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2016-06-06

AstraZeneca: TAGRISSO (OSIMERTINIB) SHOWS CLINICAL ACTIVITY IN PATIENTS WITH LEPTOMENINGEAL DISEASE FROM LUNG CANCER

Osimertinib data reported at ASCO 2016 demonstrated improved
neurological function in patients with EGFRm NSCLC and leptomeningeal
disease

Latest results reinforce pre-clinical evidence that osimertinib
crosses the blood-brain barrier

6 June 2016

AstraZeneca today announced clinical and safety data for Tagrisso
(osimertinib) in patients with leptomeningeal (LM) disease, a
complication of epidermal growth factor receptor (EGFR)
mutation-positive advanced non-small cell lung cancer (NSCLC),1 where
cancer cells spread to the cerebrospinal fluid. LM is a devastating
disease often associated with advanced lung cancer.

The updated BLOOM Phase I trial results, presented at the American
Society of Clinical Oncology (ASCO) annual meeting, showed that
irrespective of T790M status of patients, osimertinib reduced
enhanced central nervous system lesions as demonstrated by the
presence of cancer cells in MRI scans.1 Osimertinib also improved
neurological function and lowered overall levels of EGFR mutations
(EGFRm) in cerebrospinal fluid (CSF). Data from 21 patients with
pre-treated EGFRm NSCLC treated with osimertinib 160mg once daily
showed intracranial radiological improvement in seven patients,
neurological function improvement in five patients, and clearance of
tumour cells from the CSF at two consecutive visits in two patients.
None of the 21 patients treated with osimertinib received concomitant
radiotherapy or intrathecal chemotherapy. Fifteen patients remained
on treatment at data cut-off (10 March 2016), of whom seven had been
on treatment for more than nine months.

Further data from the BLOOM study showed that osimertinib crossed the
blood-brain barrier. In six of nine patients, a greater than 50%
decrease in EGFR mutation level was observed in the CSF up to cycle
9, day 1 of treatment, with a sustained reduction observed in five.
These results support previously reported preclinical data
demonstrating that osimertinib crosses the blood-brain barrier.2

Osimertinib is currently only approved in lung cancer patients
harbouring a T790M mutation.

Martin Sandelin vid Akademiska sjukhuset i Uppsala kommenterar
resultaten:

"De data som presenteras är lovande och bekräftar att osimertinib även
är aktivt i CNS (centrala nervsystemet). För lungcancerpatienter med
EGFR-mutation och spridning av sjukdomen till hjärna och hjärnhinnor
innebär det en ny möjlighet att behandla sjukdomen målriktat. För de
patienter som svarar på behandlingen innebär det att strålbehandling
av CNS kan fördröjas."

Dr James CH Yang, from the National Taiwan University Hospital and
National Taiwan University Cancer Centre, Taipei, said:
"Leptomeningeal disease carries a devastating prognosis, so the
safety, tolerability and activity profile seen with osimertinib is
encouraging. In the BLOOM study, we saw a decrease in central nervous
system lesions in patients with leptomeningeal disease, with
accompanying neurological improvement. The results build on previous
findings with osimertinib in preclinical and clinical studies and
provide evidence of the potential of osimertinib in
difficult-to-treat patients who have central nervous system
metastases."

In leptomeningeal disease, cancer cells spread to the membranes
surrounding the brain and spinal cord. The disease is currently
treated with systemic or intrathecal chemotherapy, whole-brain
radiation therapy or EGFR tyrosine kinase inhibitors (TKIs), with
median overall survival of 4.5-11 months.3,4 However, most
currently-available EGFR-TKIs have limited ability to cross the
blood-brain barrier to effectively treat or prevent brain
metastases.5-7

Osimertinib 160mg was associated with a manageable tolerability
profile over treatment periods up to 11 months. The most common
adverse events reported by patients were diarrhoea (58% overall; 5%
?Grade 3), nausea (48% overall; 0% ?Grade 3) and rash (43% overall;
0% ?Grade 3). There were no reported cases of interstitial lung
disease, hyperglycaemia or QT prolongation.

Osimertinib recently received accelerated approval as the first
indicated treatment for patients with EGFR T790M mutation-positive
locally advanced/metastatic NSCLC in the US, EU, Japan and Israel.
Osimertinib is also approved in South Korea in the same indication.

