BLINCYTO® (BLINATUMOMAB) ADDED TO CONSOLIDATION CHEMOTHERAPY SIGNIFICANTLY IMPROVES SURVIVAL IN ADULT PATIENTS WITH MEASURABLE RESIDUAL DISEASE-NEGATIVE B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)

At 3.5 Years, 83% of Patients on BLINCYTO Plus Chemotherapy Were Alive Versus 65% of Patients on Chemotherapy Alone

Trial Design and Conduct Sponsored by the ECOG-ACRIN Cancer Research Group

THOUSAND OAKS, Calif., Dec. 13, 2022 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) will present results from the E1910 randomized Phase 3 trial. This is the first study to demonstrate superior overall survival (OS) with BLINCYTO added to consolidation chemotherapy over current standard of care (multiagent consolidation chemotherapy) in newly diagnosed adult patients with Philadelphia chromosome-negative B-ALL who were measurable residual disease (MRD)-negative following induction and intensification chemotherapy. These results were featured in a press briefing on Monday, Dec. 12 at 8:30 a.m. CT and presented on Tuesday, Dec. 13 at 9 a.m. CT as a late breaking oral presentation (LBA1) at the 64^th American Society of Hematology (ASH) Annual Meeting & Exposition in New Orleans.

Experience the full interactive Multichannel News Release here: https://www.multivu.com/players/English/8812856-amgen-blincyto-blinatumomab-added-to-consolidation-chemotherapy-significantly-improves-survival/

"Treatment with BLINCYTO in addition to consolidation chemotherapy reduced the risk of death by 58% compared to chemotherapy alone. We are pleased by this remarkable improvement in overall survival, and we look forward to sharing these data with regulatory authorities as soon as possible," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Amgen continues to advance a robust development program for BLINCYTO, with a focus on minimizing chemotherapy and a subcutaneous formulation to help address remaining unmet needs for patients with B-ALL."

The Phase 3 randomized trial (E1910), activated in December 2013, evaluated the safety and efficacy of BLINCYTO added to standard of care consolidation chemotherapy compared to chemotherapy alone in patients with newly diagnosed B-ALL with no MRD after induction and intensification chemotherapy. The primary endpoint was OS and key secondary endpoints included relapse-free survival, MRD status, and incidence of adverse events. Based on a recommendation by the ECOG-ACRIN Data Safety Monitoring Committee and consistent with the pre-defined efficacy threshold, results from the planned interim analysis are now reported due to overwhelming efficacy reported in the BLINCYTO arm.

With a median follow up of 43 months, the study met its primary endpoint with a significant improvement in overall survival favoring the BLINCYTO arm; median OS was not reached vs. 71.4 months in the control arm (hazard ratio [HR] = 0.42, 95% CI: 0.24 - 0.75; two-sided p=0.003). After about 3.5 years of follow-up, 83% of the patients who went on to receive additional standard consolidation chemotherapy plus experimental BLINCYTO were alive versus 65% of those who received chemotherapy only. No new safety signals were reported for the combination.

"Adults with newly diagnosed ALL can achieve a high rate of complete remission with chemotherapy, but frequently relapse and have disappointing survival rates.^1,2 Historically, outcomes for newly diagnosed adults with ALL have been significantly worse than for children, where up to 90% of patients are cured with frontline therapy.^3,4 In this study, survival rates for adults when blinatumomab was added to chemotherapy are significantly improved in patients with MRD-negative remission, approaching those we have seen in children," said Selina M. Luger, M.D., professor of hematology-oncology at the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine, chair of the ECOG-ACRIN Leukemia Committee and an investigator on the study. "Moreover, the data provide additional clinical evidence supporting the recent guideline updates for adult ALL recommending blinatumomab as consolidation in both MRD-positive and MRD-negative patients."

Data from the trial will be submitted to global regulatory authorities, including where BLINCYTO has been previously approved.

Study E1910 was designed and conducted independently from industry with public funding. The ECOG-ACRIN Cancer Research Group sponsored the trial with funding from the National Cancer Institute (NCI), part of the National Institutes of Health. Other NCI-funded network groups took part in the study. In addition, Amgen provided BLINCYTO and support through an NCI Cooperative Research and Development Agreement (CRADA).

