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AstraZeneca's TAGRISSO® (osimertinib) Shows Potential as a New Standard of Care in 1st-Line EGFR-Mutated Non-Small Cell Lung Cancer at ESMO 2017 Congress

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Phase III FLAURA trial results show TAGRISSO reduced the risk of
progression or death by more than half, with consistent results across
all subgroups, including those with and without brain metastases

Superior median progression-free survival (PFS) of 18.9 months
compared with 10.2 months for the current standard of care

Clinically meaningful trend in overall survival benefit

AstraZeneca today announced the full results of the Phase III FLAURA
trial, which support TAGRISSO®'s (osimertinib) clear
potential as a new standard of care (SoC) in the 1st-line treatment of
adult patients with locally-advanced or metastatic epidermal growth
factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).

Results of the Phase III FLAURA trial were included at the Presidential
Symposium I of the European Society of Medical Oncology (ESMO) 2017
Congress in Madrid, Spain, and demonstrate a superior,
clinically-meaningful progression-free survival (PFS) with osimertinib
compared to current SoC EGFR tyrosine kinase inhibitors (TKIs)
(erlotinib or gefitinib).

Sean Bohen, Executive Vice President, Global Medicines Development and
Chief Medical Officer at AstraZeneca, said: "The FLAURA data are truly
exciting. Until now, even with the therapeutic advances offered by the
first- and second-generation EGFR inhibitors, less than 20% of EGFR
mutation-positive NSCLC patients survive for five years. The FLAURA data
suggest early and sustained benefit with TAGRISSO that has the potential
to significantly impact long-term patient outcomes and help address the
considerable unmet need that remains."

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA study,
from the Winship Cancer Institute of Emory University, Atlanta, GA,
said: "The FLAURA data are likely to result in a major paradigm shift in
the treatment of patients with EGFR mutation-positive advanced lung
cancer. Not only did the trial demonstrate a robust improvement in
efficacy with osimertinib when compared to other commonly-used EGFR
inhibitors, the side effects profile was also more favorable with
osimertinib."

Summary of key results:

             
Endpoint   TAGRISSO   SoC   Hazard ratio (HR)/
Odds ratio (OR)
PFS
(primary endpoint)
 

18.9 months
(median)

 

10.2 months
(median)

  HR 0.46
95% CI, 0.37-0.57, p<0.0001

Overall Survival (OS)
at 25% maturity

  N/A   N/A   HR 0.63
95% CI, 0.45-0.88, p=0.0068*

Duration of
Response (DoR)

 

17.2 months
(median)

 

8.5 months
(median)

  N/A

Objective Response
Rate (ORR)

  80%   76%   OR 1.28
0.85-1.93, p=0.2335
     

*0.0015 was the threshold required for statistical significance at the
current level of maturity. A final OS analysis is planned at a later
stage.

Highlights from the FLAURA data presented include:

  • Superior PFS (primary endpoint): Patients
    on osimertinib had less than half the risk of progression or death
    compared to patients on erlotinib or gefitinib (hazard ratio [HR]
    0.46; 95% confidence interval [CI] 0.37, 0.57; p<0.0001). The median
    PFS was 18.9 months for patients on osimertinib vs. 10.2 months for
    patients in the comparator arm.
  • Clinically meaningful preliminary overall
    survival (OS) data at 25% maturity:
    The hazard ratio for OS was
    0.63 [95% CI: 0.45, 0.88; P=0.0068] favoring osimertinib. OS data were
    25% mature at the time of the interim analysis. (21% of the patients
    on osimertinib had died and 30% of the patients on the comparator arm
    had died.) The p-value of 0.0068 was not below the threshold of 0.0015
    required for statistical significance at the current level of
    maturity. A final OS analysis is planned at a later stage.
  • PFS improvements consistent across subgroups:
    Improvements in PFS with osimertinib were consistent across all
    pre-specified patient subgroups, with at least a 40% reduction in the
    risk of progression or death, including in patients with/without
    central nervous system (CNS) metastases at study entry,
    Asian/non-Asian patients, patients with/without prior smoking history,
    and patients with Exon 19 deletion/L858R sensitizing mutations.
  • Impressive duration of response (DoR) and
    objective response rate (ORR):
    Patients treated with
    osimertinib had more than double the median DoR than those on the
    comparator arm (17.2 months vs. 8.5 months), and an ORR (a measurement
    of tumor shrinkage) of 80% vs. 76% with the comparator arm [odds ratio
    1.28 (0.85, 1.93), p=0.2335].

