Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE)

Inclusion:

Registration:

• Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory;
• Stage IV NSCLC;
• Blood sample available for cfDNA EGFR T790M central testing;
• Age ≥18 years;
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI;
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration;
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Randomization:

• Report of adequacy sample for cfDNA EGFR T790M test by central laboratory;
• Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization;
• Patients with brain metastases are allowed provided they are 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), and have not received steroids for at least 7 days before randomization; Baseline tumor assessment scans are done within 21 days before randomization;
• Evaluable disease as defined below;
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
• WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks;
• Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and defined as follows:
• Absolute neutrophil count ≥1.5 x 109/L;
• Platelet count ≥100 x 109/L;
• Haemoglobin ≥9 g/dL;
• Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases;
• Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation);
• No significant comorbidity that according to the investigator would hamper the participation on the trial;
• Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 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 sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.
• Male patients should be willing to use barrier contraception, i.e., condoms

o Male patients will be advised to arrange for the freezing of sperm samples prior to