Sean E. Harper, MD
The phase III TOWER study has been halted after an independent panel determined that blinatumomab (Blincyto) improved overall survival (OS) versus standard chemotherapy in patients with Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to Amgen, the manufacturer of the anti-CD19 immunotherapy.
TOWER is the confirmatory study for the accelerated approval of blinatumomab, which the FDA granted in December 2014, based on phase II data demonstrating strong clinical activity with the agent in ALL. The data from TOWER will be presented at an upcoming scientific meeting, Amgen reported.
“The FDA’s breakthrough therapy designation and accelerated approval of Blincyto underscore the dire prognosis for these patients. This is the first study to demonstrate an overall survival benefit for these patients with an immunotherapy, and this is a tremendously rare achievement in relapsed and refractory ALL,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen. “We will work with regulatory authorities towards a full approval for Blincyto in this population.”
The open-label phase III TOWER trial randomized patients in a 2:1 ratio to blinatumomab or investigator’s choice of 1 of 4 standard chemotherapy regimens. The primary endpoint was OS. Secondary endpoints included complete remission (CR), duration of CR, patients achieving remission with minimal residual disease (MRD), and safety.
In the phase II study that led to the approval of the drug, 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 CR with partial hematological recovery (CRh), with secondary endpoints focused on CR, CRh, relapse-free survival, and 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 MRD testing. Approximately 39% of patients who achieved a CR/CRh went on to receive a HSCT.
According to data presented 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.
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 1 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.