A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene (AURA3)

Lung cancer has been the most common cancer in the world for several decades,
and by 2008, there were an estimated 1.61 million new cases, representing 12.7%
of all new cancers. It was also the most common cause of death from cancer,
with 1.38 million deaths (18.2% of the total).
NSCLC represents approximately 80% to 85% of all lung cancers. Unfortunately,
at the time of diagnosis approximately 70% of NSCLC patients already have
advanced or metastatic disease not amenable to surgical resection. Furthermore,
a significant percentage of early stage NSCLC patients who have undergone
surgery subsequently develop distant recurrence and die as a result of their
lung cancer. Patients presenting with advanced NSCLC have a median overall
survival (OS) of 10 to 12 months.
Treatment of advanced NSCLC can be guided by the presence of certain molecular
drivers
such as EGFR, anaplastic lymphoma kinase (AnLK) and KRAS mutations. The
incidence of
Epidermal Growth Factor Receptor mutation positive (EGFRm+) NSCLC is
approximately
10-15% and 30-40% of patients in the West and Asia, respectively.
Although first- (eg, erlotinib, gefitinib) and second-generation (eg, afatinib)
Epidermal
Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) are established
therapies for patients with NSCLC known to have activating mutations in EGFR
(EGFRm+), the
emergence of a secondary T790M mutation in patients treated with an EGFR TKI
agent has
been described as a major route of development of resistance to this class of
therapy
in approximately 60% of patients.
Selective inhibition of EGFR tyrosine kinase has demonstrated clinical benefit
in
approximately 70% of patients with advanced NSCLC.
AZD9291 is a potent irreversible inhibitor of both the single EGFRm+ (TKI
sensitivity
conferring mutation) and dual EGFRm+/T790M+ (TKI resistance conferring mutation)
receptor forms of EGFR with a significant selectivity margin over wild-type
EGFR.
Therefore AZD9291 has the potential to provide clinical benefit to patients
with advanced
NSCLC harbouring both the single sensitivity mutations and the resistance
mutation following prior therapy with an EGFR-TKI.

To assess the safety and efficacy, measured as progression free survival, of
AZD9291 compared with platinum-based doublet chemotherapy in patients with EGFR
mutation positive en T790M mutation positive, locally advanced or metastatic
non small cell lung cancer, who have progressed following treatment with an
approved EGFR Tyrosine Kinase Inhibitor (EGFR-TKI).

Phase III, open-label, randomised study
Randomised in a ratio of 2:1:
- AZD9291 (80 mg orally, once daily)
- Pemetrexed (500 mg/m2) + carboplatin (AUC5) / cisplatin (75mg/m2)
(intravenously, administered on day 1 of each 21 day cycle)

Patient will be dosed with AZD9291 (80 mg orally, once daily) or with
Pemetrexed (500 mg/m2) + carboplatin (AUC5) / cisplatin (75mg/m2)
(intravenously, administered on day 1 of each 21 day cycle).

On several days during the study patients will undergo the following
assessments:
- anamnesis (at screening also medical history)
- physical examination
- WHO performance status
- vital signs (blood pressure, pulse)
- length
- weight
- CT or MRI scan
- ECG
- ophthalmolgic assessment
- blood and urine assessments
- MUGA/echocardiogram
- questionnaires (EORTC QLQ C-30, QLQ-LC13, EQ-5D-5L and PRO CTCAE) (by
e-device)
- pregnancy test

Adverse events that may be caused by AZD9291 are: diarrhea, rash and acne, dry
skin, nail changes, nail infections or changes to eyelashes, heart problems,
dryness of the eyes or thinning of the front layer of the eye, changes to the
lining of the gut and inflammation of the lungs.