Sean E. Harper, MD
Monotherapy with blinatumomab (Blincyto) has demonstrated promising complete remission (CR) or CR with partial hematological recovery (CRh) rates in adult patients with relapsed or refractory Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL), according to top-line findings from a phase II study released by the immunotherapy's developer, Amgen.
Data from the open-label phase II study were not yet made publicly available. However, in a statement Amgen said that the novel bispecific T cell engager (BiTE) antibody induced a CR/CRh in a clinically meaningful number of patients. Additionally, the company noted that adverse events (AEs) in the phase II study were consistent with prior studies.
"These top-line results are encouraging and support blinatumomab as a potential treatment option for patients with relapsed or refractory Philadelphia chromosome-positive B-cell precursor ALL," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement.
In the phase II study, blinatumomab was administered as a continuous intravenous infusion in a 6-week cycle. The immunotherapy was administered for 4 weeks followed by a 2-week treatment-free duration. For the first week of treatment blinatumomab was administered at 9 μg/day followed by a gradual dose escalation from day 8 through 29 to a final dose of 28 μg/day, which was the dose used for subsequent cycles.
Patients enrolled in the study had greater than 5% blasts in their bone marrow with an ECOG PS ≤2. All patients were relapsed or refractory to at least one second-generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) or were intolerant/refractory to imatinib or second-generation TKIs.
The primary endpoint of the study was CR/CRh within 2 cycles of treatment, with secondary outcome measures focused on minimal residual disease (MRD), duration of response, overall survival, and safety. Other outcome measures of the study are focused on MRD and the efficacy of blinatumomab against specific BCR-ABL mutations. The targeted enrollment for the study was 45 patients (NCT02000427)
"We are hopeful that our comprehensive ALL development program for blinatumomab, the first clinical and regulatory validation of the BiTE platform, will continue to demonstrate clinical effectiveness for patients with this serious disease," Harper noted.
Blinatumomab is a recombinant, single-chain monoclonal antibody that possesses antigen-recognition sites for CD3 and CD19. The CD3 complex consists of T cell surface glycoproteins, while CD19 is a tumor-associated antigen. The combination of these recognition sites into one therapy is thought to promote cytotoxic T lymphocyte and helper T lymphocyte activity against CD19-expressing B-lymphocytes.
Given its mechanism of action, the drug holds potential across a variety of B-cell malignancies. As a result, in February 2006 the FDA granted blinatumomab an orphan drug designation as a treatment for types of indolent B cell lymphoma, ALL, and chronic lymphocytic leukemia. At the time of this designation, Micromet was developing blinatumomab, labeled MT103; however, upon acquiring this company in 2012, Amgen accelerated exploration into the novel immunotherapy.
Quickly following this acquisition, the FDA granted the therapy a breakthrough therapy designation, which was followed by an accelerated approval for patients with relapsed/refractory Ph-negative ALL in December 2014. This approval established blinatumomab as the first approved agent to target CD19, a promising target under exploration for patients with B-cell malignancies.
In the Ph-negative setting, the FDA approval was based on findings from a phase II study in which blinatumomab demonstrated a CR rate of 32.4% for a median duration of 6.7 months, according to the FDA. Additionally, the rate of CR/CRh was 41.6%. Overall, 80% of patients who achieved a CR also responded by MRD testing and approximately 39% of patients who achieved a CR/CRh went on to receive a stem cell transplant.
In the pivotal phase II study in Ph-negative ALL, the most common all-grade adverse events were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). In all, 3 patients experienced treatment-related grade 5 adverse events: sepsis (n = 2) and candida infection (n = 1).
Neurological side effects occurred in approximately 50% of patients. Additionally, 11% experienced cytokine release syndrome. To address these side effects, the FDA approved blinatumomab with a Boxed Warning and Risk Evaluation and Mitigation Strategy (REMS).
Multiple phase III studies continue to assess blinatumomab for patients with ALL. An open-label phase III study comparing blinatumomab with chemotherapy is currently enrolling patients with relapsed or refractory B-precursor ALL (NCT02013167). In this trial, patients will be randomized in a 2:1 ratio to receive blinatumomab or treatment with investigator choice of 1 of 4 protocol defined chemotherapy regimens. The primary endpoint of this study is overall survival (OS).
A second phase III study, initiated by the National Cancer Institute (NCI), is exploring blinatumomab with or without chemotherapy for patients with newly diagnosed BCR-ABL-negative ALL. The primary endpoint of the study is OS, with a target enrollment goal of 360 patients (NCT02003222).
In addition to phase III studies, a phase II NCI-initiated study is looking at blinatumomab plus chemotherapy for elderly patients with newly diagnosed Ph-negative ALL. Additionally, this study is also assessing blinatumomab plus dasatinib and prednisone for elderly patients with newly diagnosed Ph-positive ALL. The primary objectives of the study are to identify dose-limiting toxicities and to assess 3-year OS rates (NCT02143414).