Best EGFR-TKI Sequence in NSCLC Harboring EGFR Mutations

Inclusion Criteria:

1. Written informed consent;
2. Male or female patient aged ≥18 years;
3. Histologically/cytologically confirmed diagnosis of stage IIIB/IV NSCLC with evidenceof activating EGFR mutations including exon 19 deletion, exon 21 L858R or otheractivating/sensitizing EGFR mutations such as exon 21 L861Q, exon 18 G719S, G719A,G719C, exon 20 S768I and V769L; co-occurrence of de novo T790M is not an exclusioncriterion; EGFR status assessed in circulating DNA is allowed;
4. Patients eligible and candidate to receive osimertinib as first- or second-linetreatment according to clinical practice and study design, as decided by Investigatorregardless study participation;
5. Patients with brain metastases are allowed provided they are asymptomatic and stable (i.e. without evidence of progression by imaging for at least two weeks prior to thefirst dose of trial treatment and without deterioration of any neurologic symptoms);
6. No evidence of concomitant drivers including KRAS mutations, HER2 mutations, ALK orROS1 rearrangements, MET mutations, BRAF mutations;
7. No previous EGFR-TKI therapy; Previous palliative radiotherapy or surgery allowed.Prior brain radiotherapy and Stereotactic Radiosurgery (SRS) are allowed. Previousneo/adjuvant chemotherapy is allowed as long as therapy was completed at least 6months before diagnosis of advanced or metastatic NSCLC;
8. At least one radiological measurable disease according to RECIST criteria version 1.1;
9. Performance status 0-1 (ECOG PS);
10. Patient compliance to trial procedures;
11. Adequate bone marrow function (ANC ≥ 1.5x109/L, platelets ≥100x109/L, haemoglobin >9g/dl);
12. Adequate liver function (AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit ofnormal unless liver metastases are present, in which case it must be ≤5x ULN,bilirubin < grade 2, transaminases no more than 3xULN/<5xULN in presence of livermetastases);
13. Normal level of alkaline phosphatase, and creatinine;
14. Female patients should be using adequate contraceptive measures, should not bebreastfeeding, until 12 months after the last dose, and must have a negative pregnancytest (serum or urine) prior to first dose of study drug (within 72 hours); or femalepatients must have an evidence of non-childbearing potential by fulfilling one of thefollowing criteria at screening:

• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be consider postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution. Documentation ofirreversible surgical by hysterectomy, bilateraloophorectomy, or bilateralsalpingectomy but not tubal ligation.

15. Male patients should be willing to use barrier contraception, i.e. condoms;
16. No significant comorbidity that according to the investigator would hamper theparticipation on the trial;

Exclusion Criteria:

1. Previous therapy with any EGFR-TKI;
2. Previous systemic anti-cancer therapy for advanced/metastatic NSCLC includingchemotherapy, biologic therapy, immunotherapy, or any investigational drug;
3. Absence of measurable lesions;
4. Concomitant radiotherapy or chemotherapy;
5. Symptomatic or immediately requiring therapy brain metastases or carcinomatousmeningitis. Subjects with asymptomatic and stable or treated brain metastases mayparticipate;
6. Diagnosis of any other malignancy during the last 3 years, except for in situcarcinoma of cervix uteri and squamous cell carcinoma of the skin;
7. History of extensive disseminated/bilateral or known presence of Grade 3 or 4interstitial fibrosis or interstitial lung disease including a history of pneumonitis,hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,obliterative bronchiolitis and pulmonary fibrosis (but not history of prior radiationpneumonitis);
8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses; or active infection including hepatitis B,hepatitis C and human immunodeficiency virus (HIV);
9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption of the study drugs;
10. Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs usinglocal clinic ECG machine-derived QTcF value;
• Any clinically important abnormalities in rhythm, conduction, or morphology ofresting ECG, e.g., complete left bundle branch block, third-degree heart block,second-degree heart block, PR interval >250 msec or history of episodes ofbradycardia (<50 BPM);
• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalaemia, congenital long QT syndrome familyhistory of long QT syndrome, or unexplained sudden death under 40 years of age infirst-degree relatives or any concomitant medication known to prolong the QTinterval;
• Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO)

11. Pregnancy or lactating female;
12. Other serious illness or medical condition potentially interfering with the study.