On September 24, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) recording that updated phase 1 safety and efficacy data for [fam-] trastuzumab deruxtecan (DS-8201), an investigational HER2 targeting antibody drug conjugate (ADC), were presented for a subgroup of patients with heavily pretreated HER2 mutated or HER2 expressing non-small cell lung cancer (NSCLC) during an Oral Session at the IASLC 19th World Conference on Lung Cancer (#WCLC2018) hosted by the International Association for the Study of Lung Cancer in Toronto, Canada (Press release, Daiichi Sankyo, SEP 24, 2018, View Source [SID1234529547]).

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An updated subgroup analysis of 11 patients with HER2 mutated NSCLC receiving a recommended expansion dose of 6.4 mg/kg showed that [fam-] trastuzumab deruxtecan demonstrated a confirmed overall response rate of 72.7 percent (8 of 11 patients) and disease control rate of 100 percent (11 of 11 patients). Preliminary estimate of median duration of response has reached 11.5 months (95 percent CI: 0.03+, 11.5) and median progression-free survival has reached 14.1 months (95 percent CI: 4.0+, 14.1) for this subgroup of patients.

"These preliminary results seen with [fam-] trastuzumab deruxtecan are encouraging, particularly given the existing unmet medical need for patients with metastatic NSCLC with HER2 alterations that have progressed on several prior therapies," said Junji Tsurutani, MD, PhD, Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan, a study investigator. "These results also demonstrate that continued evaluation of treatments that target the HER2 receptor is warranted in patients with NSCLC."

The updated subgroup analysis of 17 patients with heavily pretreated HER2 mutated or HER2 expressing (defined as IHC ≥1+ or amplified) NSCLC showed that [fam-] trastuzumab deruxtecan demonstrated a confirmed overall response rate of 58.8 percent (10 of 17 patients) and a disease control rate of 88.2 percent (15 of 17 patients). Preliminary estimate of median duration of response has reached 9.9 months (95 percent CI: 0.0+, 11.5) and median progression-free survival has reached 14.1 months (95 percent CI: 0.9, 14.1).

"Patient enrollment is currently underway into our phase 2 study of [fam-] trastuzumab deruxtecan in patients with advanced HER2 mutated or HER2 overexpressing NSCLC," said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo. "Since there are no therapies specifically approved to treat patients with HER2 altered NSCLC, continued study of [fam-] trastuzumab deruxtecan is needed to better understand the potential role of a HER2 targeting antibody drug conjugate in treating these patients."

Updated preliminary safety data for this subgroup of patients with heavily pretreated HER2 mutated or HER2 expressing NSCLC receiving [fam-] trastuzumab deruxtecan were also reported. The most common adverse events (>30 percent, any grade) included nausea (50.0 percent), decreased appetite (50.0 percent), alopecia (50.0 percent), fatigue (44.4 percent) and vomiting (38.9 percent). Grade 3 adverse events occurring in >10 percent of patients included decreased neutrophil count (11.1 percent). As previously reported, one (1) grade 5 event of pneumonitis was observed in this cohort, which was adjudicated as unrelated to [fam-] trastuzumab deruxtecan by an independent adjudication committee. Any reported cases of interstitial lung disease (ILD)/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program are evaluated by an independent adjudication committee.

Unmet Need in Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the most common cancer in the world and the leading cause of cancer deaths.1 There were approximately 1.8 million new cases of lung cancer reported globally and approximately 1.6 million deaths in 2012.1 Non-small cell lung cancer (NSCLC) accounts for approximately 80 to 85 percent of all cases.2 The five-year survival rate for metastatic NSCLC is only one percent.3

The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for metastatic NSCLC patients, who previously had limited options beyond systemic chemotherapy.4,5 However, for those who are not eligible for available treatments, or whose cancer continues to progress, new approaches are needed to help manage the disease.6

HER2 overexpression has been reported in rates ranging from 4 to 35 percent of NSCLC, depending on the published series and methods, and is associated with poor disease prognosis and shortened overall survival.4,6 HER2 mutations have more recently been identified as distinct molecular targets for NSCLC and have been reported in up to 5 percent of NSCLC.7,8 Currently, no therapy is specifically approved for HER2 mutated or HER2 overexpressing non-small cell lung cancer.