AstraZeneca is committed to exploring the full potential of
osimertinib in patients with lung cancer, including adjuvant and
locally advanced/metastatic first-line EGFRm settings, in patients
with and without brain metastases, and in those with leptomeningeal
disease.8

- ENDS -

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-third of all cancer deaths and more
than breast, prostate and colorectal cancers combined.9Patients who
have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC
patients in Europe10and 30-40% of NSCLC patients in Asia,11are
particularly sensitive to treatment with currently available
EGFR-TKIs, which block the cell signalling pathways that drive the
growth of tumour cells.12However, tumours almost always develop
resistance to treatment, leading to disease progression.13In
approximately two-thirds of patients treated with approved EGFR-TKIs
such as gefitinib and erlotinib, this resistance is caused by the
secondary mutation, T790M.13

About leptomeningeal disease

In leptomeningeal disease, cancer cells spread to the membranes
surrounding the brain and spinal cord. It is a complication that
affects 3-5% of patients with NSCLC14, and 9% of those with EGFRm
NSCLC.15 Treatment is challenging due to poor penetration of the
blood-brain barrier by most EGFR-TKI therapies, making it difficult
for drugs to reach the brain and spinal cord. 5-7 Average survival in
patients with EGFRm NSCLC and leptomeningeal disease is 4.5 to 11
months.3-4 In a recently reported "real-world" retrospective analysis
of patients with EGFRm NSCLC treated with EGFR-TKIs, overall survival
was approximately 30 months.16

About osimertinib

Osimertinib 80mg once-daily tablet is the first medicine indicated for
the treatment of adult patients with locally advanced or metastatic
EGFR T790M mutation-positive NSCLC. Non-

clinical in vitro studies have demonstrated that osimertinib has high
potency and inhibitory activity against mutant EGFR phosphorylation
across the range of clinically relevant EGFR and T790M mutant NSCLC
cell lines with significantly less activity against EGFR in wild-type
cell lines.17

Osimertinib is being compared with platinum-based doublet chemotherapy
in the confirmatory AURA3 Phase III study in patients with EGFR T790M
mutation-positive, locally advanced or metastatic NSCLC who have
progressed after EGFR-TKI therapy.18It is also being investigated in
the adjuvant and metastatic first-line settings,19,20including in
patients with and without brain metastases, in leptomeningeal
disease,8and in combination treatment.21

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 6
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 six 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
haematology.

By harnessing the power of four scientific platforms --
immuno-oncology, the genetic drivers of cancer and resistance, DNA
damage repair 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.

Om AstraZeneca

AstraZeneca är ett globalt, innovativt bioläkemedelsföretag med fokus
på forskning, utveckling och marknadsföring av receptbelagda
läkemedel, primärt för behandling av sjukdomar inom områdena
hjärta/kärl/metabolism, andningsvägar/inflammation/autoimmunitet,
cancer, infektion och neurovetenskap. AstraZeneca är verksamt i över
100 länder och våra innovativa läkemedel används av miljontals
patienter världen över.

För mer information, se www.astrazeneca.se och www.astrazeneca.com
eller följ oss på twitter. Https:/twitter.com/AstraZenecaSE
(http://Https://twitter.com/AstraZenecaSE).

För ytterligare information kontakta:

Petra Eurenius, Kommunikationschef AstraZeneca Nordic-Baltic, telefon:
0709 186562

988635.011 06.2016 SE

References

1 Yang JCH, et al. Osimertinib activity in patients (pts) with
leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC):
updated results from BLOOM, a Phase I study. Abstract 9002 [Oral
Presentation]. Presented at the annual meeting of the American
Society of Clinical Oncology, 3-7 June 2016, Chicago, USA

2 Ballard P, et al. Preclinical activity of AZD9291 in EGFR-mutant
NSCLC brain metastases. Presented at the World Congress on Lung
Cancer, 6-9 September 2015. Denver, Colorado, USA.

3 Liao BC et al. Epidermal Growth Factor Receptor Tyrosine Kinase
Inhibitors for Non-Small-Cell Lung Cancer Patients with
Leptomeningeal Carcinomatosis.
(http://www.ncbi.nlm.nih.gov/pubmed/26334749) J Thorac Oncol. 2015
Dec;10(12):1754-61

4 Umemura S
(http://www.ncbi.nlm.nih.gov/pubmed/?term=Umemura%20S%5BAuthor%5D&cauthor...)
et al. Clinical outcome in patients with leptomeningeal metastasis
from non-small cell lung cancer: Okayama Lung Cancer Study Group.
Lung Cancer. (http://www.ncbi.nlm.nih.gov/pubmed/22487432) 2012
Jul;77(1):134-9.

5 European Medicines Agency CHMP assessment report for Giotrif. 2013

6 De Vries NA et al. Restricted brain penetration of the tyrosine
kinase inhibitor erlotinib due to the drug transporters P-gp and
BCRP. (http://www.ncbi.nlm.nih.gov/pubmed/20963470) Invest New Drugs.
2012 Apr;30(2):443-9.

7 Zhao J et al. Cerebrospinal fluid concentrations of gefitinib in
patients with lung adenocarcinoma.
(http://www.ncbi.nlm.nih.gov/pubmed/22846582) Clin Lung Cancer. 2013
Mar;14(2):188-93.

8 National Institutes of Health. Oral Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have
Advanced Non-Small Cell Lung Cancer (BLOOM). Available at:
https://clinicaltrials.gov/ct2/show/NCT02228369?term=AZD9291+brain+met&r....
Accessed May 2016.

9 GLOBOCAN (...

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