Osimertinib for Advanced EGFR-positive NSCLC Patients

Inclusion Criteria:

• For inclusion in the study subjects should fulfil the following criteria:

1. Provision of informed consent prior to any study-specific procedure

2. Patients must be ≥ 18 years old

3. Locally advanced /metastatic NSCLC not responsive to surgery or radiotherapy

4. Validated activating EGFR sensitising mutations with or without T790Mresistance mutation at the time of recruitment for patients who have no priorEGFR TKI treatment.

5. Patients must be EGFR treatment naïve.

6. ECOG Performance status is 0-1 with no deterioration over the last 2 weeksprior to study recruitment.

7. Normal organ and bone marrow function measured within 28 days before the studyas defined below:

• Haemoglobin ≥ 9.0 g/dL and no blood transfusions in the 28 days prior toentry
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• No features suggestive of MDS/AML on peripheral blood smear
• White blood cells (WBC) > 3x109/L
• Platelet count ≥ 100 x 109/L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unlessliver metastases are present in which case it must be ≤ 5x ULN
• Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
• ECOG performance status 0-2

8. A life expectancy ≥ 12 weeks in all patients.

9. Females in childbearing age should be using adequate contraceptive measures,should not be breastfeeding and their pregnancy test prior to the start oftreatment must be negative. Evidence of non-child-bearing potential isfulfilled by one of the following criteria at screening:

• The post-menopausal period defined as age ≥50 years and amenorrheic for atleast 12 months following cessation of all exogenous hormonal treatments
• Women <50 years old they have been amenorrheic for 12 months or morefollowing cessation of exogenous hormonal treatments and with LH and FSHlevels in the post-menopausal range.
• Documentation of irreversible surgical sterilisation by hysterectomy,bilateral oophorectomy or bilateral salpingectomy but not a tubal ligation

10. Male patients should be willing to use barrier contraception

11. The patient is willing to comply with the protocol during the study includingundergoing treatment and scheduled visits and examinations including follow up.

12. At least one lesion, not previously irradiated, that can be accurately measuredat baseline as ≥ 10 mm in the longest diameter (except lymph nodes which musthave short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonanceimaging (MRI) and is considered suitable for accurate repeated measurements.

Exclusion Criteria:

• Patients should not enter the study if any of the following exclusion criteria arefulfilled:

1. Treatment with other EGFR-TKI within 8 days or within five half-lives of thecompound before study entry whichever is the longer; any cytotoxicchemotherapy, or other anticancer drugs against NSCLC within 14 days of studyentry

2. Previously treated with an immune checkpoint inhibitor

3. Patients with second primary cancer, except: adequately treated non-melanomaskin cancer, curatively treated in-situ cancer of the cervix, or other solidtumours curatively treated with no evidence of disease for ≥ 5 years

4. Radiotherapy to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks before the study entry

5. Any unresolved toxicities from prior therapy greater than Common TerminologyCriteria for Adverse Events (CTCAE) grade 1 at the time of study treatment withthe exception of alopecia grade 2 and platinum-related neuropathy.

6. Unstable spinal cord compression/brain metastases unless asymptomatic and notrequiring steroids for at least 2 weeks prior to the start of study treatment.For patients with brain metastases, gamma knife or stereotactic brain surgeryis allowed prior to study treatment.

7. Major surgery within 4 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery. Minor surgery is allowed.

8. Patients currently receiving or unable to stop use medications or herbalsupplements that are potent inhibitors of CYP3A4 (at least 1 week prior) andpotent inducers of CYP3A4 (at least 3 weeks prior). All patients must avoidconcomitant use of any medications, herbal supplements and/or foods with knowninducer/inhibitory effects on CYP3A4 unless part of protocol treatment.

9. Severe or uncontrolled systemic diseases, including uncontrolled hypertensionand active bleeding diatheses, which based on investigator's opinion makes itundesirable for the patient to participate in the trial or which wouldjeopardise compliance with the protocol, or having active infection includinghepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening forchronic conditions is not required.

10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiringsteroid treatment, or any evidence of clinically active ILD

11. Any of the following cardiac criteria:

12. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470msec

13. Any clinically important abnormalities in rhythm, conduction or morphologyof resting ECG (e.g., complete left bundle branch block, third-degreeheart block, second-degree heart block)

14. Any factors increasing the risk of QTc prolongation or arrhythmias such asheart failure, hypokalaemia, congenital long QT syndrome, family historyof long QT syndrome or unexplained sudden death under 40 years of age infirst degree relatives or any concomitant medication known to prolong theQT interval

15. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the drug or previous significant bowel resection that would precludeadequate absorption of Osimertinib

16. History of hypersensitivity to Osimertinib (or drugs with a similar chemicalstructure or class to Osimertinib) or any excipients of these agents

17. Males and females of reproductive potential who are not using an effectivemethod of contraception and females who are pregnant or breastfeeding or have apositive serum pregnancy test prior to study entry

18. Judgment by the Investigator that the patient should not participate in thestudy if the patient is unlikely to comply with study procedures, restrictionsand requirements

19. Previous allogeneic bone marrow transplant.