A Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

Study design This is a phase II, open-label, single-arm tissue and plasma acquisition study
assessing the efficacy, safety and underlying resistance mechanisms of osimertinib (80 mg
orally, once daily) as first-line treatment in patients with locally advanced or metastatic
EGFR mutation positive non-small cell lung cancer who are EGFR tyrosine kinase inhibitor
treatment-naïve and eligible for first-line treatment. Participants with EGFR
mutation-positive non-small cell lung cancer will be required to consent to 2 mandatory
tumour biopsies to be considered for enrolment in this study. The first biopsy will be done
prior to initiating treatment with osimertinib and the second biopsy will be obtained any
time between Investigator assessed, Response Evaluation Criteria in Solid Tumours version 1.1
(RECIST 1.1)-defined progression and up to 7 days after the discontinuation of osimertinib. A
third optional biopsy may be taken during the course of treatment at the Investigator's
discretion if the patient consents and if clinically feasible. Tumour tissue and plasma
samples will be collected and examined for genetic and non genetic aberrations that may be
important in determining response and resistance to the treatment that participants will
receive as a part of their cancer care. Patients should continue on osimertinib until
progression or until other treatment discontinuation criteria are met. However, if patients
continue to show clinical benefit to treatment as judged by the Investigator, patients may
continue to receive osimertinib beyond RECIST 1.1-defined progression. Therefore, there is no
maximum duration of treatment. Tumour assessments are to be performed at baseline and then
every 8 weeks until progression. Patients will be followed up for a period of 28 days
following discontinuation of osimertinib. Target patient population Male and female patients
aged 18 years and over with locally advanced or metastatic pathologically confirmed
adenocarcinoma of the lung, not amenable to curative surgery or radiotherapy. Patients will
have a tumour that harbours one of the EGFR mutations known to be associated with EGFR
tyrosine kinase inhibitor sensitivity, either alone or in combination with other EGFR
mutations (EGFR mutation status determined by a local laboratory). Patients must be EGFR
tyrosine kinase inhibitor treatment-naïve and eligible to receive first line treatment with
osimertinib. Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR
tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer
with a significant selectivity margin over wild type EGFR. Osimertinib (80 mg orally, once
daily) will be administered. Doses may be reduced to 40 mg if needed.

Inclusion Criteria:

1. Provision of informed consent prior

2. Patients aged 18 years or older

3. Patients with histological confirmation of locally advanced or metastatic NSCLC

4. Patients with M1 stage according to the Tumor, Node and Metastasis Classification of
Malignant Tumours (TNM)

5. Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be
associated with EGFR TKI sensitivity

6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria).

7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection
of the primary tumour or metastatic tumour tissue

8. WHO performance status 0-1

9. Life expectancy ≥12 weeks

10. Capacity to swallow

11. Patients able to complete study and within geographical proximity allowing for
adequate follow up

12. Resolution of all acute toxic effects of previous anticancer therapy

13. Female patients should be using highly effective contraceptive measures, and must have
a negative pregnancy test prior to start of dosing if of childbearing potential

14. Male patients should be willing to use barrier contraception

Exclusion Criteria:

1. Locally advanced lung cancer candidate for curative treatment through radical surgery
and/or radio(chemo)therapy

2. Patients diagnosed with another lung cancer subtype

3. Patients with an EGFR exon 20 insertion

4. Patients with just one measurable or evaluable tumour lesion that has been resected or
irradiated prior to their enrolment in the study

5. Second active neoplasia

6. Treatment with an investigational drug within five half-lives of the compound

7. Participation in another clinical study with an investigational product (IP) during
the last 3 weeks before the first day of study treatment

8. Patients who have received prior immunotherapies

9. Patients who have received prior EGFR treatments for lung cancer

10. Patients who have received prior treatment with an EGFR TKI including in the adjuvant
setting

11. Patients who have received previous treatment for metastatic or stage IV disease

12. Prior treatment with cytotoxic chemotherapy for advanced NSCLC

13. Patients with a history of cancer that has been completely treated, with no evidence
of malignant disease currently cannot be enrolled in the study if their chemotherapy
was completed less than 6 months prior and/or have received a bone marrow transplant
less than 2 years before the first day of study treatment

14. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of
starting study treatment with the exception of alopecia and grade 2, prior
platinum-therapy related neuropathy

15. Any evidence of severe or uncontrolled systemic diseases

16. Patients who have had a surgical procedure unrelated to the study within 14 days or
major surgery within 1 month prior to the administration of the study drug

17. Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis

18. Any of the following cardiac criteria: Mean resting QT interval corrected for heart
rate (QTc) more than 470 msec, obtained from 3 ECGs, using the screening clinic ECG
machine derived QTc value. Any clinically important abnormalities in rhythm,
conduction or morphology of resting ECG e.g. complete left bundle branch block, third
degree heart block and second degree heart block. Any factors that increase the risk
of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia,
congenital long QT syndrome, family history of long QT syndrome or unexplained sudden
death under 40 years of age in first degree relatives or any concomitant medication
known to prolong the QT interval

19. Spinal cord compression, symptomatic and unstable brain metastases except for those
patients who have completed definitive therapy, and have had a stable neurological
status for at least 2 weeks after completion of definitive therapy. 20.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

21.Inadequate bone marrow reserve or organ function 22.Female patients who are
breastfeeding 23.Patients currently receiving medications or herbal supplements known to be
potent inducers of cytochrome P450 24.Patient unwilling to undergo a biopsy at the time of
disease progression 25.History of hypersensitivity to active or inactive excipients of
osimertinib or drugs with a similar chemical structure or class to osimertinib 26.Judgment
by the Investigator that the patient should not participate in the study if the patient is
unlikely to comply with study procedures, restrictions and requirements 27.Involvement in
the planning and/or conduct of the study 28.Previous enrolment in the present study