Inclusion Criteria:
- 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
- Prior systemic anticancer therapy: neo/adjuvant therapy or prior therapy for locally
advanced disease will be permitted if interval between last therapy and recurrent
disease is at least 6 months. Patients with prior exposure to PD/PD-L1 inhibitors will
be excluded. Limit of 2 prior EGFR tyrosine kinase inhibitors (TKIs) (erlotinib,
gefitinib, afatinib, dacomitinib or osimertinib). Patients who develop progressive
disease after erlotinib, gefitinib, afatinib, or dacomitinib must either receive
osimertintib (T790M positive) or be T790M negative. Prior chemotherapy for metastatic
disease is permitted only if TKI was the most recent therapy received
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Evaluation of
ECOG is to be performed within 7 days prior to the date of allocation/randomization
- Absolute neutrophil count (ANC) >= 1500/uL (within 10 days prior to the start of study
treatment)
- Platelets >= 100 000/uL (within 10 days prior to the start of study treatment)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 10 days prior to the start of study
treatment)
- Criteria must be met without erythropoietin dependency and without packed red
blood cell (pRBC) transfusion within last 2 weeks
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
clearance >= 40 mL/min for participant with creatinine levels > 1.5 x institutional
ULN (within 10 days prior to the start of study treatment)
- Creatinine clearance (CrCl) should be calculated per institutional standard
- Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl
- Urine protein =< 1+ on dipstick or routine urinalysis (UA) (within 10 days prior to
the start of study treatment)
- If urine dipstick or routine analysis is >= 2+, a 24-hour urine collection for
protein must demonstrate < 1000 mg of protein in 24 hours to allow participation
in this protocol
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 x ULN (within 10 days prior to the start of study treatment)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
ULN (=< 5 x ULN for participants with liver metastases) (within 10 days prior to the
start of study treatment)
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
participant is receiving anticoagulant therapy as long as PT or activated partial
thromboplastin time (aPTT) is within therapeutic range of intended use of
anticoagulants (within 10 days prior to the start of study treatment)
- Patients on full-dose anticoagulation must be on a stable dose (minimum duration
14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If
receiving warfarin, the patient must have an INR =< 3.0. For heparin and LMWH
there should be no active bleeding (that is, no bleeding within 14 days prior to
first dose of protocol therapy) or pathological condition present that carries a
high risk of bleeding (for example, tumor involving major vessels or known
varices)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants (within 10 days prior to the start of study treatment)
- Patients on full-dose anticoagulation must be on a stable dose (minimum duration
14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If
receiving warfarin, the patient must have an INR =< 3.0. For heparin and LMWH
there should be no active bleeding (that is, no bleeding within 14 days prior to
first dose of protocol therapy) or pathological condition present that carries a
high risk of bleeding (for example, tumor involving major vessels or known
varices)
- Because the teratogenicity of ramucirumab is not known, patients who are sexually
active, must be either postmenopausal, surgically sterile, or using effective
contraception (hormonal or barrier methods)
- A male participant must agree to use a contraception during the treatment period
and for at least 3 months after the last dose of study treatment and refrain from
donating sperm during this period
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 3 months after the last dose of study treatment
- For female patients of childbearing potential, a negative serum pregnancy test within
72 hours prior to first dose of protocol therapy is required
Exclusion Criteria:
- 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
- Known active chronic infections ? human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (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 hepatitis C virus [HCV] ribonucleic acid [RNA]
[qualitative] is detected) infection
- Note: no testing for hepatitis B and hepatitis C is required unless mandated by
local health authority
- Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy
or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful
ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
- Prior exposure to ramucirumab
- 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 (e.g.,
CTLA-4, OX-40, CD137)
- Any grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to first dose of
protocol therapy
- 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
- Patients receiving chronic antiplatelet therapy, including aspirin, nonsteroidal
anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
325 mg/day) is permitted
- Untreated central nervous system (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
randomization, or after surgical resection performed at least 28 days prior to
randomization. The patient must have no evidence of grade >= 1 CNS hemorrhage based on
pretreatment magnetic resonance imaging (MRI) or IV contrast computed tomography (CT)
scan (performed within 21 days before randomization)
- 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
- Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg
diastolic for > 4 weeks) despite standard medical management
- 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
- 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
- Serious or non-healing wound, ulcer, or bone fracture within 28 days of study
treatment
- Prior history of GI perforation/fistula (within 6 months of first dose of protocol
therapy) or risk factors for perforation
- Small cell or mixed (small cell/non-small cell) lung cancer
- Pregnancy or breastfeeding
- 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-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
- History of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- 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
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial
- Severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
- Active infection requiring systemic therapy
- Known history of active TB (Bacillus tuberculosis)