About the [Fam-] Trastuzumab Deruxtecan Phase 1 Study

An open-label, two-part phase 1 study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of this study was to assess the safety and tolerability of and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.9

In the dose expansion part of the phase 1 study, [fam-] trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid tumors including NSCLC. Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan. For more information about the study, visit ClinicalTrials.gov.

About [Fam-] Trastuzumab Deruxtecan

[Fam-] trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in U.S. only; trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia. [Fam-] trastuzumab deruxtecan is in pivotal phase 2 clinical development for HER2 positive metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase 2 development for HER2 expressing advanced colorectal cancer; phase 2 development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).

[Fam-] trastuzumab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

On September 24, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion to expand the indication for Xtandi (enzalutamide) to include adult men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) (Press release, Astellas, SEP 24, 2018, View Source [SID1234529658]).2 If approved by the European Commission (EC), enzalutamide will be one of the first treatments approved for this critical stage of disease, currently associated with a significant unmet medical need. Enzalutamide was first approved by the EC in June 2013 and is currently indicated in the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated or whose disease has progressed on or after docetaxel therapy.3

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"In nmCRPC, the high risk patient is at a stage where his cancer is growing even though it’s not visible yet despite hormone therapy and will manifest itself given time. The objective of early access to enzalutamide in these patients is to delay the emergence of metastasis with the hope of improving quantity and quality of life," said Maha Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States, and lead study investigator. "The potential of an effective treatment option for this stage of disease signifies an important therapeutic advancement."

The CHMP opinion is based on the results from the pivotal phase 3 PROSPER trial which evaluated enzalutamide plus ADT vs placebo plus ADT in patients with nmCRPC and rapidly rising prostate-specific antigen (PSA) levels.1 The trial met its primary endpoint of metastasis-free survival (MFS). The median MFS was 36.6 months for men who received enzalutamide plus ADT, compared to 14.7 months with placebo plus ADT (n=1401; HR=0.29 [95% CI: 0.24–0.35]; p<0.001).1

The PROSPER trial results indicated a 71% reduction in the risk of radiographic progression or death in men with nmCRPC and rapidly rising PSA levels, compared to placebo plus ADT (HR=0.29 [95% CI: 0.24–0.35]; p<0.001).1 The most common adverse events of any grade for patients ≥10% and higher for enzalutamide plus ADT vs placebo plus ADT were: fatigue (33% vs 14%), hot flush (13% vs 8%), hypertension (12% vs 5%), nausea (11% vs 9%), fall (11% vs 4%), dizziness (10% vs 4%) and decreased appetite (10% vs 4%).1 These results were published in the June 2018 edition of the New England Journal of Medicine.1

"This positive CHMP opinion represents an important step towards providing specialist health care professionals with a new treatment option for patients with nmCRPC and rapidly rising levels of prostate specific antigen. These patients are at higher risk of developing metastasis and death. Subject to EMA approval, we have the potential to expand the use of enzalutamide in a patient population where there is a clear unmet medical need," said Steven Benner, M.D, Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas.

The positive opinion from the CHMP will now be reviewed by the EC, which has the authority to approve medicines for the 28 European Union member countries plus Iceland, Norway and Liechtenstein. The EC, which generally follows the recommendation of the CHMP, is expected to make its final decision in the final quarter of 2018.

