REGN5458 Induces Deep and Durable Responses in R/R Myeloma

Deepu Madduri, MD

Patients with relapsed or refractory multiple myeloma had deep and durable responses to the BCMA- and CD3-targeted bispecific monoclonal antibody REGN5458, early on in the course of treatment, according to findings from a first-in-human phase 1 study (NCT03761108) presented during the 2020 American Society of Hematology (ASH) Annual Meeting.¹

REGN5458 also demonstrated acceptable safety and tolerability in patients.

Results indicated that 95% (n = 18) of 19 patients who responded to treatment experienced a very good partial response (VGPR) or better and 42% achieved a complete response (CR) or a stringent CR (sCR).

At a median follow-up of 2.6 months, patients who received the agent at a dose of 3 mg, 6 mg, or 12 mg (n = 24; dosing levels [DL] 1-3) experienced an overall response rate (ORR) of 29.2%; 20.9% of these responders experienced a CR or sCR, while 4.2% had VGPR or better and 4.2% achieved a partial response (PR).

The ORR was higher among those who received REGN5458 at a dose of 24 mg or 48 mg (n = 17; DL 4-5), at 41.2%, with 11.8% of patients collectively experiencing a CR (11.8%)/sCR (5.9%) and 23.5% of patients achieving a VGPR. Patients who received 96 mg (n = 8; DL 6), the highest dose of the antibody evaluated on the trial, experienced the highest ORR, at 62.5%; all of these patients had a VGPR.

Notably, 57% of evaluable patients (n = 4/7) who received the treatment achieved minimal residual disease (MRD) negativity. Tumor responses were not affected by the level of BCMA expression in the core biopsy, as assessed by immunohistochemistry.

Responses occurred early, with the majority of patients experiencing a response by week 4; these responses proved to deepen over time. The median duration of response (DOR) with the BCMA-targeted antibody was 6.0 months (95% CI, 1.0-13.1), and 37% of those who responded maintained their response for at least 8 months. Seventy-four percent of responders continue to receive treatment.

“We saw early, deep, and durable responses, with 95% of the responders having VGPR or better,” said study author Deepu Madduri, MD, an assistant professor of medicine, hematology, and medical oncology, as well as an assistant professor of urology at Mount Sinai Hospital, during a presentation on the data.

REGN5458 targets T-cell effector function to induce cytotoxicity in multiple myeloma cells that express BCMA. Patients who are refractory to several classes of therapies are known to experience decreases in median overall survival (OS), noted Madduri. Patients with triple- and quad-refractory disease have been found to have a median OS of 9.2 months and those with penta-refractory disease have a median OS of 5.6 months.²

“It is important to address this unmet need for patients who have relapsed/refractory multiple myeloma,” Madduri emphasized. REGN5458 may provide a possible option for this patient population because of its novel mechanism of action, she added.

The phase 1 dose-escalation study examined step-up dosing of the agent. In weeks 1 and 2, REGN5458 was evaluated at a split dose followed by a single infusion in week 3. At week 16, the agent was then administered every 2 weeks thereafter. The study utilized a 4+3 design, which examined 6 dose levels: 3 mg (n = 4), 6 mg (n = 10), 12 mg (n = 10), 24 mg (n = 10), 48 mg (n = 7), and 96 mg (n = 8). Part 1 of the trial examined dose escalation until the recommended phase 2 dose (RP2D) was established, while part 2 was the dose-expansion phase.

To be eligible for participation, patients had to have active multiple myeloma, as defined by International Myeloma Working Group criteria. Additionally, patients had to have disease that was relapsed/refractory or intolerant to 3 or more lines of therapy, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an CD38-targeted antibody; or they needed to be double-refractory to an IMiD and PI combination. Patients with non-secretory multiple myeloma were permitted, but they were required to have measurable plasmacytomas.

“This trial did not require wash out for baseline hemoglobin of less than 8 g/dL, as most trials do,” Madduri noted.

