A Phase III, Open-label, Randomized Study of Osimertinib with or without Platinum Plus Pemetrexed Chemotherapy, as First-line Treatment in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2)

The reason for the study is to find out if an experimental combination of an oral medication
called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective
than giving osimertinib alone for the treatment of locally advanced or metastatic non-small
cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA)
which, if known, can help physicians decide the best treatment for their patients. One type
of mutation can occur in the gene that produces a protein on the surface of cells called the
Epidermal Growth Factor Receptor (EGFR).

Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI)
that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the
benefit observed for patients treated with osimertinib, the vast majority of cancers are
expected to develop resistance to the drug over time. The exact reasons why resistance
develops are not fully understood but based upon clinical research it is hoped that combining
osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the
onset of resistance and the worsening of a patient's cancer.

In total the study aims to enroll approximately 586 patients, consisting of approximately 30
patients who will participate in a safety run-in component of the trial, and approximately
556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the
main trial. In the main part of the trial there is a one in two chance of receiving
osimertinib alone, and the treatment is decided at random by a computer.

The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst
receiving study medication, it is expected patients will attend, on average, approximately 15
visits over the first 12 months and then approximately 4 visits per year afterwards. Each
visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the
study centre.

Inclusion Criteria:

1. Male or female, at least 18 years of age; patients from Japan at least 20 years of
age.

2. Pathologically confirmed non-squamous Non-Small Cell Lung Cancer (NSCLC). NSCLC of
mixed histology is allowed.

3. Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic Non-Small
Cell Lung Cancer (NSCLC) (clinical stage IVA or IVB) or recurrent Non-Small Cell Lung
Cancer (NSCLC) not amenable to curative surgery or radiotherapy.

4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations
known to be associated with Epidermal growth factor receptor tyrosine kinase
inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination
with other epidermal growth factor receptor (EGFR) mutations, which may include T790M.

5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable
to curative surgery or radiotherapy.

6. WHO PS of 0 to 1 at screening with no clinically significant deterioration in the
previous 2 weeks.

7. Life expectancy >12 weeks at Day 1.

8. Willing to use contraception as appropriate during the study and for a period of time
after discontinuing study treatment.

Exclusion Criteria:

1. Spinal cord compression; and unstable brain metastases, with stable brain metastases
who have completed definitive therapy, are not on steroids, and have a stable
neurological status for at least 2 weeks after completion of the definitive therapy
and steroids can be enrolled. Patients with asymptomatic brain metastases can be
eligible for inclusion if in the opinion of the Investigator immediate definitive
treatment is not indicated

2. Past medical history of Interstitial Lung Disease (ILD), drug-induced Interstitial
Lung Disease, radiation pneumonitis that required steroid treatment, or any evidence
of clinically active Interstitial Lung Disease.

3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the Investigator's opinion makes
it undesirable for the patient to participate in the trial or which would jeopardize
compliance with the protocol, or active infection including Hep. B, Hep. C and HIV.
Screening for chronic conditions is not required. Active infection will include any
patients receiving treatment for infection.

4. QT prolongation or any clinically important abnormalities in rhythm.

5. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:

- Absolute neutrophil count below the lower limit of normal (

- Platelet count below the LLN

- Hemoglobin <90 g/L. The use of granulocyte colony stimulating factor support,
platelet transfusion and blood transfusions to meet these criteria is not
permitted.

- ALT >2.5 x the upper limit of normal (ULN) if no demonstrable liver metastases or
>5 x ULN in the presence of liver metastases

- AST >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of
liver metastases

- Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of
documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases

- Creatinine clearance <60 mL/min calculated by Cockcroft and Gault equation or 24
hour urine collection (refer to Appendix I for appropriate calculation)

6. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant bowel resection that would
preclude adequate absorption of osimertinib.

7. Prior treatment with any systemic anti-cancer therapy for advanced Non-Small Cell Lung
Cancer (NSCLC) not amenable to curative surgery or radiation including chemotherapy,
biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant and
neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy,
investigational agents), or definitive radiation/chemoradiation with or without
regimens including immunotherapy, biologic therapies, investigational agents are
permitted as long as treatment was completed at least 12 months prior to the
development of recurrent disease.

8. Prior treatment with an Epidermal growth factor receptor tyrosine kinase inhibitors
(EGFR-TKI).

9. Major surgery within 4 weeks of the first dose of investigational product (IP).
Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy
via video assisted thoracoscopic surgery are permitted.

10. Radiotherapy treatment to more than 30% of the bone marrow or( with a wide field of
radiation within 4 weeks of the first dose of investigational product (IP).

11. History of hypersensitivity to active or inactive excipients of investigational
product (IP) or drugs with a similar chemical structure or class to investigational
product (IP).