The FLAURA safety data for osimertinib was in line with that observed in
prior clinical trials, with a low rate of Grade ≥3 adverse events (AEs).
In patients treated with osimertinib, the most common AEs were diarrhea
(58%, any grade [2% Grade ≥3]) and dry skin (32%, any grade [<1% Grade
≥3]), and in the comparator arm group the most common AEs were diarrhea
(57%, any grade [2% Grade ≥3]) and dermatitis acneiform (48%, any grade
[5% Grade ≥3]). Of the patients on osimertinib, 33.7% had a Grade ≥3 AE,
compared to 44.8% in the comparator arm, and 13.3% of patients on
osimertinib had an AE leading to treatment discontinuation compared to
18.1% in the comparator arm.

This indication is not yet FDA approved. AstraZeneca is in discussions
with global health authorities regarding regulatory submissions for
osimertinib based on the FLAURA data. A status of regulatory submissions
is usually provided with the Company's quarterly results announcement.

TAGRISSO once-daily tablets are approved by the US Food and Drug
Administration (FDA) 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 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.

TAGRISSO® (osimertinib) 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%)

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 one-quarter of all cancer deaths, more than
breast, prostate and colorectal cancers combined. Approximately 10% to
15% of patients in the US and Europe, and 30% to 40% of patients in Asia
have epidermal growth factor receptor mutation-positive (EGFRm) NSCLC.
These patients are particularly sensitive to treatment with
currently-available EGFR tyrosine kinase inhibitors (TKIs), which block
the cell signaling pathways that drive the growth of tumor cells.
However, tumors almost always develop resistance to EGFR-TKI treatment,
leading to disease progression. Approximately half of patients develop
resistance to approved EGFR-TKIs, such as gefitinib and erlotinib, due
to the resistance mutation, EGFR T790M. TAGRISSO targets this secondary
mutation that leads to disease progression. There is also a need for
agents with improved central nervous system efficacy since approximately
25% of patients with EGFRm NSCLC have brain metastases at first
diagnosis, increasing to approximately 40% within two years of diagnosis.

About TAGRISSO® (osimertinib)

TAGRISSO® (osimertinib) is a third-generation, irreversible
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
designed to inhibit both EGFR sensitizing and EGFR T790M resistance
mutations, with clinical activity against central nervous system (CNS)
metastases. TAGRISSO 40mg and 80mg once-daily oral tablets have been
approved in more than 50 countries, including the US, EU, Japan and
China, for patients with EGFR T790M mutation-positive advanced non-small
cell lung cancer. Eligibility for treatment with TAGRISSO is dependent
on confirmation that the EGFR T790M mutation is present in the tumor.

TAGRISSO is also being investigated in the adjuvant and metastatic
1st-line settings, including in patients with and without CNS
metastases, in leptomeningeal metastases and in combination with other
treatments.

About FLAURA

FLAURA assessed the efficacy and safety of osimertinib 80mg orally once
daily vs. standard-of-care epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors (TKIs) (either erlotinib [150mg orally, once
daily] or gefitinib [250mg orally, once daily]) in previously untreated
patients with locally advanced or metastatic EGFR mutation-positive
non-small cell lung cancer. The trial was a double-blinded, randomized
study, with 556 patients across 30 countries.

The primary endpoint of the trial was progression-free survival, and
secondary endpoints included overall survival, objective response rate,
duration of response, disease control rate, safety and measures of
health-related quality of life.

About AstraZeneca in Lung Cancer

AstraZeneca is using ground-breaking science to develop a wide range of
medicines for patients with lung cancer. We are pioneering precision
medicines that target molecular mutations in tumor cells, as well as
those that aim to boost 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.

US-14134 Last Updated 8/17

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