BCMAxCD3 bispecific antibody REGN5459 provided rapid and deep responses to heavily pretreated patients with relapsed/refractory multiple myeloma who have exhausted all other standard options, and due to its low affinity to CD3, the agent may also help reduce the burden of cytokine release syndrome (CRS) in this population, according to Attaya Suvannasankha, MD.

According to preliminary data from a first-in-human phase 1/2 trial (NCT04083534) presented at the 2023 AACR Annual Meeting, patients with relapsed/refractory multiple myeloma who had progressed on 3 or more prior lines of therapy (n = 43) achieved an objective response rate (ORR) of 65.1%. Patients treated at higher dose levels ranging from 480 mg to 900 mg (n = 21) experienced an ORR of 90.5%, of which 61.9% were complete responses or better.

Moreover, 53.5% of patients treated with REGN5459 across all dose levels experienced cytokine release syndrome (CRS); the majority, or 46.5%, of these events were grade 1. The toxicity was determined to be manageable and did not lead to discontinuation in any patients.

“We’re extremely encouraged that this group of heavily pretreated patients showed a tremendous response rate [with REGN5459] at that effective dose, and [that] the AEs [were] manageable,” Suvannasankha said.“Although we continue to see CRS, the vast majority [of the cases] were low grade and [could be] managed with antipyretics, some steroid usage, and tocilizumab [Actemra]. Mitigating CRS continues to be key [in] allowing us to safely administer such [immunotherapies]. Adjustment to CD3 affinity, as shown in this [study], may help decrease CRS and should be further explored.”

In an interview with OncLive^®, Suvannasankha discussed the unique mechanism of action of REGN5459, the early efficacy and safety of the immunotherapy in heavily pretreated patients with relapsed/refractory multiple myeloma, and opportunities for further exploration.

Suvannasankha is an associate professor of clinical medicine in the Department of Medicine, Division of Hematology/Oncology, at Indiana University (IU) School of Medicine, and a full member specializing in hematopoiesis & hematologic malignancies at IU Melvin and Bren Simon Comprehensive Cancer Center, IU Health System, Bloomington, Indiana.

OncLive^®: Please provide some background on REGN5459. What makes this agent unique?

Suvannasankha: This group of patients needs effective therapy. Ultimately, multiple myeloma is not yet curable. [For] patients who have already [exhausted] all [viable] therapies, survival is only projected to be 9 months or less. This immunotherapy uses technology to create a molecule that binds to [BCMA] on the myeloma cells, and the other arm binds to CD3 on the T cells. This engages the T cells to kill myeloma cells.

What’s unique about the molecule cell is that it binds to the T cells with lower affinity. [You might wonder]: Why would that be a good thing? Wouldn’t that make the molecule kill the cancer less effectively? As it turns out, the limitation of these kinds of immunotherapy is cytokine release syndrome [CRS]. That occurs because of inflammation after the T cells try to kill off the cancer cells. Adjusting the [agent's] T-cell binding affinity may mitigate CRS, which [was] observed in preclinical models when this agent was under development.

Could you expand on the preclinical data observed with REGN5459? How did this research inspire this first-in-human phase 1/2 trial?

The company that makes this medicine had a preclinical model where they used a platform that adjusts the different antibodies to grab onto the T cell with different [levels] of binding strength. As they [reduced] the binding to the T cells, they saw less CRS when the T cells were killing off the cancer cells. Based on this, the hypothesis [was] that this molecule could potentially still give patients with multiple myeloma an effective treatment [that] may be better tolerated if we can decrease the incidence of CRS.

What was examined in the early-phase study?

This is a phase 1/2 clinical trial, which means that there are two portions. In the first portion, we were evaluating the safety of this medicine and [aimed] to identify the dose that we would [use] to [evaluate] efficacy in the phase 2 expansion. In the phase 1 portion, patients [first] received a low dose [of REGN5459]. We escalated to the full dose [once] each cohort [was] safely treated. Once the phase 2 dose [was] defined, additional patients were treated at that dose.

What should be known about the patient population enrolled to the trial?

