On November 16, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, reported final overall survival (OS) results for the Phase III MYSTIC trial, a randomised, open-label, multi-centre, global trial of Imfinzi (durvalumab) monotherapy and the combination of Imfinziand tremelimumab, an anti-CTLA4 antibody, versus standard-of-care (SoC) platinum-based chemotherapy in previously-untreated patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, NOV 16, 2018, View Source [SID1234531487]).

In the primary analysis population of patients, whose tumours express PD-L1 on 25% or more of their cancer cells as determined by the VENTANA PD-L1 (SP263) Assay, Imfinzi monotherapy and the combination of Imfinzi plus tremelimumab did not meet the primary endpoints of improving OS compared to SoC chemotherapy. While the OS result did not meet statistical significance, a hazard ratio (HR) of 0.76 (97.54% CI 0.564-1.019; nominal p=0.036) was observed with Imfinzimonotherapy. The combination therapy had an HR of 0.85 (98.77% CI 0.611-1.173; nominal p=0.202); the data support further analysis in exploratory subgroups.

The safety and tolerability profiles for Imfinzi and the Imfinzi plus tremelimumab combination were consistent with previous trials.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: "We are encouraged to see that Imfinzi monotherapy activity is in-line with that of the anti-PD-1 class in previously-untreated patients with Stage IV non-small cell lung cancer; however, we are disappointed that these results missed statistical significance. We remain confident in Imfinzias the cornerstone of our IO programme and continue to evaluate its potential in ongoing non-small cell lung cancer trials, including Imfinzi and Imfinzi plus tremelimumab in combination with chemotherapy."

Imfinzi is approved for unresectable, Stage III NSCLC in more than 40 countries, including the US, EU and Japan, based on the Phase III PACIFIC trial. Imfinzi is currently being tested in a range of Phase III trials for Stage IV NSCLC.

Immuno-oncology Phase III trials in Stage IV, 1st-line NSCLC

PEARL

Imfinzi monotherapy vs SoC chemotherapy
NEPTUNE

Imfinzi + tremelimumab vs SoC chemotherapy
POSEIDON

Imfinzi + chemotherapy or Imfinzi + tremelimumab + chemotherapy
vs SoC chemotherapy

About MYSTIC
The MYSTIC trial is a randomised, open-label, multi-centre, global Phase III trial of Imfinzi(durvalumab) monotherapy or Imfinzi in combination with tremelimumab versus SoC chemotherapy in the 1st-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type, locally-advanced or metastatic (Stage IV) non-small cell lung cancer.

The trial was conducted in 167 centres across 17 countries, including the US, Canada, Europe, Russia, Australia and parts of Asia, including Japan, Korea, Thailand, Taiwan and Vietnam. Primary endpoints included progression-free survival (PFS) for the combination, and OS in monotherapy and in combination therapy. The combination of Imfinzi and tremelimumab did not meet the primary endpoint of improving PFS compared to SoC in patients whose tumours express PD-L1 on 25% or more of their cancer cells in July 2017.

About Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved for unresectable, Stage III NSCLC in more than 40 countries including the US, EU, and Japan based on the Phase III PACIFIC trial. Imfinzi is also approved for previously-treated patients with advanced bladder cancer in the US, Canada, Brazil, Israel, India, United Arab Emirates, Australia and Hong Kong.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small-cell lung cancer (SCLC), bladder cancer, head and neck cancer and other solid tumours.

About tremelimumab
Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T cell activation and boosting the immune response to cancer. Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma and blood cancers.

About Stage IV NSCLC
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths: more than breast, prostate and colorectal cancers combined. Lung cancer is broadly split into NSCLC and SCLC, with 80-85% classified as NSCLC. Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease. Approximately 85% of Stage IV patients are diagnosed after the tumour has spread outside of the lung. For these patients, prognosis is particularly poor, as only 1 in 10 will be alive five years after diagnosis.

About AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease and lines of therapy. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa and Tagrisso and ongoing FLAURA, ADAURA and LAURA Phase III trials.