PROSPER Trial Results
PROSPER is a double-blind, placebo-controlled, pivotal phase 3 trial conducted at 300 sites in 32 countries that randomised 1,401 patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen (PSA) doubling time of 10 months or less, 2:1 to either receive once-daily enzalutamide plus androgen deprivation hormone therapy (ADT) (n=933) or placebo plus ADT (ADT alone [n=468]), respectively.1

Secondary outcomes included a statistically significant delay in the median time to first use of new antineoplastic therapy (TTA) of 39.6 vs 17.7 months; HR=0.21 [95% CI: 0.17–0.26]; p<0.001 for patients who received enzalutamide plus ADT compared to those who received placebo plus ADT.1

About Prostate Cancer
Prostate cancer is the most common cancer diagnosis for men in the European Union (EU).4 There are 375,842 men in the EU currently diagnosed with prostate cancer, accounting for an estimated 23.2% of all cancers in men in 2018.4 Some studies estimate that, within five years of diagnosis,10–20% of men with prostate cancer will develop CRPC.5

CRPC refers to the subset of men whose prostate cancer progresses despite castrate levels of testosterone (i.e., less than 50 ng/dL).6 Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising PSA level.6 Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.7,8

About Enzalutamide
Enzalutamide is an oral, once-daily androgen receptor signaling inhibitor. Enzalutamide directly targets the androgen receptors (AR) and exerts its effects on three steps of the AR signaling pathway:3

Inhibits androgen binding: Androgen binding induces a conformational change that triggers activation of the receptor3
Prevents nuclear translocation: Translocation of the AR to the nucleus is an essential step in AR-mediated gene regulation3
Impairs DNA binding: Binding of the AR to the DNA is essential for modulation of gene expression3
Enzalutamide is currently approved in Japan for castration-resistant prostate cancer9 and in July 2018 the United States Food and Drug Administration (FDA) broadened the approved indication for enzalutamide to include men with nmCRPC.10

Important Safety Information for Enzalutamide in the EU
For important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: View Source

About XTANDI (enzalutamide) capsules in the U.S.

XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer.

Important Safety Information for XTANDI in the U.S.

Warnings and Precautions
Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).

Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in <1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

On September 24, 2018 BioXcel Therapeutics, Inc. ("BTI") (Nasdaq: BTAI), a clinical stage biopharmaceutical development company utilizing novel artificial intelligence approaches to identify the next wave of medicines across neuroscience and immuno-oncology, and Nektar Therapeutics (Nasdaq: NKTR) reported that the companies are expanding their ongoing research collaboration into a new clinical partnership (Press release, BioXcel Therapeutics, SEP 24, 2018, View Source [SID1234529853]). The collaboration will clinically evaluate the novel combination of BTI’s BXCL701, a small molecule immune-modulator, DPP 8/9 and FAP inhibitor; Nektar’s NKTR-214, a CD122-biased agonist; and a checkpoint inhibitor as a potential therapy for pancreatic cancer.

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Under the terms of the expanded collaboration agreement, BTI will be responsible for initiating and managing the clinical program. The primary objectives of the study are to evaluate safety and efficacy of the triplet combination of BXCL701, NKTR-214 and a checkpoint inhibitor for the treatment of patients with unresectable or metastatic pancreatic cancer. Additionally, correlative immune activation markers will also be evaluated in blood and tumor tissue.

"We are excited to expand our collaboration with Nektar to initiate a clinical program for this novel triplet combination regimen," said Vimal Mehta, Chief Executive Officer of BTI. "Mechanistically, we believe the action of BXCL701 on macrophages and neutrophils within the tumor tissue can activate the innate immune system and then in combination with NKTR-214 and an anti-PD1, we can then prime adaptive immune cells in order to trigger T-cell driven anti-cancer activity and the generation of T-cell memory. The exciting preclinical data presented at this year’s ASCO (Free ASCO Whitepaper) Meeting highlighted the complementary mechanisms by which these three agents can synergize to generate durable responses in various animal models."

"We believe it is essential to target multiple dimensions of the immune system in parallel in order to address the multi-faceted etiologies underlying cancer cell growth in difficult-to-treat tumors such as pancreatic cancer," said Jonathan Zalevsky, Senior Vice President, Biology & Preclinical Development of Nektar Therapeutics. "This experimental triplet combination regimen of BXCL701, NKTR-214 and a checkpoint inhibitor is designed to leverage multiple mechanisms of action at once to better fight pancreatic cancer while potentially generating long-term cancer immunity. We’re pleased to be working with BTI on this program."