E1910 Study Design
In the E1910 Phase 3 randomized trial, 488 patients aged 30-70 with newly diagnosed B-ALL were enrolled. All participants initially received 2.5 months of combination induction chemotherapy (step 1). After remission induction (step 1), if patients were in complete remission, they continued on-study and received an intensification course of high dose chemotherapy (step 2). Subsequently, their remission and MRD status were determined. All patients were then randomized/assigned to receive four cycles of consolidation chemotherapy with or without four 28-day cycles of BLINCYTO (step 3). Following FDA approval of blinatumomab for MRD-positive patients in March 2018, MRD-positive participants were assigned to the blinatumomab arm. MRD-negative patients continued to be randomized. After completion of consolidation chemo +/- BLINCYTO, patients were given 2.5 years of chemotherapy maintenance therapy timed from the start of the intensification cycle (step 4).

For more information, please visit ClinicalTrials.gov.

About BLINCYTO® (blinatumomab)
BLINCYTO is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that targets CD19 surface antigens on B cells. BiTE molecules fight cancer by helping the body's immune system detect and target malignant cells by engaging T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. By bringing T cells near cancer cells, the T cells can inject toxins and trigger cancer cell death (apoptosis). BiTE immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

• relapsed or refractory CD-19 positive B-cell precursor ALL in adults and children.
• CD-19 positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. 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.

In the European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

• adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
• adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
• pediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

• Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO^®. Interrupt or discontinue BLINCYTO^® and treat with corticosteroids as recommended.
• Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO^®. Interrupt or discontinue BLINCYTO^® as recommended.

Contraindications

BLINCYTO^® is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

• Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO^® overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO^® until CRS resolves. Discontinue BLINCYTO^® permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
• Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO^® in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO^® treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life–threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO^® as outlined in the PI.
• Infections: Approximately 25% of patients receiving BLINCYTO^® in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO^® as needed.
• Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO^® treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO^® as needed to manage these events.
• Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO^® infusion and interrupt BLINCYTO^® if prolonged neutropenia occurs.
• Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO^® are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO^® is being administered.
• Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO^® treatment with a median time to onset of 3 days. In patients receiving BLINCYTO^®, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO^® treatment. BLINCYTO^® treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
• Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO^® in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO^® and dexamethasone as needed.
• Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO^®, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
• Preparation and administration errors have occurred with BLINCYTO^® treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
• Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO^® treatment, during treatment, and until immune recovery following last cycle of BLINCYTO^®.
• Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO^® (with preservative). When prescribing BLINCYTO^® (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO^® (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO^® solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.

Adverse Reactions

• The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO^® were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified 39%), tremor (31%), and chills (28%). Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
• The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO^® were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
• Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
• In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).

Dosage and Administration Guidelines

• BLINCYTO^® is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
• It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

Please see full Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

About BiTE^® Technology
BiTE^® (bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage patient's own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has a goal of leading to off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of hematologic malignancies and solid tumors, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential. To learn more about BiTE technology, visit www.AmgenBiTETechnology.com.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That's why we're relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer. 

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company's history, moving with great speed to advance those innovations for the patients who need them. 

For more information, follow us on www.twitter.com/amgenoncology. 

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.

Amgen is one of the 30 companies that comprise the Dow Jones Industrial Average and is also part of the Nasdaq-100 index. In 2022, Amgen was named one of the "World's Best Employers" by Forbes and one of "America's 100 Most Sustainable Companies" by Barron's.

For more information, visit Amgen.com and follow us on Twitter, LinkedIn, Instagram, TikTok and YouTube.

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CONTACT: Amgen, Thousand Oaks
Megan Fox, 805-447-1423 (media)
Jessica Akopyan, 805-440-5721 (media)
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¹ Maffini E., et al. Clin Hematol Int. 2019; 1(2):85-93.
² Jabbour E., et al. Cancer. 2015; 121:2517-2528.
³ Leukemia & Lymphoma Society. Acute Lymphoblastic Leukemia (ALL). Available at: https://www.lls.org/research/acute-lymphoblastic-leukemia-all. Accessed on November 29, 2022.
⁴ National Cancer Institute. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. Available at: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq#:~:text=%5B74%2D78%5D-,Overall%20Prognosis,patients%20alive%20at%205%20years. Accessed on November 29, 2022. 

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