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2018-10-19

AstraZeneca: New data on mechanisms of acquired resistance after 1st-line Tagrisso in NSCLC support initiation of ORCHARD t...

Phase III FLAURA trial shows MET-amplification and EGFR C797S mutation
among most frequent resistance mechanisms

AstraZeneca today presented new data on the mechanisms of acquired
resistance from the Tagrisso (osimertinib) pivotal Phase III FLAURA
trial during an oral late-breaker abstract session at the ESMO 2018
Congress (European Society of Medical Oncology) in Munich, Germany.
MET-amplification and the epidermal growth factor receptor (EGFR)
C797S mutation were among the most frequent resistance mechanisms
observed after treatment with 1st-line Tagrisso in patients with
previously-untreated EGFR-mutated (EGFRm) non-small cell lung cancer
(NSCLC) who experienced disease progression during the trial period.
As expected, there was no evidence of the acquired EGFR T790M
mutation in the 1st-line Tagrisso arm.

Based on those findings, AstraZeneca today announced the initiation of
a new clinical trial, Osimertinib Resistance CoHorts, Addressing 1L
Relapse Drivers (ORCHARD), an open-label, multi-centre, multi-drug
Phase II platform trial in patients with advanced NSCLC who have
experienced disease progression following 1st-line therapy with
Tagrisso.

Klaus Edvardsen, Senior Vice President, Head of Oncology, Global
Medicines Development, said: "We are committed to following the
science to improve survival for all patients with EGFR-mutation
positive NSCLC at every stage of disease. The ORCHARD trial will
increase our understanding of resistance mechanisms and explore
potential new treatment options to address the next stage of disease
after 1st-line Tagrisso."

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial
from Winship Cancer Institute of Emory University, Atlanta, US, said:
"The FLAURA trial ushered in a new standard of care with osimertinib
as 1st-line therapy for EGFRm NSCLC. Today's results provide
direction for continued research into new treatment options after
progression on 1st-line osimertinib therapy by studying
MET-amplification and EGFR C797S, among other resistance mechanisms."

Results from the preliminary FLAURA subgroup analysis showed that
following treatment with Tagrisso in the 1st-line setting, the most
frequent acquired resistance mechanisms detected in patient plasma
were MET-amplification (15%) and the EGFR C797S mutation (7%),
followed by HER2-amplification and the PIK3CA and RAS mutations
(2-7%). For the comparator EGFR-TKI arm, the most frequent acquired
resistance mechanism to erlotinib or gefitinib was the EGFR T790M
mutation (47%).

Data from the Phase III AURA3 trial, also presented at the congress,
were consistent with the FLAURA findings. The most frequent mutations
detected in patient plasma after progression with 2nd-line Tagrisso
included EGFR C797 mutations (15%; C797S n=10; C797G n=1),
MET-amplification (19%), HER2-amplification (5%) and the PIK3CA
mutation (5%).

Tagrisso has now received approval in more than 40 countries for the
1st-line treatment of patients with metastatic EGFRm NSCLC, including
the US, Japan and in the European Union. Other global health
authority reviews and submissions of the 1st-line data are ongoing,
including China, with a decision expected in the second half of 2019.

- ENDS -

NOTES TO EDITORS

About EGFRm NSCLC

Lung cancer is the leading cause of cancer death among both men and
women, accounting for about one-fifth of all cancer deaths, more than
breast, prostate and colorectal cancers combined. Lung cancer is
broadly split into NSCLC and small cell lung cancer (SCLC), with
80-85% classified as NSCLC. Approximately 10-15% of NSCLC patients in
the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.
These patients are particularly sensitive to treatment with EGFR-TKIs
which block the cell-signalling pathways that drive the growth of
tumour cells. Approximately 25% of patients with EGFRm NSCLC have
brain metastases at diagnosis, increasing to approximately 40% within
two years of diagnosis. The presence of brain metastases often
reduces median survival to less than eight months.

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI
designed to inhibit both EGFR-sensitising and EGFR T790M-resistance
mutations, with clinical activity against central nervous system
metastases. Tagrisso 40mg and 80mg once-daily oral tablets have now
received approval in more than 40 countries, including the US, Japan
and in Europe, for 1st-line EGFRm advanced NSCLC, and more than 80
countries, including the US, Japan, China and in Europe, for 2nd-line
use in patients with EGFR T790M mutation-positive advanced NSCLC.
Tagrisso is also being developed in the adjuvant setting (ADAURA), in
the locally-advanced unresectable setting (LAURA), and in combination
with other treatments.

About the FLAURA trial

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg
orally once daily vs. standard-of-care EGFR-TKIs (either erlotinib
[150mg orally, once daily] or gefitinib [250mg orally, once daily])
in previously-untreated patients with locally-advanced or metastatic
EGFRm NSCLC. The trial was double-blinded and randomised, with 556
patients across 29 countries.

About the ORCHARD trial

ORCHARD is an open-label, multicentre, multi-drug Phase II platform
trial in patients with advanced EGFRm NSCLC whose disease has
progressed on 1st-line therapy with Tagrisso. The initial trial is
expected to have multiple treatment arms which will examine both
targeted and non-targeted combination options and plans to recruit
150 patients. As learnings about acquired resistance to Tagrisso from
FLAURA accumulate, as well as other trials, additional treatment arms
may be added.

About AstraZeneca in Lung Cancer

AstraZeneca has a comprehensive portfolio of approved and potential
new medicines in late-stage development for the treatment of lung
cancer across all stages of disease and lines of therapy. We aim to
address the unmet needs of patients with EGFRm NSCLC with our
approved medicines, Iressa and Tagrisso, and with the Phase III
ADAURA and LAURA trials.

Our Immuno-Oncology portfolio includes Imfinzi, an anti-PDL1 antibody,
which is in development as monotherapy (ADJUVANT, PACIFIC2, MYSTIC
and PEARL trials) and in combination with tremelimumab and/or
chemotherapy (MYSTIC, NEPTUNE, POSEIDON and CASPIAN trials).

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
precision 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 commercialisation of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal & Metabolism
and Respiratory. AstraZeneca operates in over 100 countries and its
innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us
on Twitter @AstraZeneca.

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