Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.

Abstract

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.

Treatment Options for Triple-class Refractory Multiple Myeloma

“…2 lines of therapy (PI and IMiD) of the bispecific antibody construct AMG 420 showed promising evidence of activity, with 13 of 42 patients experiencing a response. 50 Of these, 3 were CRs and 2 were PRs. 50 The median time to any response was 1 month.…”

“…50 Of these, 3 were CRs and 2 were PRs. 50 The median time to any response was 1 month. 50 Safety was comparable to that of other immunotherapies, with SAEs in 50% of patients.…”

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

“…In a first-in-human study of AMG 420 immunotherapy (NCT02514239), which binds to BCMA on MM cells and CD3 on T cells, 42 patients received AMG 420 (0.2-800 µg/d) (Table S1). There were 13/42 responders (6 stringent complete responses (sCRs), 3 complete responses (CRs), 2 very good partial responses (VGPRs), and 2 partial responses (PRs)) [72]. A number of BiTEs targeting CD33, CD123, and CLEC12A/CCL-1 (CD371) have been developed for AML [73][74][75][76].…”

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

“…AMG420 was administered as a continuous intravenous infusion due to its short half-life at doses ranging from 0.2 to 800 mcg/die. At the MTD of 400 mcg/day, the ORR was 70%, with 5/10 patients obtaining MRD-negative sCRs (10 −4 ) [119]. Dose-limiting toxicities were cytokine release syndrome (CRS, 1 patient) and peripheral neuropathy (2 patients).…”