Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Non-small Cell Lung Cancer

Inclusion Criteria:

* Histological or cytological proof of advanced NSCLC; for PART B: treated with first line therapy for metastatic disease only.
* Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20)
* Able and willing to give written informed consent
* Able and willing to undergo blood sampling for PK and PD analysis
* Life expectancy \>=3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
* WHO performance status of 0 or 1.
* Able and willing to undergo a tumor biopsies prior to start, after two weeks (part A only) and upon progression of disease
* Measurable disease according to RECIST 1.1
* Adequate organ system function measured by laboratory values

Exclusion Criteria:

* Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
* History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 3. Symptomatic or untreated leptomeningeal disease.
* Symptomatic brain metastasis.
* Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
* History of interstitial lung disease or pneumonitis
* Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
* Opthalmological diseases
* Patients with left ventricular ejection fraction (LVEF) \< 55%
* Patients with cardiac comorbidities
* Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)