A randomized, non-comparative, phase II study investigating the best epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sequence in advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR mutations

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• Previous therapy with any EGFR-TKI; 2) Previous systemic anti-cancer therapy for advanced/metastatic NSCLC including chemotherapy, 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 carcinomatous meningitis. Subjects with asymptomatic and stable or treated brain metastases may participate; 6) Diagnosis of any other malignancy during the last 3 years, except for in situ carcinoma of cervix uteri and squamous cell carcinoma of the skin; 7) History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial 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 radiation pneumonitis); 8) Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or active infection; 9) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude 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 using local clinic ECG machine-derived QTcF value; • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, seconddegree heart block, PR interval >250 msec or history of episodes of bradycardia (<50 BPM); • 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; • 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. E.4.EN - Principal exclusion criteria (up to 4000 characters) (Criteri di esclusione principali, in inglese)

• Written informed consent; 2) Male or female patient aged =18 years; 3) Histologically/cytologically confirmed diagnosis of stage IIIB/IV NSCLC with evidence of activating EGFR mutations including exon 19 deletion, exon 21 L858R or other activating/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 exclusion criterion; EGFR status assessed in circulating DNA is allowed; 4) Patients eligible and candidate to receive osimertinib as first- or second-line treatment according to clinical practice and study design, as decided by Investigator regardless 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 the first dose of trial treatment and without deterioration of any neurologic symptoms); 6) No evidence of concomitant drivers including KRAS mutations, HER2 mutations, ALK or ROS1 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. Previous neo/adjuvant chemotherapy is allowed as long as therapy was completed at least 6 months 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 >9 g/dl); 12) Adequate liver function (AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal 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 liver metastases); 13) Normal level of alkaline phosphatase, and creatinine; 14) Female patients should be using adequate contraceptive measures and should not be breastfeeding, until 4 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following 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 been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution. • Documentation of irreversible surgical by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy 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 the participation on the trial;