Pembrolizumab and Itacitinib (INCB039110) for NSCLC

Inclusion Criteria:

- 1. Stage IV non-small cell lung cancer (NSCLC)

- 2. Provide written informed consent for the trial.

- 3. Patients ≥ 18 years of age

- 4. Tumor PD-L1≥ 50% as assessed by the PD-L1 IHC 22C3 pharmDx assay (Dako North
America).

- 5. Subject must have adequate tumor burden at a safely accessible site for biopsy by
either bronchoscopy or imaging guidance. NOTE: If sites chosen for biopsy were
previously irradiated, there must be evidence of tumor growth/viable tumor as assessed
by the investigator.

- 6. At least one measurable lesion according to Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1

- 7. ECOG performance status 0 or 1

- 8. Adequate Organ Function Laboratory Values System Laboratory Value Hematological
Absolute neutrophil count (ANC) ≥1,250/mcL Platelets ≥100,000/mcL Hemoglobin ≥9 g/dL
or ≥5.6 mmol/L Renal Serum creatinine OR ≤1.5 X upper limit of normal (ULN) OR
Measured or calculated creatinine clearance (GFR can also be used ≥50 mL/min for
subject with creatinine levels in place of creatinine or CrCl) > 1.5 X institutional
ULN Creatinine clearance should be calculated per institutional standard. Hepatic
Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for
subjects with liver metastases

- 9. Subjects of reproductive potential must agree to use acceptable birth control
methods.

Exclusion Criteria:

- 1. Sensitizing mutations in Epidermal growth factor receptor (EGFR) or anaplastic
lymphoma kinase (ALK) or ROS1 proto-oncogene receptor tyrosine kinase (ROS1)
translocations

- 2. Currently participating in or has participated in a study of an investigational
agent or anticipated use of an investigational device within 4 weeks of the first dose
of study treatment.

- 3. Untreated symptomatic central nervous system (CNS) metastases and/or carcinomatous
meningitis.

- 4. Received prior systemic cytotoxic chemotherapy, biologic therapy, targeted therapy
or immunotherapy for incurable (metastatic) NSCLC.

- 5. Diagnosis of immunodeficiency or exposure to systemic corticosteroid therapy or any
other form of immunosuppressive therapy within 7 days prior to enrollment. (Nasal or
oral inhalers are permissible). Patients on physiologic replacement doses of steroids
(mineralocorticoid or less than or equal to a prednisone 10 mg daily dose) will also
be permitted to enroll.

- 6. Prior monoclonal antibody within 4 weeks prior to enrollment, or individuals who
have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.

- 7. Known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, non-invasive bladder tumors, or in situ cervical cancer

- 8. Active autoimmune disease requiring systemic treatment within the past 3 months
prior to enrollment. Subjects that require intermittent use of steroid-containing
bronchodilators or local steroid injections or topical steroid medications are not
excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjogren's syndrome are not excluded from the study.

- 9. Interstitial lung disease or history of pneumonitis that has required oral or IV
steroids

- 10. Active infection requiring systemic therapy with IV antibiotics

- 11. History or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- 12. Known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- 13. Pregnant or breastfeeding women

- 14. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).

- 15. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- 16. Known active Hepatitis B (e.g., HBsAg positive or HBV DNA detectable) or Hepatitis
C (e.g., HCV RNA [qualitative] is detected).

- 17. Anticipated receipt of any live vaccine within 30 days prior to the first dose of
trial treatment.

Note: For the purposes of determining eligibility above, enrollment is defined as the date
of subject consent.