Richard Pazdur, MD
The FDA has granted an accelerated approval to the anti-CD19 immunotherapy blinatumomab (Blincyto) as a treatment for patients with Philadelphia chromosome-negative relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), based on findings from a phase II trial.
Blinatumomab, a novel bispecific T cell engager (BiTE) antibody specific to CD19 and CD3, demonstrated a complete remission (CR) rate of 32% for a median duration of 6.7 months, according to the FDA. Additionally, the rate of CR or CR with partial hematological recovery (CRh) was 42%.
A decision on the new drug application for blinatumomab was not expected until May 19, 2015, placing the agency's actions well ahead of deadline. The rapid approval follows a priority review and a breakthrough therapy designation, and establishes blinatumomab as the first approved agent to target CD19, a promising target under exploration for patients with B-cell malignancies.
“Immunotherapies, especially Blincyto with its unique mechanism of action, are particularly promising for patients with leukemia,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA's Center for Drug Evaluation and Research, said in a statement. “Recognizing the potential of this novel therapy, the FDA worked proactively with the sponsor under our breakthrough therapy designation program to facilitate the approval of this novel agent.”
In the study, intravenous blinatumomab was administered for 4 weeks followed by a 2-week resting period for up to 5 cycles to 189 patients with Ph- ALL. The median age of patients was 39 and 34.1% had undergone a hematopoietic stem cell transplantation (HSCT) prior to entering the trial. The primary endpoint of the study was CR or CRh, with secondary endpoints focused on CR, CRh, relapse-free survival, and overall survival (OS).
According to the FDA label for the drug, the CR rate was 32.4% (95% CI, 25.7-39.7), the CRh rate was 9.2% (95% CI, 5.4-14.3), and the combined CR/CRh rate was 41.6% (95% CI, 34.4-49.1). Overall, 80% of patients who achieved a CR also responded by minimal residual disease (MRD) testing. Approximately 39% of patients who achieved a CR/CRh went on to receive a HSCT.
According to data at the 2014 ASCO Annual Meeting, CR/CRh rates were 50%, 47%, 36%, and 34% for patients treated with no prior salvage therapies, 1 prior therapy, 2 prior therapies, and 3 or more therapies, respectively. The median relapse-free survival was 5.9 months with blinatumomab (95% CI, 4.8-8.3). The median OS was 6.1 months (95% CI, 4.2-7.5). A total of 74% of patients were minimal residual disease responders.
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).
The FDA recommended dose and schedule for blinatumomab in patients who weighed at least 45 kg is 9 mcg/day on days 1-7 and at 28 mcg/day on days 8-28 of the first 42-day cycle, and 28 mcg/day on days 1-28 in later cycles.
"The FDA's breakthrough therapy designation and accelerated approval of Blincyto underscores the critical need for new treatment options for patients with relapsed or refractory B-cell precursor ALL, who are often young adults," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the company developing the drug, said in a press release. "Blincyto is the first clinical and regulatory validation of the BiTE platform, a new and innovative approach that helps the body's own immune system fight cancer."
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.
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 this time, Micromet was developing blinatumomab, labeled MT103; however, upon acquiring this company in 2012, Amgen accelerated exploration into the novel immunotherapy.
An open-label phase III study comparing blinatumomab with chemotherapy is currently enrolling patients with relapsed or refractory B-precursor ALL. 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.