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AstraZeneca Presents Tagrisso® (osimertinib) Data in Patients with EGFR T790M-Mutation Positive Lung Cancer and Central Nervous System Metastases

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AstraZeneca today reported further evidence that Tagrisso®
(osimertinib), the potential new standard of care for patients with
metastatic epidermal growth factor receptor (EGFR) T790M
mutation-positive non-small cell lung cancer (NSCLC), also shows
clinical activity in those patients with disease progression to central
nervous system (CNS) metastases. The data, presented at the 2017
American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago,
IL, June 2-6, are consistent with earlier clinical and preclinical
findings showing the potential of osimertinib to penetrate the
blood-brain barrier.

In a further analysis of the Phase III AURA3 trial, osimertinib
80mg tablets once-daily demonstrated a median time without disease
worsening or death (progression-free survival, PFS) of 11.7 months in
patients with EGFR T790M mutation-positive advanced NSCLC with ≥1
measurable and/or non-measurable CNS metastases on baseline brain scan,
as measured by Blinded Independent Central Review (BICR). Standard
platinum-based doublet chemotherapy demonstrated a PFS of 5.6 months in
the same patient population (HR 0.32; 95% confidence interval [CI] 0.15,
0.69). Among patients who were evaluable for response, CNS objective
response rate (ORR) was 70% with osimertinib and 31% with chemotherapy
(odds ratio [OR], 5.13; 95% CI 1.44, 20.64). In the AURA3 trial, the
most common (≥20%) adverse reactions observed in osimertinib-treated
patients were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity
(22%), and fatigue (22%).

Dr. Marina-Chiara Garassino, the Thoracic Oncology Unit, Medical
Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy, said: "The results of osimertinib in patients with CNS
metastases are consistent with what has already been reported in the
overall AURA3 population. These data suggest that, like the overall EGFR
T790M mutation-positive NSCLC population, patients who have progressed
to develop CNS metastases may also be able to benefit from osimertinib."

Data were also reported from the BLOOM trial on an EGFR
mutation-positive, T790M unselected, advanced NSCLC cohort of 21
patients with leptomeningeal metastases (LM) treated with osimertinib at
an off-label dose of 160mg po (oral) once daily. The overall LM response
by investigator assessment was 43%, and of the 10 patients with an
‘abnormal' neurological assessment at baseline, seven (70%) had an
improvement. The most common adverse events (AEs) were diarrhea (n=13),
nausea (n=11), paronychia (n=9) and rash (n=9). All were Grade 1/2,
except one case each of diarrhea and nausea (both Grade ≥3). Six
patients had dose interruptions, four patients had an AE leading to dose
reduction, and four patients had an AE leading to discontinuation. Three
patients had an AE leading to death, however no deaths were considered
possibly causally-related to osimertinib by the investigator.

Sean Bohen, Executive Vice President, Global Medicines Development and
Chief Medical Officer at AstraZeneca, said: "Osimertinib's potential for
blood-brain barrier penetration was recognized at an early stage of
development, and it is gratifying to see those findings reflected in
positive progression-free survival outcomes in patients with CNS
metastases in the AURA3 trial and in responses in patients with
leptomeningeal metastases in the BLOOM study."

LM are incurable and notoriously difficult to treat, as existing
therapies are often unable to effectively cross the blood-brain barrier,
leaving patients with limited treatment options. The use of osimertinib
for these patients is not approved and subject to further clinical
research.

In March 2017, the US Food and Drug Administration (FDA) granted full
approval for Tagrisso 80mg once-daily tablets for the treatment
of patients with metastatic EGFR T790M mutation-positive NSCLC, as
detected by an FDA-approved test, whose disease has progressed on or
after an EGFR tyrosine kinase inhibitor (TKI) therapy. Tagrisso
is the first and only approved medicine in the US indicated for NSCLC
patients who have tested positive for the EGFR T790M mutation, and is
now approved in 50 countries worldwide.

Important Safety Information

  • There are no contraindications for TAGRISSO
  • Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.5% and was
    fatal in 0.6% of 833 TAGRISSO-treated patients. Withhold TAGRISSO and
    promptly investigate for ILD in patients who present with worsening of
    respiratory symptoms indicative of ILD (eg, dyspnea, cough, and
    fever). Permanently discontinue TAGRISSO if ILD is confirmed
  • Heart rate-corrected QT (QTc) interval prolongation occurred in
    TAGRISSO-treated patients. Of the 833 TAGRISSO-treated patients, 0.7%
    of patients were found to have a QTc > 500 msec, and 2.9% of patients
    had an increase from baseline QTc > 60 msec. No QTc-related
    arrhythmias were reported. Conduct periodic monitoring with ECGs and
    electrolytes in patients with congenital long QTc syndrome, congestive
    heart failure, electrolyte abnormalities, or those who are taking
    medications known to prolong the QTc interval. Permanently discontinue
    TAGRISSO in patients who develop QTc interval prolongation with
    signs/symptoms of life-threatening arrhythmia
  • Cardiomyopathy occurred in 1.9% and was fatal in 0.1% of 833
    TAGRISSO-treated patients. Left Ventricular Ejection Fraction (LVEF)
    decline ≥ 10% and a drop to < 50% occurred in 4% of 655
    TAGRISSO-treated patients. Conduct cardiac monitoring, including an
    assessment of LVEF at baseline and during treatment in patients with
    cardiac risk factors. Assess LVEF in patients who develop relevant
    cardiac signs or symptoms during treatment. For symptomatic congestive
    heart failure or persistent, asymptomatic LV dysfunction that does not
    resolve within 4 weeks, permanently discontinue TAGRISSO
  • Keratitis was reported in 0.7% of 833 TAGRISSO-treated patients in
    clinical trials. Promptly refer patients with signs and symptoms
    suggestive of keratitis (such as eye inflammation, lacrimation, light
    sensitivity, blurred vision, eye pain, and/or red eye) to an
    ophthalmologist
  • Advise pregnant women of the potential risk to a fetus. Advise females
    of reproductive potential to use effective contraception during
    TAGRISSO treatment and for 6 weeks after the final dose. Advise males
    with female partners of reproductive potential to use effective
    contraception for 4 months after the final dose
  • The most common adverse reactions (≥20%) in patients treated with
    TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail
    toxicity (22%), and fatigue (22%)