These patients had relapsed/refractory multiple myeloma. They [progressed on] at least 3 more prior lines of therapy, and they exhausted all available treatment choices. Based on these eligibility criteria, patients who ended up participating had a median of more than 5 prior lines of therapy, and over 70% [were previously treated with] the 5 most promising agents currently available in [this disease]. That includes lenalidomide [Revlimid], pomalidomide [Pomalyst], carfilzomib [Kyprolis], and bortezomib [Velcade], as well as CD38 antibodies. [This] group has really tried out every [other] standard of care [option in multiple myeloma].

What were the preliminary efficacy and safety data presented at this year’s meeting?

We presented the safety and efficacy of this agent in 43 patients who were treated in the study. Once we [escalated to] the full phase 2 dose in the higher-dose cohort, the ORR was over 90%. We’re very impressed that [76.2%] of [these patients who received the higher doses] achieved a very good partial response or better. Among these folks who have achieved complete remission, we looked deeper to define how deep that remission is by [using] a minimal residual disease [MRD] test. [We saw that] 79% of [the 22 patients who achieved a CR or better and had available data] were also MRD negative.

The treatment response not only occurred early but was also durable and deepened over time. The time to response [was] less than a month, meaning that this treatment could hopefully [pause the] rapid progression of myeloma in some patients. As we observed patients for a longer [period of] time, their responses to treatment deepened. It's projected that over 78% of patients [will] continue to be in remission [at] the 12-month mark.

This agent shows a reasonable [toxicity] profile. Common adverse effects include CRS, some cough, dyspnea, and infection. Infection occurred in [62.8%] of patients, most of which [were] low grade. Some high-grade infections included pneumonia, upper respiratory infections, and bladder infection, but these [effects] were treated successfully with antibiotics. [Of the] 2 patients who died, 1 was from pneumonia and other was from COVID-19.

What next steps should be taken with this agent? Are any additional efforts exploring REGN5459 underway?

The technology of this bispecific antibody is very promising [for patients with] multiple myeloma. Patients have a much better future compared with what they had available to them previously. I hope that this kind of technology gets moved [into] earlier lines of therapy so patients don’t have to wait too long [for effective treatment]. This bispecific technology is also being looked at in cancers outside of multiple myeloma. If adjusting CD3 binding helps decrease CRS [in myeloma], it may also be applicable in other cancers.

What should your colleagues take away from this research?

Bispecific [antibody] technology is here to stay for multiple myeloma. It [should be a] high priority to find a way to mitigate AEs [associated with immunotherapies], in this case CRS. This should allow us to safely deliver this medicine, particularly [to] patients who are older [or] frailer. Ultimately, infection is still a problem in myeloma treatment. This group of patients is already [highly] immunocompromised prior to starting treatment. Being able to move this agent to earlier lines should help treat patients whose immune systems are more intact.

We also need to think about preventing infection, and not just waiting for it to happen. [This involves] being on the lookout for infection. Also, administering an infusion of intravenous immunoglobulin has now been accepted as a standard [practice] in patients whose level of [immunoglobulin becomes] too low when they’re on this kind of therapy.

Is there anything that you would like to add?

Immunotherapy is being explored in every disease. I’m delighted that the [AACR] organizers chose our work and let us highlight this new technology in multiple myeloma, [which is] a relatively rare disease. This kind of technology that we [explored] in multiple myeloma may be applicable to other diseases.

Most of all, I would like to extend my gratitude to all patients and their families who participated in this study. This is a first-in-human clinical trial, which means that [these patients] paved the way for further [investigation of this agent]. I would also like to acknowledge the support from my institution, as well as co-investigators, collaborators, sponsors, and the research team [who made] this study available, particularly given the challenges of the COVID-19 pandemic.

Disclosures: Dr. Suvannasankha reports working in an advisory role for Regeneron Pharmaceuticals, Inc.,GlaxoSmithKline, Bristol Myers-Squibb, and Janssen ; she reports receiving research support from Regeneron Pharmaceuticals,GlaxoSmithKline, Bristol Myers-Squibb, Janssen, Sutro, and Genentech.

Reference

Suvannasankha A, Kapoor P, Pianko MJ, et al. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMAxCD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT013.