Our extensive late-stage Immuno-Oncology programme focuses on 75-80% of patients with lung cancer without a known genetic mutation. Imfinzi, an anti-PDL1 antibody is in development as monotherapy (ADJUVANT BR.31, PACIFIC-2, PACIFIC-5, MYSTIC and PEARL Phase III trials) and in combination with tremelimumab and/or chemotherapy (MYSTIC, NEPTUNE, POSEIDON, ADRIATIC and CASPIAN Phase III trials).

About AstraZeneca’s approach to immuno-oncology
IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. At AstraZeneca and MedImmune, our biologics research and development arm, our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with small, targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.

About AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

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On November 16, 2018 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported the outcome of FALUCA, its Phase III trial of fruquintinib in advanced non-small cell lung cancer ("NSCLC") patients in China who have failed two lines of systemic chemotherapy (Press release, Hutchison China MediTech, NOV 16, 2018, https://www.chi-med.com/phase-iii-faluca-results/ [SID1234531461]). The trial did not meet the primary endpoint to demonstrate a statistically significant increase in overall survival ("OS") compared to placebo.

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Fruquintinib demonstrated, in FALUCA, a statistically significant improvement in all secondary endpoints including progression-free survival ("PFS"), objective response rate ("ORR"), disease control rate ("DCR") and duration of response ("DoR") as compared to the placebo. The safety profile of the trial was in line with that observed in prior clinical studies. Full detailed results are expected to be disclosed at an upcoming scientific meeting.

"While the study demonstrates a significant reduction in disease progression in this challenging lung cancer patient population, we are disappointed that this benefit did not translate into an increase in overall survival," commented Simon To, Chairman of Chi-Med. He added, "We remain confident that the high selectivity and lower off-target toxicities of fruquintinib are major points of differentiation. The recent first approval of fruquintinib monotherapy for advanced colorectal cancer, the imminent launch in China, and the commencement of several combination collaborations with immunotherapies both in China and in the U.S., reinforces our belief in fruquintinib."

Fruquintinib was first approved by the National Medical Products Administration of China (NMPA) in September 2018, for the treatment of advanced colorectal cancer, becoming the first China-discovered and developed pharmaceutical for a mainstream oncology indication to be unconditionally approved in China. Chi-Med has established a manufacturing facility in Suzhou, China, to produce fruquintinib. The market launch of fruquintinib in CRC in China, in collaboration with Eli Lilly and Company ("Lilly"), is now imminent.

Fruquintinib is also in multiple ongoing clinical trials in the U.S. and China, including in combination with checkpoint inhibitors, chemotherapy, and other targeted therapy agents.

About Other Fruquintinib Development Programs
Global Development
Phase I monotherapy in the U.S.: In December 2017, Chi-Med initiated a multi-center, open-label, Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of fruquintinib in U.S. patients with advanced solid tumors (clinicaltrials.gov identifier NCT03251378). This study is almost complete, and proof-of-concept ("POC") studies are expected to begin in 2019.

China Development
Colorectal cancer in China: The NMPA approved the first NDA for fruquintinib for the treatment of patients with advanced colorectal cancer in September 2018. The NDA is supported by data from the successful FRESCO study, a Phase III pivotal registration trial of fruquintinib in 416 patients with advanced colorectal cancer in China, which was highlighted in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held on June 5, 2017 (clinicaltrials.gov identifier NCT02314819).

Gastric cancer in China: In October 2017, Chi-Med initiated a pivotal Phase III clinical trial of fruquintinib in combination with Taxol (paclitaxel), known as the FRUTIGA study, in approximately 500 patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after first-line standard chemotherapy (clinicaltrials.gov identifier NCT03223376). An interim analysis on FRUTIGA, to establish POC, is anticipated during the first half of 2019 and if successful could trigger a POC milestone from Lilly. The FRUTIGA study followed a Phase I/II clinical trial in 34 patients with gastric cancer that demonstrated that combination therapy of fruquintinib and Taxol was generally well-tolerated with promising tumor response (clinicaltrials.gov identifier NCT02415023).