BTI and Nektar Therapeutics initially announced a preclinical research collaboration in November 2017. This collaboration focused on utilizing the complementary mechanisms of BXCL701 and NKTR-214 to stimulate the body’s own immune system to overcome immunosuppressive mechanisms in the tumor microenvironment.

On September 24, 2018 Amgen (NASDAQ:AMGN) reported that the Japanese Ministry of Health, Labour and Welfare has granted marketing approval for BLINCYTO (blinatumomab) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) (Press release, Amgen, SEP 25, 2018, View Source;p=RssLanding&cat=news&id=2368696 [SID1234530180]). BLINCYTO was developed in Japan by Amgen Astellas BioPharma K.K. (AABP), a joint venture between Amgen and Astellas Pharma Inc., a pharmaceutical company headquartered in Tokyo.

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"As proof-of-concept for our bispecific T cell engager technology, BLINCYTO has laid the groundwork for Amgen to deliver on our passion of addressing cancer by exploring numerous biologic pathways and therapeutic modalities," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "This innovation is a good example of how we provide new options to patients with serious illnesses like cancer. In bringing BLINCYTO to Japanese patients, we reinforce our commitment to deliver novel cancer therapies on behalf of patients worldwide."

BLINCYTO is the first-and-only bispecific T cell engager (BiTE) immunotherapy construct approved globally. It is also the first approved immunotherapy from Amgen’s BiTE platform, an innovative approach that helps the body’s immune system target cancer cells.

"Today’s approval of BLINCYTO marks a significant milestone that reinforces our commitment to addressing unmet medical needs of patients in Japan," said Steve Sugino, president and representative director, AABP. "As our first oncology treatment approved in the region, we are proud to provide a much-needed innovative treatment option for adults and children with relapsed or refractory B-cell ALL, one of the most aggressive B-cell malignancies."

Hitoshi Kiyoi, M.D., Ph.D., professor of internal medicine, Hematology and Oncology, Nagoya University Graduate School of Medicine said, "The standard therapy for relapsed or refractory B-cell ALL has not been established in Japan and therefore different chemotherapy regimens have been selected, depending on the condition and background of each patient. BLINCYTO is a much-needed and important new treatment option for patients with relapsed or refractory B-cell ALL, as demonstrated by the efficacy and survival benefit seen in the TOWER study."

The approval is based on data from multiple global studies, including the Phase 3 TOWER study and Japan Phase 1b/2 Horai study. In the TOWER study, BLINCYTO demonstrated a superior improvement in median overall survival (OS) versus standard of care (SOC) chemotherapy. Median OS was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus 4.0 months (95 percent CI: 2.9, 5.3) for SOC (HR for death=0.71; p=0.012). Safety results among subjects who received BLINCYTO were comparable to those seen in the previous Phase 2 studies of BLINCYTO in adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. In the TOWER study, major adverse reactions were pyrexia (39.0 percent), decrease in white blood cell count (14.6 percent), cytokine release syndrome (13.5 percent), febrile neutropenia (10.9 percent), headache (10.1 percent), elevated liver enzyme (10.1 percent) and decrease in platelet count (10.1 percent). In the Phase 1b/2 Horai study, BLINCYTO was administered to 35 Japanese adult and pediatric patients with relapsed or refractory B-cell precursor ALL. The safety results from the Horai study were comparable to those seen in the global studies, including TOWER. In the Horai study, major adverse reactions in adult patients were cytokine release syndrome (46.2 percent), pyrexia (46.2 percent), decrease in white blood cell count (38.5 percent) and decrease in platelet count (34.6 percent), and major adverse reactions in pediatric patients were elevated liver enzyme (66.7 percent), pyrexia (66.7 percent), cytokine release syndrome (55.6 percent) and abdominal pain (44.4 percent).

