Ramucirumab and Atezolizumab After Progression on Any Immune Checkpoint Blocker in NSCLC

Inclusion Criteria:

- Histologically or cytologically confirmed squamous or non-squamous non-small cell lung
cancer. Patients with known EGFR or ALK mutations are eligible only if they have
received at least one line of targeted therapy for these mutations.

- Availability of archival biopsy tissue or willingness to undergo a "baseline" biopsy
prior to initiation of the trial for biomarker analysis, including PD-L1 by IHC

- Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by
chest x-ray, or ≥ 10 mm with calipers by clinical exam.

- Prior use of an immune checkpoint blocker alone or in combination therapy.

- At least 18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

- Normal bone marrow and organ function as defined below:

- Absolute neutrophil count ≥ 1,500/mcl

- Platelets ≥ 100,000/mcl

- Hemoglobin ≥ 9.0 g/dL

- Total bilirubin ≤ 1.5 x ULN

- AST(SGOT)/ALT(SGPT) ≤ 3.0 x ULN or 5.0 x ULN in the setting of liver metastasis

- Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min. if serum creatinine is >1.5
times the ULN, a 24-hour urine collection to calculate creatinine clearance must
be performed

- Adequate coagulation function as defined by:

- INR ≤ 1.5

- PTT/aPTT < 1.5 x ULN

- Note: 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).

- Urinary protein ≤ 1+ on dipstick or routine urinalysis; 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

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry and for
the duration of study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she must inform her treating physician
immediately.

- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

- Treatment with cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.

*Note: Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea or premedication for
contrast dye allergy) are eligible. The use of inhaled corticosteroids for chronic
obstructive pulmonary disease (COPD) and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.

- A history of other malignancy ≤ 3 years previous with the exception of patients with a
negligible risk of metastasis or death and with expected curative outcome (such as
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin
cancer, localized prostate cancer treated surgically with curative intent, or ductal
carcinoma in situ treated surgically with curative intent) or undergoing active
surveillance per SOC management (e.g., Rai Stage 0 chronic lymphocytic leukemia,
prostate cancer with Gleason score ≤ 6 and prostate-specific antigen (PSA ≤ 10 ng/mL,
etc.).

- Currently receiving any other investigational agents.

- Symptomatic or untreated asymptomatic brain metastases. Patients with treated brain
metastases are eligible if they are 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 may have no evidence of Grade ≥1 CNS hemorrhage based on
pretreatment MRI or IV contrast CT scan (performed within 21 days before
randomization).

- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to atezolizumab, ramucirumab, any other immune checkpoint
blockade, chimeric or humanized antibodies, fusion proteins, or other agents used in
the study.

- 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.

- Arterial or venous thromboembolic event, including but not limited to myocardial
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
within 6 months prior to enrollment.

- Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg
diastolic for > 4 weeks) despite standard medical management.

- Gastrointestinal perforation, and/or fistula, or risk factors for perforation within 6
months prior to enrollment.

- Grade 3 or 4 gastrointestinal bleeding within 3 months prior to enrollment.

- History of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis.

*Note: Patients with a history of autoimmune hypothyroidism on a stable dose of
thyroid replacement hormone are eligible. Patients with controlled type 1 diabetes
mellitus on a stable insulin regimen are eligible.

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.

- Hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2 months prior to
Cycle 1 Day 1 or with radiographic evidence of intratumor cavitation or radiologically
documented evidence of major blood vessel invasion or encasement by cancer.

- Serious or non-healing would, ulcer, or bone fracture within 28 days prior to Cycle 1
Day 1.

- Undergone major surgery within 28 days prior to Cycle 1 Day 1, or minor
surgery/subcutaneous venous access device placement within 7 days prior to Cycle 1 Day
1, or has elective or planned major surgery to be performed during the course of the
clinical trial.

- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis, cirrhosis at a level of Child-Pug B or worse, cirrhosis (any degree)
with a history of hepatic encephalopathy or clinically meaningful ascites resulting
from cirrhosis (defined as ascites from cirrhosis requiring diuretics or
paracentesis), fatty liver, and inherited liver disease.

--Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV
surface antigen (HBsAg) positive and HBV core antibody (HbcAb) positive with reflex
positive HBV DNA. Note: Patients with past or resolved hepatitis B infection (defined
as having a negative HBsAg test and a positive HBcAb test or treated HCV with negative
HCV RNA are eligible.

- Known HIV-positivity.

- Active tuberculosis.

- Administration of a live, attenuated influenza vaccine within 4 weeks before Cycle 1
Day 1 or at any time during the study.

- Severe infections within 2 weeks prior to Cycle 1 Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia.
Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1.
Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
tract infection or chronic obstructive pulmonary disease) are eligible.

- History of deep venous thrombosis, pulmonary embolism, or any other significant
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
are not considered "significant") during the 3 months prior to Cycle 1 Day 1.

- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
serum pregnancy test within 7 days of study entry.