Amgen announced that the US Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for Blincyto (blinatumomab) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukaemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 per cent. This indication is approved under accelerated approval based on MRD response rate and haematological relapse-free survival (RFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Blincyto, the first-and-only approved bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy, is now also the first-and-only therapy to be FDA-approved for MRD.
MRD refers to the presence of cancer cells that remain detectable, despite a patient's having achieved complete remission by conventional assessment. MRD is only measurable through the use of highly sensitive testing methods that detect cancer cells in the bone marrow with a sensitivity of at least one cancer cell in 10,000 cells -- versus about one in 20 with a conventional microscope-based evaluation.
"Until today, no therapy has been satisfactory in eradicating MRD or approved specifically to treat this high-risk patient population," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "This approval not only supports the use of Blincyto earlier in the ALL treatment continuum, but represents a paradigm shift in the management of ALL."
"The detection of remaining cancer cells after a complete remission is the strongest prognostic factor for relapse in patients with ALL. It's critical to test for and know your patients' MRD status, because we know that treating to MRD-negativity will help to obtain better possible clinical outcomes for patients," said Elias Jabbour, M.D., associate professor, Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston. "In the BLAST study, blinatumomab led to no detectable cancer cells in approximately 80 per cent of patients with MRD-positive ALL. This approval provides a much-needed treatment option to destroy the remaining detectable traces of leukemia."
The accelerated approval is based on results from the phase 2 single-arm BLAST study (n=86), which found that Blincyto converted most patients to an MRD-negative state after a single cycle of therapy. Blincyto met the primary endpoint, inducing a complete MRD response, which is no detectable MRD, in 81 per cent of patients (95 per cent CI: 71.6, 89.0). Median haematological RFS was 22.3 months.
Safety results among MRD-positive patients were consistent with the known safety profile of Blincyto in relapsed or refractory B-cell precursor ALL. The most common adverse reactions (greater than 20 per cent) were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor and chills.
The FDA-approved prescribing information for Blincyto includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blincyto is also under a risk evaluation and mitigation strategy (REMS) programme in the US.
Blincyto is a bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. Blincyto was granted breakthrough therapy and priority review designations by the FDA in 2014, and is now fully approved in the US for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. Blincyto is now also approved under accelerated approval for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 per cent. This indication is approved under accelerated approval based on MRD response rate and haematological relapse-free survival (RFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In November 2015, Blincyto was granted conditional marketing authorization in the European Union for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. Additional regulatory applications for Blincyto are underway and have been submitted to health authorities worldwide.
The BLAST study is the largest ever prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, phase 2 study evaluating the efficacy, safety and tolerability of Blincyto in adult patients with MRD-positive B-cell precursor ALL in complete haematologic remission after three or more cycles of intensive chemotherapy. Patients received continuous IV infusion of Blincyto 15 µg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo haematopoietic stem cell transplantation (HSCT) at any time after the first cycle, if eligible. The primary endpoint was the rate of complete MRD response within the first treatment cycle. The key secondary endpoint was RFS at 18 months. Additional secondary endpoints included incidence and severity of adverse events, overall survival (OS), time to haematological remission and duration of complete MRD response.
To evaluate the association between complete MRD response and subsequent RFS and OS, landmark analyses were performed at 45 days (day by which all first cycle MRD responses had been assessed) for patients with and without a complete MRD response in the first cycle. Patients who relapsed, died, or were censored before day 45 were excluded to correct for immortal time bias. Improvement in median RFS was seen for Blincyto patients achieving a complete MRD response compared to MRD nonresponses, 23.6 months versus 5.7 months, respectively (p=0.002).
ALL is a rare and rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children. Nearly 50 per cent of adult patients and 25 per cent of pediatric patients with B-cell ALL eventually relapse or are refractory to treatment. Poor outcomes have been observed in patients who relapse after achieving a complete response but have persistent MRD, or disease that remains at the molecular level after treatment. Five-year OS rates are as high as 75 per cent for patients that achieve MRD-negative status, compared with 33 per cent among patients that remain MRD-positive. In paediatric patients, MRD-positive status after treatment is associated with a 15-times higher risk of relapse compared with those with undetectable residual disease.
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body's immune system to detect and target malignant cells. The modified antibodies are designed to bridge T cells to tumor cells, using the patient's own immune system to eradicate cancer. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of causing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.