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. Note: Results of PD-L1 testing are not required for enrollment.
• 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/cumm
• Platelets ≥ 100,000/cumm
• 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 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