Inclusion Criteria:

1. Age > 18 years.
2. Signed informed consent prior to the performance of any study-specific procedures, including fresh tumor biopsies.
3. Histologically or cytologically proven advanced (stage IIIB/IV) NSCLC subjects who are immunotherapy naïve.
4. Escalation Phase: Subjects may be enrolled with ≤ 2 lines of prior systemic anti-cancer therapy (but no immunotherapy). Subjects who have had no prior systemic anti-cancer therapy (i.e. first-line therapy) or declined first-line treatment are permitted in the Escalation Phase.
5. Expansion Phase: Initially, only immunotherapy naïve subjects who have progressed on first-line cytotoxic chemotherapy or who have declined first-line treatment with cytotoxic chemotherapy will be enrolled. Subjects with no prior systemic anti cancer therapy (i.e. first line therapy) may be enrolled in a second cohort if approved by the SMC. Subjects previously treated with systemic adjuvant therapy, other than immunotherapy for recurrent advanced NSCLC, are also eligible.
6. Measureable disease as defined by the RECIST 1.1.
7. Availability of archival or fresh tumor specimen that is suitable for analysis. Acceptable samples must have been acquired using core needle biopsy or excisional biopsy. Samples that were acquired using fine needle aspiration are not acceptable.
8. Tumor lesion accessible for biopsy after the start of treatment. (Note: this lesion should be separate from measurable lesions that will be used for response assessment.)
9. ECOG performance status (PS) score 0-1.
10. Tumors lack activating epidermal growth factor receptor (EGFR) mutations or ALK rearrangement (no EGFR or ALK testing is required if a subject has a KRAS mutation or squamous cell histology).

11. Has adequate bone marrow, renal and hepatic function based upon laboratory tests as follows:

    • Absolute neutrophil count > 1500/µL
    • Platelet count > 100 x 103/µL
    • Hemoglobin > 9 g/dL, transfusion permitted
    • Total bilirubin < 1.5 x upper limit of normal (ULN) (or < 3 x ULN for subjects with Gilbert's syndrome)
    • Creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate calculation
    • AST < 2.5 x ULN (5.0 x ULN in the presence of liver metastasis)
    • ALT < 2.5 x ULN (5.0 x ULN in the presence of liver metastasis).
12. Highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) for both male and female subjects if the risk of conception exists (Note: The effects of the trial treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception, defined in Protocol Appendix 9.3, or as stipulated in national or local guidelines. Highly effective contraception must be used for the duration of trial treatment, and at least for 60 days after stopping trial treatment or 6 months after stopping chemotherapy [or per label]. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately).
13. Resolution of toxicity from prior anti-cancer therapy, to NCI CTCAE v4.03 Grade 0 or 1, except for alopecia. Subjects may be enrolled if their toxicity is determined to be irreversible and will not put them at undue risk from study treatment, based on the Investigator's assessment.

Exclusion Criteria:

1. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints), such as PD-1, PD-L1, or cytotoxic T lymphocyte antigen-4.
2. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on Investigator's judgment are acceptable.
3. Concurrent anticancer treatment within 28 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy]; immune therapy, or cytokine therapy, except for erythropoietin.
4. Major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); or use of any investigational drug within 28 days before the start of trial treatment.
5. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before initiation of the trial treatment (with the exception of subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily). Note: Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be ≤10 mg per day of prednisone or equivalent.
6. Previous malignant disease other than the target malignancy to be investigated in this trial within the last 5 years (with the exception of adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and the subject was deemed to have been cured with no additional therapy required or anticipated to be required.
7. Rapidly progressive disease.
8. ECOG performance status score ≥ 2.
9. Women who are pregnant or breastfeeding.
10. History of pneumonitis or other interstitial lung disease
11. Active or history of any autoimmune disease including colitis and inflammatory bowel disease (subjects with diabetes Type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
12. Vaccination within 4 weeks of the first dose of avelumab and while on study is prohibited except for administration of inactivated vaccines (e.g. inactivated influenza vaccines).
13. Significant acute or chronic infection including, among others: Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA).
14. CNS malignancy, the known presence of untreated or symptomatic CNS metastases. Subjects with treated brain metastasis must be stable and off steroids and anti-convulsants for at least 1 month prior to the start of study treatment. Subjects with suspected brain metastases at Screening should have a CT/MRI of the brain prior to study entry.
15. A history of hypersensitivity to other humanized monoclonal antibodies.
16. Significant cardiovascular disease (New York Heart Association Class II or greater), myocardial infarction within the 6 months prior to study entry, unstable angina, or cerebral vascular accident / stroke (< 6 months prior to enrollment), or serious uncontrolled cardiac arrhythmia requiring medication / active intervention, corrected QT interval [QTc] prolongation of > 470ms and/or prior diagnosis of congenital long QT syndrome.
17. Legal incapacity or limited legal capacity.
18. Current alcohol or drug abuse.
19. Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
20. Prior organ transplantation or allogeneic bone marrow transplantation.
21. Any uncontrolled medical condition (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment or confound interpretation of study assessments.
22. Inability to comply with visit schedule or other protocol requirements