The aim of the COMBINATION trial is to prospectively study the sequential approach of using afatinib combined with a short course of chemotherapy, followed by osimertinib, upon progression and acquisition of a T790M mutation, also combined with a short course of chemotherapy.

The investigators hypothesized that treating advanced stage EGFR mutation positive NSCLC in first line with afatinib and osimertinib in second line (in T790M positive tumors) will cause an apoptotic cell death in a large part of TKI-sensitive cancer cells, resulting in a large reduction of the tumor bulk. Adding cytotoxic chemotherapy after 6 weeks of EGFR-TKI will destroy remaining TKI-resistant subclones at an early stage, when the TKI-resistance tumor volume is the smallest and most vulnerable. The investigators will administer only 2 cycles of chemotherapy to limit toxicity, while maintaining a substantial anti-cancer effect. After progression on afatinib-chemotherapy combination, some participants will develop T790M and will be able treated by osimertinib-chemotherapy combination.

So, this strategy will allow the investigators to timely sequence the most appropriate drugs (afatinib and osimertinib with chemotherapy) to get the highest anti-cancer efficiency. In this way, the investigators will avoid long periods of maintenance treatments with chemotherapy or anti-VEGFR treatments that are associated with toxicity, costs, and necessitate the participants to come into the ward for intravenous medication. The limited cycles of chemotherapy also allows the treating physician to again treat the participant with the same chemotherapy regimen once progression occurs after all sensible targeted therapy options have been used.

Therefore, the investigators hypothesize that this sequential combination strategy will be more effective than other available strategies and will improve the quality of patient care as compared to current general practice.

Inclusion Criteria:

1. Histologically confirmed NSCLC, positive for non-exon20insertion uncommon EGFR mutations that are eligible for afatinib therapy in first line
2. WHO PS 0-2
3. Be willing and able to provide written informed consent for the trial.
4. Be above 18 years of age on day of signing informed consent.
5. Patients must have radiological measurable disease
6. Demonstrate adequate organ function, as deemed acceptable by the treating physician in the context of metastatic NSCLC.

Exclusion Criteria:

1. Inability to provide informed consent
2. Inability to take study medications
3. Patients with symptomatic or unstable CNS metastases
4. Prior EGFR TKI or platinum-doublet therapy for advanced stage NSCLC. Prior (neo)adjuvant treatments are allowed when the last administration is one year or more.
5. Evidence of interstitial lung disease or active, non-infectious pneumonitis.
6. Active infection requiring systemic therapy.
7. Active Hepatitis B or C.
8. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
9. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit.