This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy in KRASm NSCLC.

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)