Subcutaneous Isatuximab Elicits Comparable Efficacy, Safety to IV Formulation in Relapsed/Refractory Myeloma

Subcutaneous administration of isatuximab-irfc (Sarclisa) through a syringe pump or on-body delivery system (OBDS) demonstrated similar efficacy and safety compared with intravenous (IV) isatuximab when combined with pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory multiple myeloma, according to interim results from a phase 1b study (NCT04045795).

Patients received treatment in 1 of 4 cohorts: 10 mg/kg of IV isatuximab (IV), 1000 mg of subcutaneous isatuximab (SC1000), the recommended phase 2 dose (RP2D) of 1400 mg of subcutaneous isatuximab (SC1400), or 1400 mg of isatuximab via an on-body delivery system (OBDS).

Findings presented at the 19th International Myeloma Society Annual Meeting showed that the overall response rate (ORRs) for patients in the IV (n = 12), SC1000 (n = 12), SC1400 (n = 10), and OBDS (n = 22) cohorts were 66.7%, 66.7%, 80.0%, and 77.3%, respectively. Additionally, 50.0%, 41.7%, 40.0%, and 40.9% of patients in the IV, SC1000, SC1400, and OBDS cohorts, respectively, experienced a very good partial response (VGPR) or better,

Specifically, 33.3%, 16.7%, 20.0%, and 27.3% of patients in the IV, SC1000, SC1400, and OBDS cohorts, respectively, had a VGPR, and the rates of stringent complete response (sCR) or complete response (CR) were 16.7%, 25.0%, 20.0%, and 13.6%.

The combined ORR among patients in the SC1400 and OBDS cohorts (n = 32) was 78.1%, with 40.6% of patients achieving a VGPR or better. The VGPR rate and sCR/CR rates were 25% and 15.6%, respectively.

“Subcutaneous delivery of isatuximab would optimize convenience of administration, with the intent to enhance comfort and quality of life of the patients, and reduce health care resources,” lead study author, Hang Quach, MBBS, FRACP, FRCPA, MD, a professor of hematology at St. Vincent’s Hospital, University of Melbourne, in Victoria, Australia, and colleagues, wrote in a poster of the data.

Isatuximab is an anti-CD38 monoclonal antibody that binds to an epitope of CD38 and kills multiple myeloma cells. The phase 3 ICARIA-MM study (NCT02990338) led to the approval of IV isatuximab plus pomalidomide and dexamethasone in multiple countries for patients with relapsed/refractory multiple myeloma who have had at least 2 prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor (PI).

The multicenter, open-label phase 1b study investigated the safety, pharmacokinetics, and efficacy of subcutaneous isatuximab vs IV isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who have received at least 2 prior lines of treatment.

A total of 56 patients were randomized 2:1 by sequential assignment to cohorts administering isatuximab at 1000 mg subcutaneously through syringe pump (n = 12), 10 mg/kg IV (n = 12), or 1400 mg subcutaneously through syringe pump (n = 10). An expansion cohort was later implemented, where patients received 1400 mg of isatuximab subcutaneously through an OBDS, which was a wearable abdominal bolus injector applied by a healthcare professional (n = 22). Based on these findings, 1400 mg was selected as the recommended phase 2 dose (RP2D) for subcutaneous isatuximab. In total, 32 patients in the study were treated at the RP2D.

In all cohorts, isatuximab was administered once weekly for 4 weeks during cycle 1, and then once every 2 weeks in subsequent cycles in combination with pomalidomide and dexamethasone. The median duration of OBDS injection was 10 minutes at first and subsequent administrations.

The primary end points of this trial were safety, including dose-limiting toxicity and injection-site reactions, plus pharmacokinetics. Key secondary end points included ORR per the International Myeloma Working Group response criteria, progression-free survival (PFS), and CD38 receptor occupancy.

At enrollment, 67%, 33%, 60%, and 50% of patients in the IV, SC1000, SC1400, and OBDS cohorts, respectively, had International Staging System stage II to III disease. The OBDS cohort had received a median of 3.0 (range, 2-6) prior treatment lines, compared with 3.5 (range, 2-7), 3.0 (range, 2-6), and 2.5 (range, 1-4) in the IV, SC1000, and SC1400 cohorts, respectively. Of the IV cohort, 58.3% of patients were refractory to lenalidomide, 58.3% were refractory to a PI, and 50.0% were refractory to both.

Of the SC1000 cohort, 91.7% of patients were refractory to lenalidomide, 75.0% were refractory to a PI, and 66.7% were refractory to both. Of the SC1400 cohort, 70.0% of patients were refractory to lenalidomide, 50.0% were refractory to a PI, and 40.0% were refractory to both. Of the OBDS cohort, 95.5% (n = 21) of patients were refractory to lenalidomide, 72.7% (n = 16) were refractory to a PI, and 72.7% (n = 16) were refractory to both.

