Patients with relapsed or refractory multiple myeloma who were treated with the two highest doses of REGN5459, a bispecific antibody targeting BCMA and CD3, experienced a 90.5% overall response rate.
This is according to results of a Phase I/II clinical trial presented at the AACR Annual Meeting 2023 in Florida.
REGN5459 binds to BCMA on malignant plasma B cells that constitute multiple myeloma and CD3 on T cells, bringing the two cell types together so that the latter can attack the former.
A common side effect of bispecific antibody immunotherapy is cytokine release syndrome (CRS), a potentially life-threatening complication in which activated immune cells release many cytokines into the bloodstream, resulting in systemic inflammation.
CRS can cause symptoms including fever, low blood pressure and low oxygen levels, which often occur before the patient can receive the intended full dose. To mitigate these early events, patients receive progressive increments of the bispecific antibody therapy and are monitored to treat these adverse events. These challenges can create barriers to effective treatment.
The advantage of REGN5459 is that it binds relatively loosely to CD3 on T cells, which may mitigate CRS and decrease T-cell exhaustion, explained Attaya Suvannasankha, an associate professor of clinical medicine in the Division of Hematology and Oncology at Indiana University School of Medicine, who presented the study.
“Dialling down the strength of binding to CD3 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 CRS, which may enable us to more safely deliver treatment to patients, particularly those who are older or more frail,” Suvannasankha explained.
Clinical trial results
The overall response rate in the study population was 65.1%. Among the 21 patients treated at the higher doses (480mg and 900mg), the response rate was 90.5%, of which 61.9% were complete responses or better, including 38.1% that were stringent complete responses, a deeper response category characterised by the absence of clonal myeloma cells in the bone marrow and a normal blood test result for free light chains.
Responses occurred early and deepened with time, with a projected 78.1% of patients continuing to respond at a year.
“In comparison to the average lifespan of heavily pretreated patients at this stage, which is six to nine months, that the one-year progression-free survival may be more than 70% is very promising,” Suvannasankha said.
Just over 50% of patients experienced CRS and most cases were not severe, so all patients were able to escalate treatment to the full planned dose.
Continuous T-cell activation can also cause T-cell exhaustion, leaving the body vulnerable to infection. “While infections continue to occur with bispecific antibody treatments, we are excited about the data in this study. The severity of infection and the disruption to treatment were manageable,” she added.
According to Suvannasankha, the response rate demonstrates that binding affinity can be reduced without sacrificing clinical activity. “Low-affinity T-cell engagers potentially result in T cells that continue killing the cancer cells but with fewer side effects,” she said.