A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients with Previously Treated AL Amyloidosis (SWOG S1702; NCT#03499808)

Abstract

Background: Isatuximab (SAR650984) is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in AL amyloidosis. It has been shown to be efficacious and well tolerated in relapsed and refractory multiple myeloma as a single agent and in combination. Here we report on the preliminary results of a prospective multi-center, phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included age ≥ 18 years, relapsed or refractory systemic AL amyloidosis, ≥ 1 prior line of therapy, measurable disease (defined as a positive monoclonal serum immunofixation electrophoresis (IFE) or urine IFE, a serum free light chain ratio outside of the normal range (0.25-1.65), and a difference in the involved versus the uninvolved serum free light chain of ≥ 4.5 mg/dL), at least one organ involved, not refractory to daratumumab, ECOG performance status 0-2, creatinine clearance ≥25 mL/min as measured by 24-hour urine collection or as estimated by Cockcroft and Gault formula, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28 day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: At data cut-off (July 24, 2020), 43 patients were registered from March 2018 to September 2019 at 14 institutions. Thirty six patients were eligible with 35 patients receiving at least one dose of isatuximab. Of the eligible patients, the median age was 70 (range 40-81). Prior therapies included proteasome inhibitors in 32 patients (89%), high dose therapy followed by autologous stem cell transplant in 17 patients (47%), immunomodulatory therapy in 9 patients (25%), and anti-CD38 monoclonal antibody therapy in 2 patients (6%). Single organ system involvement was seen in 19 patients (53%), ≥ 2 organ systems in 17 patients (47%), 16 patients (44%) had renal involvement, and 24 (67%) had cardiac involvement. For those with cardiac involvement, 7 patients (29%) had cardiac biomarker stage II and 9 patients (38%) had stage III disease using the Revised Mayo Staging (Kumar S et al., J Clin Oncol, 2012). A total of 17 patients remain on therapy. The median duration on treatment for eligible patients is currently 11.8 months (current range, 0.3-22.1). Of the 19 patients who discontinued treatment, the most common reasons included adverse events in 5 patients (26%), disease progression in 4 patients (21%), sub-optimal response in 2 patients (11%), and concerns related to COVID-19 in 2 patients (11%). The current median follow up is 16.3 months. The most common drug-related AEs were infusion related reactions in 18 patients (50%) with the majority (16/18) being grade I or II, anemia in 9 patients (25%) with the majority (8/9) being grade I, and lymphopenia in 8 patients (22%). Patient characteristics and preliminary safety data were previously presented at the International Symposium on Amyloidosis. The overall hematologic response rate was 77%. Hematological complete response (CR) was observed in 1 of 35 evaluable (completing at least 1 dose) patients (3%), very-good-partial response (VGPR) in 19 patients (54%), and partial response (PR) in 7 patients (20%). Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab in these patients is associated with a good safety profile similar to other monoclonal antibodies against CD38. The data will be updated at the meeting. Disclosures Sanchorawala: Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Janssen: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Takeda: Research Funding; Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding. Neparidze:GlaxoSmithKline: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member . Sarosiek:Spectrum: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Usmani:Incyte: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Celgene: Other; Seattle Genetics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Isatuximab is FDA approved for relapsed refractory myeloma in combination with pomalidomide and dexamethasone. Isatuximab is not FDA approved for AL amyloidosis.

AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies

“…ISA is approved as a third-line therapy in combination with pomalidomide and dexamethasone and a second-line therapy in combination with carfilzomib and dexamethasone based on the positive results of the ICARIA and IKEMA phase 3 studies, respectively ( 105 , 106 ). The preliminary result of a multicenter phase 2 study of isatuximab for patients with previously treated AL amyloidosis proved to be safe with encouraging efficacy based on 3% hematologic complete response, 54% very good partial response, and 1-year estimated PFS of 85% ( 107 ). A trial investigating isatuximab for the treatment of high-risk, newly diagnosed AL is currently ongoing, and results are eagerly awaited ( NCT04754945 ).…”

AL amyloidosis: untangling new therapies

“…Preliminary results presented at the Amer i can Society of Hematology meet ing in Decem ber 2020 dem on strated an ORR of 77% and a 1year esti mated PFS and OS of 85% and 97%. 35 Isatuximab is also being eval u ated in the newly diag nosed set ting among patients with advanced car diac dis ease (NCT04754945). AntiCD38 anti body drug con ju gate STI 6129, com pris ing a fully human antiCD38 anti body con ju gated to the micro tu bule inhib i tor duostatin, is also being stud ied in a phase 1b study in the relapsed set ting (NCT04316442).…”

Current Updates on the Management of AL Amyloidosis

“…Therapy is aimed at achieving deep and rapid hematological response, which reverses amyloid-mediated organ dysfunction, and improves OS [ 13 - 15 ]. Table 2 [ 9 , 16 - 44 ] summarizes therapeutic combinations in the management of AL amyloidosis.…”