INDICATION

TAGRISSO is indicated for the treatment of patients with
metastatic epidermal growth factor receptor (EGFR)
T790M mutation-positive non-small cell lung cancer (NSCLC), as detected
by an FDA-approved test, whose disease has progressed on or after EGFR
tyrosine kinase inhibitor therapy.

Please see complete Prescribing
Information
 including Patient Information.

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and
women, accounting for about 26% of all cancer deaths in the US, more
than breast, prostate and colorectal cancers combined. Among patients
with NSCLC, up to 40% have brain metastases at some time in the course
of their disease. Patients who have EGFR mutation-positive NSCLC, which
occurs in 10% to 15% of NSCLC patients in the US and Europe and 30% to
40% of NSCLC patients in Asia, are particularly sensitive to treatment
with currently available EGFR-TKIs, which block the cell signaling
pathways that drive the growth of tumor cells. However, tumors almost
always develop resistance to treatment, leading to disease progression.
Approximately two-thirds of patients develop resistance to approved
EGFR-TKIs such as gefitinib and erlotinib due to the secondary mutation,
EGFR T790M.

About Tagrisso®
(osimertinib)

Tagrisso® (osimertinib) 40mg and 80mg
once-daily oral tablet has been approved in 50 countries, including the
US, EU, Japan and China, for patients with EGFR T790M mutation-positive
advanced NSCLC. Eligibility for treatment with Tagrisso is
dependent on confirmation that the EGFR T790M mutation is present in the
tumor.

Tagrisso is a third generation, irreversible EGFR-TKI designed to
inhibit both EGFR sensitizing and EGFR T790M resistance mutations, with
clinical activity against CNS metastases. Tagrisso is also
being investigated in the adjuvant and metastatic first-line settings,
including in patients with and without CNS metastases, in leptomeningeal
metastases, and in combination with other treatments.

About the AURA3 trial

AURA3 compared the efficacy and safety of osimertinib 80mg once daily
and platinum-based doublet chemotherapy in 419 patients with EGFR T790M
mutation-positive, locally advanced or metastatic NSCLC whose disease
had progressed on or after treatment with a previous EGFR-TKI. The trial
was carried out in more than 130 locations worldwide, including the US,
Canada, Europe, China, Japan, Korea, Taiwan and Australia.

The primary endpoint of the trial was PFS, and secondary endpoints
included OS, ORR, DoR, DCR, safety and measures of health-related
quality of life (HRQoL).

About the BLOOM trial

In the BLOOM trial, patients with EGFR mutation-positive advanced NSCLC
who had progressed on prior EGFR-TKI therapy and had leptomeningeal
metastases confirmed by positive cerebrospinal fluid cytology received
osimertinib off-label dose 160mg once daily. Response was assessed (by
investigator) in two cohorts: EGFR T790M unselected and EGFR
T790M-positive (by central test). Analyses were based on cerebrospinal
fluid (CSF) cytology, brain MRI imaging and neurological examination
every six weeks until progression.

About Central Nervous System (CNS) Metastases

Parenchymal brain metastases (BM) and leptomeningeal metastases (LM) are
different forms of CNS metastases with a particularly devastating
prognosis. While separate conditions, they may occur in parallel and are
notoriously difficult to treat. BM are a common complication of advanced
cancer and form when primary tumor cells disseminate through the blood
stream and proliferate in the brain, while LM is much rarer and occurs
when tumor cells spread to the meninges surrounding the brain and spinal
cord.

About AstraZeneca in Lung Cancer

AstraZeneca uses ground-breaking science to develop a wide range of
therapies for patients with lung cancer. We are pioneering
biomarker-guided therapies that aim to eliminate lung cancer by
targeting molecular mutations in tumor cells and by boosting the power
of the immune response against cancer. We are committed to transforming
outcomes for patients with lung cancer, whose treatment options are
currently limited.

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 New Oncology as one of AstraZeneca's five Growth Platforms
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 hematology.

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

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in three
main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and
Respiratory. The Company also is selectively active in the areas of
autoimmunity, neuroscience and infection. AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit www.astrazeneca-us.com
and follow us on Twitter @AstraZenecaUS.

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