EGFR-mutated Lung Cancer in Randomized Investigator-Initiated Study

Inclusion Criteria:

* The subject has given written consent to participate in the study.
* Histological or cytological diagnosis of NSCLC.
* Clinical stage III/IV disease (with or without CNS metastasis) or a recurrence not amenable for curative treatment intention.
* Measurable disease according to RECIST 1.1 criteria or equivalent/modified criteria.
* Any WHO PS.
* Age ≥ 18 years, no upper age limit.
* EGFR-mutation in tumor (in cases where tumor tissue is not available for mutation analysis, circulating tumor-DNA (ctDNA) in plasma may serve as inclusion criteria), which is presumably predictive of sensitivity to EGFR TKI.
* Treatment-naive with regard to TKI's
* Negative pregnancy test (blood or urine test)
* For fertile participants, adequate contraception should be used; intrauterine device, bilateral tubal occlusion, vasectomy or abstinence (a reduced effect of hormonal contraception methods due to the drugs cannot be excluded). Pregnancy should be avoided during treatment and the first 4 months following treatment discontinuation.

Exclusion Criteria:

* Condition incompatible with the study or with the planned treatment.
* Present (not radically treated/no planned radical treatment of) other primary malignancy with metastatic potential.
* Co-enrolment in other interventional trial if incompatible with ERIS according to investigator (e.g. due to potential drug interactions).
* Intake of hypericum perforatum (intake must be interrupted before start of study treatment).
* All subjects should avoid concomitant use of medications with known interaction with planned treatment, whenever feasible. If the administration of a medication interacts with any of the three investigational treatments and cannot be exchanged or managed in order to avoid interactions the patient is excluded from the trial.

  * Drugs that can either increase or decrease the concentration of osimertinib in plasma:

    * Strong activators of CYP3A. Simultaneous administration should be avoided.
    * Regular CYP3A4-inhibitors should be used with caution or be avoided.
  * Drugs that can either increase or decrease the concentration of afatinib in plasma:

    * Strong inhibitors of P-glycoprotein should not be administered simultaneously with afatinib, instead it should preferably be 6-12 hours between.
    * Strong activators of P-glycoprotein may reduce exposure of afatinib
  * Drugs that can either increase or decrease the concentration of dacomitinib in plasma:

    * Proton pump inhibitors should be avoided.
    * Simultaneous administration of drugs that are metabolized by CYP2D6 should be avoided. If simultaneous use of that kind of medications are considered necessary, dose recommendations for simultaneous use of respective drug should be followed.
* Any evidence of severe or uncontrolled systemic diseases which in the investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
* Gastrointestinal conditions incompatible with swallowing or precluding absorption of the study drug.
* Pregnancy or refusal to use contraceptives.
* Abnormal findings of blood chemistry not compatible with the study drug according to investigator.
* History of hypersensitivity to the study drug (or drugs with a similar chemical structure or class) or any excipients.
* Severe hepatic impairment/renal function incompatible with study drug according to investigator.
* Hereditary conditions with galactose intolerance, total lactase deficiency or glucose -galactose malabsorption.
* Congenital long QT syndrome.
* Judgment by the investigator that the subject should not participate in the study, e.g., if the subject is unlikely to comply with study procedures, restrictions and requirements.