Lung cancer in China: Fruquintinib is being studied in a Phase II study in combination with Iressa (gefitinib) in patients with untreated advanced or metastatic NSCLC (clinicaltrials.gov identifier NCT02976116). Preliminary results were highlighted in an oral presentation at the 18th World Conference on Lung Cancer on October 16, 2017.

Programmed cell death protein-1 ("PD-1") checkpoint inhibitor combination: It is an important part of Chi-Med’s strategy to explore the potential synergies of its drug candidates in combination with other anti-cancer treatments in several solid tumor settings. In October 2018, Chi-Med entered into a further collaboration in China to evaluate the combination of fruquintinib with genolimzumab (GB226), a PD-1 inhibitor being developed by Genor Biopharma Company Limited.

About FALUCA
The FALUCA trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III registration study targeted at treating patients with advanced non-squamous NSCLC, who have failed two lines of systemic chemotherapy. 527 patients were randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus best supportive care ("BSC"); or placebo plus BSC. The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and DoR. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT02691299.

About Fruquintinib
Fruquintinib (brand name: Elunate) is a small molecule, selective and highly potent inhibitor of VEGFR 1, 2 and 3. VEGFR inhibitors play a pivotal role in tumor-related angiogenesis, cutting off the blood supply that a tumor needs to grow rapidly. The global market for anti-angiogenesis therapies was estimated at over US$18 billion in 2017, including both monoclonal antibodies and small molecules approved in around 30 tumor settings. During the discovery research process, which began at Chi-Med in 2007, fruquintinib was successfully designed to be differentiated by improving kinase selectivity in comparison to other approved small molecule tyrosine kinase inhibitors (TKIs), to minimize off-target toxicities, improve tolerability and provide more consistent target coverage, resulting in better clinical efficacy. The superior tolerability, along with fruquintinib’s low potential for drug-drug interaction based on preclinical assessment, suggests that it may be highly suitable for innovative combinations with other anti-cancer therapies.

In October 2013, Chi-Med entered into a licensing, co-development and commercialization agreement in China with Lilly for fruquintinib. Under the terms of the agreement, the costs of development of fruquintinib, carried out by Chi-Med, are shared; Chi-Med has received upfront payments and development and regulatory approval milestone payments; and upon commercialization in China, Chi-Med would receive royalties. Chi-Med and Lilly agreed to develop fruquintinib in three initial solid tumor indications, including CRC, NSCLC and gastric cancer.

The most common adverse reactions included hypertension, hand-foot syndrome and proteinuria. Clinically effective management of these adverse effects is feasible. For important safety information about fruquintinib, please see www.chi-med.com.

On November 16, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its updated data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma (Press release, Agios Pharmaceuticals, NOV 16, 2018, View Source [SID1234531460]). The data were featured in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in New Orleans. AG-881 is an investigational, oral, selective, potent inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes and was designed for enhanced brain penetrance for development in IDH-mutant glioma.

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"With additional follow-up, the AG-881 Phase 1 dose-escalation data continue to show a favorable safety profile at the doses selected for the perioperative study. Longer treatment duration and a reduction in tumor growth rates are encouraging signs of clinical activity in low-grade glioma," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "Ultimately, use of an IDH inhibitor in this difficult-to-treat disease has the potential to improve the current treatment paradigm by delaying the multiple rounds of surgery, radiation and chemotherapy that many patients endure."

"With no curative or approved targeted therapies and a high frequency of IDH1 mutations in low-grade glioma, we are committed to advancing one of our IDH inhibitors to a registrational study in this disease," said Chris Bowden, M.D., chief medical officer at Agios. "We are continuing to collect clinical data for both ivosidenib and AG-881, along with feedback from regulators and the neuro-oncology community, to make an internal decision on our glioma pivotal strategy by the end of this year."

Study Status

AG-881 is being evaluated as a single agent in an ongoing Phase 1 dose-escalation trial in IDH1/2 mutant advanced solid tumors, including glioma. Enrollment was completed in June 2017. Dose escalation data as of March 29, 2018 were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. As of the updated July 20, 2018 data cut-off, study design, enrollment and baseline characteristics of the 52 glioma patients remain unchanged, as reported below.

