FDA Approves BLINCYTO® (blinatumomab) To Treat Minimal Residual Disease-Positive B-Cell Precursor Acute Lymphoblastic Leukemia In Adults And Children

THOUSAND OAKS, Calif., March 29, 2018 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that the U.S. 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 leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent. This indication is approved under accelerated approval based on MRD response rate and hematological 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.¹ 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.^1,2,3

"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 Leukemia, The University of Texas MD Anderson Cancer Center, Houston. "In the BLAST study, blinatumomab led to no detectable cancer cells in approximately 80 percent 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 percent of patients (95 percent CI: 71.6, 89.0). Median hematological 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 percent) 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) program in the U.S.

About BLINCYTO^® (blinatumomab)

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 U.S. 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 percent. This indication is approved under accelerated approval based on MRD response rate and hematological 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.

About the BLAST Study

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 hematologic 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 hematopoietic 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 hematological 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).

Results from the BLAST study were presented at the 57^th Annual Meeting and Exposition of the American Society of Hematology in 2015 and published in Blood in 2018.

About ALL and MRD

ALL is a rare and rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.^4,5 Nearly 50 percent of adult patients and 25 percent of pediatric patients with B-cell ALL eventually relapse or are refractory to treatment.^6,7 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.^1,8 Five-year OS rates are as high as 75 percent for patients that achieve MRD-negative status, compared with 33 percent among patients that remain MRD-positive.⁸ In pediatric patients, MRD-positive status after treatment is associated with a 15-times higher risk of relapse compared with those with undetectable residual disease.⁹ For more information about MRD, please visit AmgenOncology.com.

About BiTE^® Technology

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.

INDICATION

BLINCYTO is indicated for the treatment of adults and children with:

• B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
• Relapsed or refractory B‑cell precursor acute lymphoblastic leukemia (ALL)

About Amgen

Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

References:

1. Paeitta E. Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept? Bone Marrow Transplant. 2002;29:459-465
2. Gökbuget N, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120:1868-1876.
3. Brüggemann M, et al. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012;120:4470-4481.
4. Cancer Research UK. About acute lymphoblastic leukaemia (ALL). http://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about. Accessed Jan. 31, 2018.
5. Mayo Clinic. Acute lymphocytic leukemia. http://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915. Accessed Jan 31, 2018.
6. Katz A, Chia V, Schoonen M, et al. Acute lymphoblastic leukemia: an assessment of international incidence, survival, and disease burden. Cancer Causes Control. 2015;26:1627-1642.
7. Conter V, et al. Acute lymphoblastic leukemia. Orphanet Encyclopedia. http://www.orpha.net/data/patho/GB/uk-ALL.pdf. Accessed Jan. 30, 2018.
8. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009:113: 4153-4162.
9. Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical Significance of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia. N Engl J Medicine.1998:339: 591-598.

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