BLINCYTO is now approved in 57 countries, including the United States (U.S.), all member countries in the European Union (EU) and the European Economic Area, Canada and Australia.

About the TOWER Study
The TOWER study was a Phase 3, randomized, active-controlled, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. The study enrolled a difficult-to-treat patient population which included patients with one or more relapses or refractory disease. In the BLINCYTO arm, this included 35 percent of patients that had relapsed post-allogenic hematopoietic stem cell transplant (alloHSCT) and excluded those with late first relapse (≥12 months after initial remission). Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of SOC chemotherapy (n=134). The determination of efficacy was based on OS. These results were published in The New England Journal of Medicine.1

About the Horai Study
The Horai study is a Phase 1b/2, single-arm, open-label study evaluating the safety and efficacy of BLINCYTO in Japanese adult and pediatric patients with relapsed or refractory B-cell precursor ALL. The primary endpoint for the Phase 1b portion was incidence of dose-limiting toxicities; the primary endpoint for the Phase 2 portion was complete remission or complete remission with partial hematologic recovery within 12 weeks of treatment with BLINCYTO. Secondary endpoints include duration of response, OS and relapse-free survival. An extension of the study is ongoing. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT02412306.

About ALL in Japan
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.2,3 Japan is reported to have approximately 5,000 ALL patients, and it is estimated that of these, there are around 520 patients with relapsed or refractory ALL annually.4-7 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.8 Prognosis for children with ALL who are refractory or experience a relapse is extremely poor, and post-relapse survival is only achieved in 40-50 percent of patients.9-11

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a novel immune-oncology technology that can be engineered to target any tumor antigen expressed by any type of cancer. The modified antibodies are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. BiTE antibody constructs help connect the T cells to the targeted cell, with the intent of causing T cells to inject toxins which trigger cancer cell death (apoptosis). Amgen is developing BiTE antibody constructs to uniquely (or specifically) target numerous hematologic malignancies and solid tumors.

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 effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration (FDA) in 2014, and now carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved under accelerated approval for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent.

BLINCYTO is approved in the EU for the treatment of Ph- relapsed or refractory B-cell precursor ALL in adults and children.

Important Japan Product Information

Indication:
Relapsed or refractory B-cell acute lymphoblastic leukemia

Dosage and Administration:
In general, blinatumomab (Genetical Recombination) is administered as continuous intravenous infusion with the following dosing regimen for 28 days followed by a 14-day treatment-free interval. This constitutes one cycle and is repeated up to 5 cycles. After that, blinatumomab (Genetical Recombination) is administered with the following dosing regimen for 28 days followed by a 56-day treatment-free interval. This constitutes one cycle and is repeated up to 4 cycles. Of note, dose of BLINCYTO can be reduced as appropriate depending on patient’s condition.

Patients with a body weight of ≥45 kg: 9 μg/day on Days 1 to 7 of Cycle 1, then 28 μg/day.
Patients with a body weight of <45 kg: 5 μg/m2 (body surface area [BSA])/day on Days 1 to 7 of Cycle 1, then 15 μg/m2 (BSA)/day. The dose should not exceed the dose for patients with a body weight of ≥45 kg.
For more information, see the latest Japan Package Inserts.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication
BLINCYTO is indicated for the treatment of 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% 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.

BLINCYTO is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

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 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 patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients 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 (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO as outlined in the PI.
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 (GGT), 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, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. 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 adult population 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).

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Cantor Fitzgerald Global Healthcare Conference. On Tuesday, October 2, 2018, Susan M. Molineaux, Ph.D., the company’s Founder, President and Chief Executive Officer will present a corporate update at 9:10 a.m. EDT at the
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Leerink Partners Rare Disease & Oncology Roundtable. On Wednesday, October 3, 2018, Susan M. Molineaux, Ph.D., the company’s Founder, President and Chief Executive Officer will participate in a fireside chat to discuss immunooncology at the Leerink Partners Rare Disease & Oncology Roundtable being held in New York City at 8:30 a.m. EDT.