The primary objectives of the trial were to determine the safety, tolerability, and dose-limiting toxicities (DLTs) of REGN5458 and to identify the RP2D. Key secondary objectives included ORR, DOR, progression-free survival, MRD status, and OS.

A total of 49 patients received treatment on the study. The median age of participants was 64 years (range, 41-81), with 31% (n = 15) of patients aged 70 years or older. Fifty-one percent of study participants were male, the majority of patients (69%; n = 34) had an ECOG performance status of 1, and 63% (n = 31) had Revised ISS stage II disease. Sixty-seven percent of patients had previously undergone autologous transplantation.

“These patients are quite heavily pretreated, as their median prior lines of therapy was 5 and 61% of these patients were actually refractory to their last line of therapy,” Madduri explained. “One hundred percent of these patients were triple-refractory and 57% of patients were penta-refractory. If you broke this refractory status down further, 80% were carfilzomib [Kyprolis] refractory, 92% were pomalidomide [Pomalyst] refractory, and 100% were refractory to an anti-CD38 monoclonal antibody.”

Thirty-one percent (n = 15) of patients are receiving ongoing treatment, while 4% (n = 2) have completed treatment; 65% (n = 32) of patients have discontinued treatment. Reasons for treatment discontinuation included disease progression (49%; n = 24), patient non-compliance or patients/physician decision (6%; n = 3), toxicity (4%; n = 2), and death (6%; n = 3). The deaths

that occurred were because of infections that were unrelated to treatment, including sepsis (4%; n = 2) and COVID-19 (2%; n = 1).

An exploratory analysis on global health status (GHS) and quality of life (QoL) was also conducted. Patients included in the analysis completed a baseline assessment and at least 1 post-baseline assessment questionnaire.

“At week 4, we saw an observed meaningful improvement from baseline in QoL, further supporting the tolerability profile of REGN5458,” said Madduri. “In addition, the QoL was maintained throughout weeks 8-24.”

Regarding safety, the most common adverse effects (AEs) reported on the trial were hematologic, although grade 3 or higher AEs were infrequent, according to Madduri. Any-grade anemia occurred in 37% (n = 18) of patients; this was grade 3 or higher in 22% (n = 11) of patients. Lymphopenia (any grade, 18%; grade 3 or higher, 12%) and thrombocytopenia (any grade, 18%; grade 3 or higher, 6%) were also reported. The most frequently experienced nonhematologic toxicity was cytokine release syndrome (CRS) which occurred in 39% (n = 19) of patients.

CRS onset most commonly occurred within the first week of treatment, said Madduri. No grade 3 or higher CRS was reported, but 84% (n = 16/19) and 16% of patients (n = 3/19) had grade 1 and 2 CRS. Thirty-eight percent (n = 9) of patients in the DL 1-3 cohort experienced grade 1 CRS. In the DL 4-5 cohort, grade 1 CRS was reported in 29% (n = 5) of patients, while grade 2 CRS was noted in 12% (n = 2) of patients. These rates in the DL 6 cohort were 25% (n = 2) and 13% (n = 1), respectively.

The median time to CRS onset was 18.7 hours, while the median duration of CRS was 11.7 hours. Supportive measures to manage this toxicity included tocilizumab (Actemra; 32%) and steroids (21%).

No correlation between CRS and dose level was identified, according to Madduri. Moreover, no relation between CRS and response was observed.

DLTs were experienced by 2 patients; 1 patient who received the agent at 24 mg and had grade 4 acute kidney injury that was resolved with supportive care, while the other patient received the agent at 96 mg and experienced grade 3 elevated alanine transaminase/aspartate transaminase, which was also resolved with supportive care. The latter patient continues to receive ongoing treatment and has a VGPR. No cases of grade 3 or higher neurotoxicity were reported; only 6 patients (12%) experienced grade 1 and 2 neurotoxicity.

The phase 2 portion of the study has begun recruitment.

_References:

_{1. Madduri D, Roske A, Brayer J, et al. REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 291. https://bit.ly/3oxIfI9}

_{2. Gandhi U, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7}