Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy).

Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs.

Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

Inclusion criteria:

• Aged 18 years or older
• Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung
• Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X)
• Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. Only applicable in Part B
• Must have adequate fresh or archival tumour tissue at the late disease progression immediately prior to the study entry
• Part A: Progression of disease (RECIST 1.1) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v1.1) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v1.1) while on continuous treatment with single agent of the second generation irreversible EGFR TKI (e.g. afatinib or dacomitinib)
• No intervening systemic therapy between cessation of EGFR TKI and study treatment
• Patient must have measurable disease per RECIST 1.1 presented after tumour biopsy for the late disease progression
• Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
• Life expectancy of >= 3 months
• Fasting plasma glucose < 8.9 mmol/L (< 160mg/dL) and HbA1C < 8%
• Adequate organ function
• Recovered from any previous therapy related toxicity to <= Grade 1 at study entry (except for stable sensory neuropathy <= Grade 2 and alopecia)
• Written informed consent that is consistent with ICH-GCP guidelines and local regulations
• No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation

Exclusion criteria:

• Part A only: For patient who has been treated with afatinib: last treatment at reduced dose below the assigned dose level
• Patient whose disease progressed on insufficient dose of EGFR TKI immediately prior to study in the opinion of the investigator
• More than 2 prior EGFR TKI treatment regimens for Part B
• Chemotherapy, biological therapy or investigational agents (except EGFR TKIs) within 4 weeks
• Use of previous EGFR TKIs except afatinib within 3 days
• Radiotherapy within 4 weeks prior to the start of study treatment
• Active brain or subdural metastases
• Meningeal carcinomatosis.
• Major surgery (as judged by the investigator) within 4 weeks
• Known hypersensitivity to afatinib, monoclonal antibody
• Prior severe infusion-related reaction to a monoclonal antibody
• History or presence of clinically relevant cardiovascular abnormalities
• Female patients of childbearing potential (see Section 4.2.2.3) and male who are able to father a child
• Any history of or concomitant condition that, in the opinion of the investigator not to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug
• Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
• Disease that is considered by the investigator to be rapidly progressing or life threatening such as extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumour (subjects who are intended for urgent chemotherapy)
• Requiring treatment with any of the prohibited concomitant medications
• Known pre-existing interstitial lung disease (ILD)
• Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug
• Active hepatitis B infection active hepatitis C infection and/or known HIV carrier.
• Previous treatment with agents targeting the insulin like growth factor (IGF) signalling pathway.
• Previous treatment with EGFR TKI which cannot be documented as either reversible or irreversible (Part B only)
• Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. AZD9291 or CO-1686)

Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.

For study documents - upon signing of a 'Document Sharing Agreement'.

For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.