The New England Journal of Medicine published results from the Phase 3 TOWER study evaluating the efficacy of blinatumomab versus standard of care (SOC) chemotherapy in high-risk adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), one of the most aggressive B-cell malignancies.
Results from the analysis showed that median overall survival (OS) was 7.7 months (95 percent CI: 5.6, 9.6) for blinatumomab versus four months (95 percent CI: 2.9, 5.3) for SOC (hazard ratio [HR] for death=0.71; p=0.012).
The TOWER study is the confirmatory study for the Phase 2 trial that supported the U.S. Food and Drug Administration’s (FDA) accelerated approval designation for blinatumomab in 2014.
Blinatumomab is a bispecific CD19-directed CD3 T cell engager antibody construct.
It is the first bispecific antibody construct from Amgen's CD19-directed CD3 T cell engager platform, which helps the body’s immune system target cancer cells and represents an entirely new area of oncology research.
CD19-directed CD3 T cell engager antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.
“Historically, patients with relapsed or refractory ALL have a poor prognosis, with an overall survival of just four months on standard of care chemotherapy," said Max S. Topp, M.D., professor and head of Hematology, University Hospital of Wuerzburg, Germany. "Findings from this head-to-head study showed that blinatumomab almost doubled the median overall survival from four to 7.7 months, offering these high-risk patients a much needed alternative to chemotherapy that is both innovative and effective.”
The survival benefit for blinatumomab was independent of allogeneic stem cell transplant (alloSCT), as the median OS, censored at the time of alloSCT, was 6.9 months for blinatumomab versus 3.9 months for SOC.
Improvement in OS was generally consistent regardless of age, prior salvage therapy or prior alloSCT.
The magnitude of this benefit appeared greatest in earlier lines of salvage.
Neutropenia and infection greater than or equal to grade 3 appeared less frequently with blinatumomab compared to SOC, while neurological events appeared at a similar rate between arms.
"Adults with Ph- relapsed or refractory B-cell precursor ALL are in critical need of new treatment options," said Hagop M. Kantarjian, M.D., professor and chair of the Department of Leukaemia at The University of Texas MD Anderson Cancer Center, Houston. “Results from the TOWER study reinforce the potential of this single agent bispecific T cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved.”
Evaluation of key secondary endpoints showed that remission rates were also higher for blinatumomab versus SOC.
In the blinatumomab group, 34 percent of patients achieved complete remission versus 16 percent in the SOC group.
Patients receiving blinatumomab also had a higher rate of combined complete remission or complete remission with partial or incomplete hematologic recovery (44 percent versus 25 percent).
Among patients with complete remission or complete remission with partial or incomplete hematologic recovery, 76 percent in the blinatumomab group versus 48 percent in the SOC group achieved minimal residual disease (MRD) negative status, a measure of eradication of residual disease at the molecular level.
Also among these patients, the median duration of remission was 7.3 months in the blinatumomab group versus 4.6 months in the SOC group.
For the key secondary efficacy endpoint of event-free survival, six month estimates in the blinatumomab and chemotherapy groups were 30.7 percent and 12.5 percent, and the HR was 0.55 (95 percent CI: 0.43, 0.71), favouring blinatumomab.
“As the first study of an immunotherapy to demonstrate overall survival benefit in adult patients with Ph- relapsed or refractory B-cell precursor ALL, TOWER represents an important advance in the understanding of this aggressive, ultra-orphan disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “As demonstrated by the data published today in the New England Journal of Medicine, blinatumomab has proven to improve overall survival, extend remission rates and reduce minimal residual disease in these high-risk patients who previously have had limited effective options.”
Safety results among subjects who received blinatumomab were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL.
For the most common adverse events (greater than or equal to 10 percent incidence rate) in the blinatumomab arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least 5 percent higher for blinatumomab compared to SOC chemotherapy.
ALL is a rare and rapidly progressing cancer of the blood and bone marrow.
Adult patients diagnosed with Ph- B-cell precursor ALL are often young, with a median age at diagnosis of 34-39.
Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.
Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.