Forty-eight percent of patients (n=25) had World Health Organization (WHO) classified Grade 2 tumors, 42% (n=22) had Grade 3 tumors, 8% (n=4) had Grade 4 tumors and 2% (n=1) was unknown.
The median age of these patients is 42.5 years (ranging from 16-73 years).
Patients received a median of two prior systemic therapies (ranging from one to six).
Seventy-three percent of patients (n=38) had previously received temozolomide and 58% percent (n=30) had previously received radiotherapy.
Patients received daily doses of AG-881 ranging from 10 mg to 300 mg.
Updated safety and efficacy data on the 52 patients with enhancing and non-enhancing glioma, including an exploratory tumor volume growth rate analysis, are reported below.

Fourteen patients remain on treatment, including 13 patients with non-enhancing disease.
Of the 38 patients who discontinued treatment, 76.3% (n=29) discontinued for disease progression and 5.2% (n=2) discontinued due to an AE.
The median treatment duration was 6.3 months (ranging from 0.2-32 months) for all glioma patients, 15 months (ranging from 1-32 months) for non-enhancing glioma and 3.25 months (ranging from 0.2- 32 months) for patients with enhancing disease.
Thirty-seven percent of patients (n=19, including 15 patients with non-enhancing disease) remained on treatment for ≥1 year.
Safety Data

The safety analysis conducted for all 52 glioma patients as of the data cut-off demonstrated that AG-881 continues to have a favorable safety profile at dose levels below 100 mg.

The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common (>30%) being increases in alanine aminotransferase (ALT) (n=23), increases in aspartate aminotransferase (AST) (n=21), headache (n=19) and fatigue (n=17).
Grade 3 or higher AEs were observed in 19% of all patients (n=10). AEs occurring in more than one patient included seizure (n=4), ALT increases (n=3) and AST increases (n=2).
As reported in June, dose limiting toxicities (DLTs) of Grade 2 or higher elevated transaminases occurred in five glioma patients at the higher dose levels (≥100 mg) and resolved to Grade ≤1 with dose modification or discontinuation. There were no new DLTs reported as of the new data cut-off or any treatment-related on-treatment deaths.
Doses of 10 mg and 50 mg are under evaluation in an ongoing perioperative study in non-enhancing glioma.
Efficacy Data

Efficacy data from the 52 glioma patients (22 with non-enhancing and 30 with enhancing disease) as of the data cut-off showed:

One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained partial response according to the investigator by Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG) and remains on treatment.
One patient with non-enhancing disease and a 1p19q co-deletion had a confirmed / sustained minor response according to the investigator by RANO-LGG and remains on treatment.
Sixty-nine percent of patients (n=36) had a best response of stable disease, including 82% (n=18) patients with non-enhancing disease.
For non-enhancing patients with available data (n=18), the average volumetric six-month tumor growth was 6.8% following treatment with AG-881; pre-treatment volumetric growth rates were not available for these patients. For a similar population of IDHm low-grade glioma patients in the ongoing Natural History study, the average six-month volumetric growth prior to treatment was 24.5%.
Ongoing Glioma Perioperative Study Presented in Trials in Progress Poster
A perioperative ‘window’ trial with ivosidenib and AG-881 (10 mg and 50 mg) in up to 45 IDH1m non-enhancing low-grade glioma patients is ongoing and being presented today as part of a trials in progress poster. The goal of the trial is to confirm CNS penetrance and tumor 2-HG suppression of ivosidenib and AG-881 as part of the strategy to finalize internal pivotal development plans by year-end 2018.

About Glioma
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low-grade glioma) to rapidly progressing (high-grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH1 mutation.

