This is an open-label phase I/II multi-center study consisting of two parts. Part A of this study is designed to identify the recommended phase 2 dose (RP2D) of lapatinib combined with trametinib in patients with metastatic KRASm and PIK3CA wild-type (PIK3CAwt) non-small cell lung cancer (NSCLC). Part B is designed to perform a randomized comparison of the lapatinib-trametinib combination versus standard of care therapy in patients with metastatic KRASm/PIK3CAwt NSCLC.

Inclusion Criteria:

• Histological or cytological proof of metastatic 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 wild-type (exon 9 and 20)
• Age ≥ 18 years
• Able and willing to give written informed consent
• WHO performance status of 0 or 1 (part A and B)

Exclusion Criteria:

• Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
• History of another primary malignancy
• Symptomatic or untreated leptomeningeal disease
• Symptomatic brain metastasis
• History of interstitial lung disease or pneumonitis
• Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients
• Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), or a history of uveitis, retinal vein occlusion, central serous retinopathy, or retinal detachment
• Patients with left ventricular ejection fraction (LVEF) < 50%