FDA Approval: Blinatumomab

Abstract

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035-9. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the mechanism of action of blinatumomab, how the toxicities of blinatumomab reflect the mechanism of action, and the level of evidence supporting use of blinatumomab for the treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia.

Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance

“…The frequent occurrence of bypass signaling resistance suggests the need for an approach whereby co-targeting multiple pathways could serve as a strategy to delay or overcome resistance. Bi-specific antibodies present one such approach, and have recently been approved in leukemia, with several other bi-specific antibodies in advanced clinical development (22,23). For NSCLC, the novel bi-specific antibody JNJ-61186372 targeting EGFR and Met was recently reported to be effective in EGFR TKI resistant preclinical models (24,25).…”

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

“…Once a T cell is fully activated, it is capable of lysing several tumor cells in consecutive order, a process termed "serial killing" [5]. The most advanced CD3 bispecific protein is Blinatumomab, a CD3/CD19 Bispecific T cell Engager (BiTE ® ) that received FDA approval for the treatment of refractory B-precursor acute lymphoblastic leukemia (ALL) following impressive efficacy data observed in a phase II trial [6]. Due to its small size of around 50 kDa, Blinatumomab is rapidly cleared from circulation and therefore requires a continuous intravenous (i.v.)…”

“…Furthermore, a CD3/EGFR BiTE ® caused acute toxicity in cynomolgus monkeys likely due to EGFR expression in normal tissue [10]. Not surprisingly, most CD3 bispecific proteins currently in clinical trials are targeting receptors whose expression is confined to the hematopoietic lineage (CD19, CD20, CD123) [6,11,12], or receptors with exceptionally high tumor specificity, such as carcinoembryonic antigen (CEA) [13], prostate-specific membrane antigen (PSMA) [14] or MHCI-gp100 complex [15]. Thus, the applicability of T cell redirection with currently available technologies is limited to antigens with extraordinarily high tumor specificity, which impedes the application to many solid tumor types, where no antigens with comparable high specificity are available.…”

Bispecific antibodies in cancer immunotherapy

“…Currently, 2 bispecific antibodies, catumaxomab (anti-EpCAM and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3), have been approved for patient care and have made a substantial impact on both research and the development of biologics. [7][8][9] Many more diverse formats for bispecific antibodies are now in transit from the bench to bedside (Table 1). This review is focused on bispecific antibodies that recruit immune cells for cancer therapy, which was first demonstrated in vitro 30 y ago.…”

“…62 The BiTE antibody blinatumomab (AMG 103, MT103) is approved by the US Food and Drug Administration for treatment of patients with Philadelphia chromosome-negative precursor Bcell acute lymphoblastic leukemia (B-ALL). 8,9 Blinatumomab is composed of 2 scFvs, one targeting CD19 and one against CD3, with equilibrium dissociation constants (K D ) of 10 ¡9 and 10 ¡7 M, respectively. 66 After engagement of T cells via the anti-CD3 domain, blinatumomab creates a structural immune synapse with CD19 C cells, 68 leading to T-cell activation and cytotoxicity toward CD19 C cells.…”