On November 16, 2018 apceth Biopharma GmbH, an established contract manufacturing organization in the field of gene and cell therapy, reported it has started supplying clinical batches of DCprime’s cell-based cancer vaccine DCP-001 to a phase II clinical study for the treatment of Acute Myeloid Leukemia (AML) (Press release, apceth, NOV 16, 2018, View Source [SID1234531454]). AML is a haematological cancer characterized by high risk of relapse, even after initial response to chemotherapy. Cancer vaccination with dendritic cells could be a successful strategy to boost the patient’s immune system and result in lasting disease control. DCprime announced yesterday that the first patient has been treated with the product DCP-001 at the Amsterdam University Medical Center (UMC).

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"We are proud to be the manufacturing partner of DCprime for DCP-001, the first off-the shelf dendritic cell vaccine in a cancer indication with high unmet medical need", explained Dr Christine Günther, CEO of apceth Biopharma. "Our long-term collaboration with DCprime has always been constructive and cooperative, from technology transfer to the large-scale manufacturing process."

Dr Erik Manting, CEO of DCprime, commented: "Based on the recently published encouraging results of the phase I trial with our lead product DCP-001, we aim to confirm these results in the phase II ADVANCE-II trial and we are happy with the enrollment of the first patient. We would like to thank the apceth Biopharma team for their important contribution to the manufacturing of our product."

On November 16, 2018 Amgen (NASDAQ: AMGN) 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 current indication for BLINCYTO (blinatumomab) monotherapy to include adult patients with Philadelphia chromosome negative CD19 positive 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 (Press release, Amgen, NOV 16, 2018, View Source [SID1234531408]). The application included data from the Phase 2 BLAST study in frontline and relapsed/refractory ALL, the largest prospective trial for MRD-positive ALL ever conducted. BLINCYTO, a bispecific CD19-directed CD3 T cell engager, is the first BiTE immunotherapy to receive regulatory approval globally.

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MRD refers to the presence of cancer cells that remain detectable, despite a patient 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.1-3

"The continued acknowledgment of MRD status as an approvable endpoint is an important step in the larger paradigm shift of ALL management as early intervention within the ALL treatment continuum has been shown to be an important step in eliminating dangerous detectable disease," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We appreciate the efforts undertaken by the ALL community to work with regulators and other decision makers on the role of MRD in recurrence of disease and look forward to a final decision by the European Commission."

The CHMP opinion is based on data from the Phase 2 BLAST study, which found that BLINCYTO induced a complete MRD response, or no detectable MRD, in 78 percent of patients within one treatment cycle. Safety results among MRD-positive patients were consistent with the known safety profile of BLINCYTO in relapsed or refractory B-cell precursor ALL.

The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions based on the decision of the EC. The CHMP previously adopted a negative opinion in July 2018 but revised the opinion following a re-examination request by Amgen.

In March 2018, the U.S. Food and Drug Administration (FDA) approved BLINCYTO 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. BLINCYTO is the first immunotherapy from Amgen’s BiTE platform, an innovative approach that helps the body’s immune system target cancer cells.

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 at any time after the first cycle, if eligible. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Additional secondary endpoints included incidence and severity of adverse events, overall survival (OS), time to hematological remission and duration of complete MRD response.

Results from the BLAST study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in 2015 and published in Blood in 2018. Long-term OS data results from the BLAST study will also be featured in an oral presentation during the ASH (Free ASH Whitepaper) 2018 Annual Meeting on Dec. 3.

About ALL and MRD
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.4,5 Poor outcomes have been observed in patients who achieve first or second complete hematologic remission but have persistent MRD, which remains detectable at the molecular level after treatment.1,6 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.6 For more information about MRD, please visit AmgenOncology.com.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody construct is an innovative technology that can be engineered to target any tumor antigen expressed by any type of cancer. The protein molecules are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. BiTE antibody construct helps 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 FDA in 2014, and 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 MRD greater than or equal to 0.1 percent.

BLINCYTO is now approved in 57 countries, including all member countries in the European Union and the European Economic Area, Canada, Japan, and Australia.

Important EU BLINCYTO (blinatumomab) Safety Information

This product is subject to additional monitoring in the EU. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

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 for evidence of CRS, 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 of neurological toxicity 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 increase (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).