At a data cutoff of January 20, 2022, of the 12 patients in the IV cohort, 8 discontinued treatment because of disease progression (n = 7) or withdrawal (n = 1). Of the 12 patients in the SC1000 cohort, 9 discontinued treatment because of disease progression (n = 6), withdrawal (n = 1), or other reasons (n = 2). Of the 10 patients in the SC1400 cohort, 5 discontinued treatment because of disease progression. Of the 22 patients in the OBDS cohort, 3 discontinued treatment because of disease progression.

The median follow-up in the IV, SC1000, and SC1400 cohorts was 20.6 months, 23.8 months, and 18.1 months, respectively, vs 6.5 months for the OBDS cohort. This difference was caused by the sequential accrual process. Study authors noted that longer follow-up is needed in the OBDS cohort.

Additional data showed that the estimated median PFS was 22 months (95% CI, 2.3-not calculable [NC]) in the IV cohort, 12.5 months (95% CI, 5.6-NC) in the SC1000 cohort, and not reached in the SC1400 (95% CI, 5.6-NC) and OBDS (95% CI, 5.6-NC) cohorts.

Regarding safety, the incidence of all-causality treatment-emergent adverse effects (TEAEs) of grade 3 or higher was comparable across cohorts. All incidences of infusion/injection reactions were grade 2 and happened only at the first IV or subcutaneous injection.

Patients who received subcutaneous isatuximab at 1400 mg through an OBDS had no injection reactions, compared with an injection reaction rate of 10% or less in each of the other study cohorts. Patients in the OBDS cohort also displayed high levels of local tolerability, with 22.7% (n = 5) experiencing a total of 7 injection-site reactions, which were all grade 1, out of 305 total administrations. These episodes included 5 instances of injection-site erythema, 1 injection-site induration, and 1 injection-site hemorrhage.

Investigators observed grade 3/4 TEAEs in 100% of patients in the IV cohort, 91.7% of patients in the SC1000 cohort, 90.0% of patients in the SC1400 cohort, and 100% of patients in the OBDS cohort. The rate of grade 3/4 TEAEs among patients who received the RP2D was 96.9%.

The OBDS cohort experienced a lower incidence of treatment-related grade 3/4 TEAEs (77.3%) vs the other cohorts, where the rates of treatment-related grade 3/4 TEAEs were 83.3%, 91.7%, and 80.0% in the IV, SC1000, and SC1400 groups, respectively. However, study authors noted this difference may have been caused by shorter follow-up with the OBDS cohort. The incidence of treatment-related grade 3/4 TEAEs was 78.1% in patients given the RP2D.

Grade 5 TEAEs were observed in 2 (9.1%) of patients in the OBDS cohort and none of the other cohorts, for a total of 6.3% of the RP2D group.

Serious TEAEs were reported in 75.0%, 75.0%, 70.0%, and 50.0% of the IV, SC1000, SC1400, and OBDS cohorts, respectively. In total, serious TEAEs occurred in 56.3% of the RP2D group. Serious treatment-related TEAEs were reported in 16.7%, 25.0%, 50.0%, and 9.1% of the IV, SC1000, SC1400, and OBDS cohorts, respectively, with a total of 21.9% of the RP2D group.

The most common TEAEs of grade 3 or higher in the OBDS cohort included neutropenia (77.3%), anemia (13.6%), and thrombocytopenia (9.1%; n = 2). Notably, 1 patient each in the IV and OBDS cohorts and 2 patients in the SC1400 cohort developed febrile neutropenia.

No patients prematurely discontinued isatuximab due to a TEAE. However, 1 patient from the SC1000 cohort and 2 patients from the SC1400 cohort prematurely discontinued pomalidomide because of TEAEs. Two patients in the SC1400 cohort prematurely discontinued dexamethasone because of TEAEs.

Pharmacokinetics were comparable between the subcutaneous cohorts after the 1000 mg or 1400 mg first dose, likely because of an unbalanced distribution of pharmacokinetic influential covariates between the SC1000 and SC14000 cohorts. The mean trough concentration at the end of each weekly dosing period was higher in patients who received 1400 mg of isatuximab through an on-body delivery system or pump than in those who received 10 mg/kg of IV isatuximab. All subcutaneous and OBDS cohorts reached high CD30 receptor occupancy saturation by isatuximab on bone marrow plasma cells.

“Isatuximab subcutaneous administration by on-body delivery system is well tolerated, requires a short duration of injection, and provides a convenient, hands-free option,” the study authors concluded.

Reference

Quach H, Parmar G, Ocio EM, et al. Subcutaneous isatuximab administration by an on-body delivery system in combination with pomalidomide-dexamethasone in relapsed/refractory multiple myeloma patients: interim phase 1b study results. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022. Los Angeles, CA. P-267