Amgen announced that the New England Journal of Medicine published results from the Phase 3 TOWER study evaluating the efficacy of Blincyto (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% CI: 5.6, 9.6) for BLINCYTO versus four months (95% 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 Blincyto in 2014. Blincyto is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct.
“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 BLINCYTO 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 Blincyto was independent of allogeneic stem cell transplant (alloSCT), as the median OS, censored at the time of alloSCT, was 6.9 months for Blincyto 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 Blincyto 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 Leukemia 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 Blincyto versus SOC. In the Blincyto group, 34%of patients achieved complete remission versus 16% in the SOC group. Patients receiving Blincyto also had a higher rate of combined complete remission or complete remission with partial or incomplete hematologic recovery (44% versus 25%).
Among patients with complete remission or complete remission with partial or incomplete hematologic recovery, 76% in the Blincyto group versus 48% 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 Blincyto group versus 4.6 months in the SOC group. For the key secondary efficacy endpoint of event-free survival, six month estimates in the Blincyto and chemotherapy groups were 30.7% and 12.5%, and the HR was 0.55 (95% CI: 0.43, 0.71), favoring Blincyto.
“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, BLINCYTO 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 Blincyto 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% incidence rate) in the Blincyto arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least 5% higher for Blincyto compared to SOC chemotherapy.
ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Adult patients diagnosed with Ph- B-cell precursor ALL are often young, with a median age at diagnosis of 34-39.3,4
Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.5 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.6
References
1. Cancer Research UK. Acute lymphoblastic leukaemia risks and causes. www.cancerresearchuk.org/about-cancer/type/all/about/acute-lymphoblastic-leukaemia-risks-and-causes. Accessed Dec. 13, 2016
2. Mayo Clinic. Acute lymphocytic leukemia. www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915. Accessed Dec. 13, 2016.
3. Kenderian SS, Al-Kali A, Gangat N, et al. Monosomal karyotype in Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood Cancer J. 2013;3e122.
4. Faderl S, Kantarjian HM, Thomas DA, et al. Outcome of Philadelphia chromosome-positive adult lymphoblastic leukemia. Leuk Lymphoma. 2000;36(3-4):263-73.
5. Davis T, Farag SS. Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine. Int J Nanomedicine. 2013:8:3479-88.
6. Advani AS. New immune strategies for the treatment of acute lymphoblastic leukemia: Antibodies and chimeric antigen receptors. Hematology Am Soc Hematol Educ Program. 2013;131-7.
