The BCMA- and CD3-directed bispecific antibody REGN5459 led to fast onset, deep, and dose-dependent responses sustained over time, with a high frequency of manageable low-grade cytokine release syndrome in patients with relapsed/refractory multiple myeloma.
The BCMA- and CD3-directed bispecific antibody REGN5459 led to fast onset, deep, and dose-dependent responses sustained over time, with a high frequency of manageable low-grade cytokine release syndrome (CRS) in patients with relapsed/refractory multiple myeloma, according to findings from a first-in-human phase 1/2 trial (NCT04083534) that were presented at the 2023 AACR Annual Meeting.1,2
At a median follow-up of 9 months (range, 1-32), in the total population (n = 43), the objective response rate (ORR) was 65.1%, which included a very good partial response or better (≥VGPR) rate of 58.1% and a complete response or better (≥CR) rate of 51.2%.
“REGN5459, a BCMAxCD3 bispecific antibody with low affinity to CD3, showed manageable safety and promising efficacy in heavily pretreated [patients with] relapsed/refractory multiple myeloma,” lead study author Attaya Suvannasankha, MD, of Indiana University Simon Cancer Center in Indianapolis, said in a presentation of the data.
Multiple myeloma remains incurable despite improved outcomes with combination therapy. REGN5459 binds to BCMA on multiple myeloma cells and, with low affinity to CD3 on T cells, triggers T-cell activation and plasma cell depletion with low cytokine release preclinically.
“Low-affinity T-cell engagers potentially result in T cells that continue killing the cancer cells but with fewer side effects,” Suvannasankha said in a press release.2
To be eligible for enrollment in the trial, patients had to have active multiple myeloma by International Myeloma Working Group criteria, relapsed/refractory disease or intolerance to at least 3 lines of therapy including an anti-CD38 antibody, proteasome inhibitor, and immunomodulatory drug, or have exhausted all available treatment options.1
In phase 1, patients in dose levels 1 through 4 received a split dose of 0.5 mg and 10 mg of REGN5459 on days 1 and 2 of week 1 followed by between a split dose of 1.5 mg and 30 mg on days 1 and 2 of week 2, and between 3 mg and 60 mg in weeks 3 through 16. In dose levels 5 through 8, patients received a single 5-mg dose of REGN5459 on day 1 of week 1 followed by a single dose between 15 mg and 25 mg on day 1 of week 2, a split dose of 60 mg to 450 mg on days 1 and 2 of week 3, and 120 mg to 900 mg on day 1 of week 4 and thereafter.
In dose levels 1 through 8, treatment after week 16 was administered every 2 weeks. In dose level 5, fixed step-up dosing was used to reduce the risk of CRS.
In phase 2, patients received a single 5-mg dose of REGN5459 on day 1 of week 1, a single 25-mg dose on day 1 of week 2, a split dose of 240 mg on days 1 and 2 of week 3, and 480 mg on day 1 of week 4 and thereafter.
Patients received 20 mg of dexamethasone administered over 4 hours prior to each infusion. Dexamethasone was tapered beginning in weeks 3 and 4 with the shorter infusion duration.
The primary objectives of phase 1 were to establish the safety, tolerability, and dose-limiting toxicities of the regimen and determine its recommended phase 2 dose (RP2D). In phase 2, ORR was evaluated. Key secondary end points were duration of response (DOR), progression-free survival, minimal residual disease (MRD) negative–status, overall survival, pharmacokinetic properties, and immunogenicity.
Regarding baseline characteristics, the median patient age was 67 years (range, 26-85), and 39.5% (n = 17) of patients were 70 years of age or older. Approximately half (51.2%; n = 22) of patients were female, and most were White (79.1%; n = 34). Most patients had an ECOG performance status of 1 (62.8%; n = 27), Revised International Staging System stage II disease at study entry (53.5%; n = 23), and prior autologous transplant (86%; n = 37).
The minority of patients had measurable extramedullary plasmacytoma (14%; n = 6), 50% or greater marrow plasmacytosis (30.2%; n = 13), and high-risk cytogenetics (16.3%; n = 7). The median soluble BCMA level was 0.24 mg/L (range, 0.025-4.2).
