This phase II trial studies how well ramucirumab and pembrolizumab work in treating EGFR mutant non-small cell lung cancer that has come back (recurrent) or spread to other places in the body (metastatic) while on systemic therapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab, a drug which has anti-angiogenic and pleotropic immunomodulatory effects and may synergize with the effect of an anti-PD-1 agent. The study investigates the effect of targeted anti-antitumor activity of immune checkpoint inhibitor pembrolizumab and immune-suppressive activity of VEGF-inhibitor ramicirumab to evaluate the efficacy and the tolerability of the combination.

PRIMARY OBJECTIVE:

I. To evaluate response rate of the combination of ramucirumab and pembrolizumab in EGFR mutant non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVE:

I. To evaluate safety, tolerability, and survival for patients receiving pembrolizumab and ramucirumab.

EXPLORATORY OBJECTIVE:

I. To characterize predictive immunologic biomarkers of response in tissue and peripheral blood of patients receiving ramucirumab and pembrolizumab combination therapy.

OUTLINE:

Patients receive ramucirumab intravenously (IV) over 60 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then every 6 months for 1 year.

Inclusion Criteria:

1. Adult patients aged ≥18 years
2. Histologically confirmed recurrent or metastatic non-small cell carcinoma of the lung with sensitizing EGFR mutations. Exon 20 resistance mutations will not be permitted but uncommon sensitizing mutations are allowed.
3. Prior Systemic Anticancer Therapy: Neo/adjuvant therapy or prior therapy for locally advanced disease will be permitted. Patients with prior exposure to PD/PD-L1 inhibitors will be excluded. No limit on prior EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib or osimertinib). Prior chemotherapy for metastatic disease is permitted only. A 7 day washout period or four half-lives after the last treatment dose, whichever is longer, is required for TKI. A 4 week washout is required for cytotoxic chemotherapy.
4. Measurable disease per RECIST criteria
5. ECOG performance status of 0-1
6. Adequate organ function, hematologic, hepatic, renal and coagulation parameters as defined in the protocol.
7. Because the teratogenicity of ramucirumab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).
8. Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to first dose of protocol therapy.

Exclusion Criteria

1. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
2. Known active chronic infections - HIV/AIDS, known active Hepatitis B or C. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
3. Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis.
4. Prior exposure to ramucirumab.
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
6. Any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
7. History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
8. Patients receiving dipyridamole, clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.
9. Uncontrolled CNS metastases. Patients with treated brain metastases are eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to first dose of study treatment, or after surgical resection performed at least 28 days prior to first dose of study treatment. The patient must have no evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed within 28 days before first dose of study treatment). Note: Patients who received systemic therapy that adequately and appropriately treated CNS metastases, including tyrosine kinase inhibitors, are eligible provided that CNS disease control is confirmed by pretreatment MRI within 28 days of receiving first dose of study treatment.
10. Hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
11. Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
12. Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
13. Major surgery within 28 days or device placement within 7 days prior to the first dose of protocol therapy. Patient has elective or planned major surgery to be performed during the course of the clinical trial.
14. Serious or non-healing wound, ulcer, or bone fracture within 28 days of study treatment.
15. Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
16. Small cell or mixed (small cell/non-small cell) lung cancer
17. Pregnancy or breastfeeding.
18. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
19. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
20. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
21. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
23. Active infection requiring systemic therapy.
24. Known history of active TB (Bacillus Tuberculosis).