The median number of prior lines of therapy was 5 (range, 2-9). Most patients (95.3%; n = 41) had received at least 3 prior lines of therapy; 93% (n = 40) and 72.1% (n = 31) of patients received at least 4 and 5 prior lines of treatment, respectively. Additionally, most patients were refractory to triplet (81.4%; n = 35) or quadruplet therapy (62.8%; n = 27); approximately one-fifth (20.9%; n = 9) of patients were penta-refractory. Eighty-six percent (n = 37) of patients were refractory to their last prior line of therapy.
Additional efficacy data demonstrated that the ORR was 90.5% with higher doses of REGN5459 ranging from 480 mg and 900 mg (n = 21); the VGPR or better and CR or better rates were 76.2% and 61.9%, respectively. Among 9 patients who received between 120 mg and 240 mg of REGN5459, the ORR was 66.7%, including a 22.2% CR rate and 44.4% stringent CR (sCR) rate. Among 13 patients who received between 3 mg and 60 mg of REGN5459, the ORR was 23.1%, with a CR rate of 7.7% and an sCR rate of 15.4%.
“Reponses were observed in doses above dose level 3, with 90% of patients responding at the higher doses,” Suvannasankha said.
Among patients who achieved a CR or better with available MRD data (n = 19/22), 79% (n = 15) were MRD negative at a sensitivity of 10–5.
Suvannasankha noted that responses occurred early, were durable, and deepened over time. The median time to response was 0.8 months, and the longest responses were ongoing for 26 months or more at date cutoff. The median DOR was not reached, and the estimated 12-month DOR rate was 78.1% (95% CI, 54.9%-90.3%).
Regarding safety, the maximum tolerated dose was not reached, and the RP2D was determined to be 480 mg. The most frequent treatment-emergent adverse effects (TEAEs) occurring in at least 35% of patients were CRS (53.5%; n = 23), cough (39.5%; n = 17), diarrhea (39.5%; n = 17), fatigue (39.5%; n = 17), neutropenia (39.5%; n = 17), and anemia (34.9%; n = 15).
Infections occurred in 62.8% of patients (n = 27), the most common of which were urinary tract infections (UTIs; 18.6%), pneumonia (16.3%), sinusitis (16.3%), and upper respiratory tract infection (16.3%). Grade 3/4 infections occurred in 30.2% (n = 13) of patients, the most common of which were pneumonia (9.3%), COVID-19 (7%), sepsis (7%), and UTI (4.7%).
Additional any-grade TEAEs included lymphopenia (30.2%; n = 13), thrombocytopenia (23.3%; n = 10), headache (27.9%; n = 12), pyrexia (27.9%; n = 12), nasal congestion (23.3%; n = 10), nausea (23.3%; n = 10), infusion-related reaction (20.9%; n = 9), and rhinorrhea (20.9%; n = 9).
In the overall population, grade 1, 2, and 3 CRS occurred in 46.5%, 2.3%, and 4.7% of patients, respectively. No cases of grade 4 or 5 CRS were reported. The median time to first CRS onset was 17 hours (range, 1-84) and median duration was 15 hours (range, 1-219). Tocilizumab and steroids were used for supportive care in 16.3% (n = 7) and 9.3% (n = 4) of patients, respectively.
In patients dosed with between 480 mg and 900 mg of REGN5459, CRS occurred in 81% of patients (grade 1, n = 16; grade 2, n = 1). In the 120 mg to 240 mg cohort, the rate of CRS was 33.3% (grade 1, n = 2; grade 3, n = 1). In the lowest dose cohort (3 mg to 60 mg), 23.1% of patients experienced CRS (grade 1, n = 2; grade 3, n = 1). “Fixed step-up dosing was introduced after one patient experienced grade 3 CRS with 10 mg on day 1,” Suvannasankha said.
One patient experienced grade 2 immune effector cell–associated neurotoxicity syndrome in the 10 mg to 30 mg dose level.
Seven patients (16.3%) discontinued treatment because of TEAEs, and two deaths occurred owing to pneumonia and COVID-19.
Suvannasankha concluded by stating, “Further development of REGN5459 is under consideration.”
Disclosures: Dr Suvannasankha disclosed research support from Bristol Myers Squibb, Genentech, GSK, Janssen, Regeneron Pharmaceuticals, Inc., and Sutro BioPharma, Inc.; and advisory board participation for Bristol Myers Squibb, GSK, Janssen, and Regeneron Pharmaceuticals, Inc.