Inclusion Criteria:
- Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer
- Patients must either have tumors that harbor an EGFR mutation in exon 19 or exon 21,
or must be never smoker wild-types. Never smoker wild-types are defined as patients
with tumors without an ALK or ROS1 rearrangement, and are not harboring any EGFR
mutation (this includes exons 19 or 21, exon 20, and any other rare EGFR mutations).
Never smoker wild-type patients must have smoked less than 100 cigarettes in a
lifetime. Patients with an EGFR mutation in exon 19 or 21 may be included irrespective
of their smoking history. If tissue-based testing for EGFR mutation status is not
available, blood-based EGFR testing that confirms presence of a mutation in exon 19 or
21 is acceptable, and these patients may be included in the study
- Patients must have measurable disease by CT or MRI, defined as at least one lesion
that can be accurately measured in at least one dimension in accordance with RECIST
criteria v 1.1
- Patients with tumors that harbor an EGFR exon 19 or exon 21 mutation must have
received prior treatments with one or more TKIs. A washout period of at least 2 weeks
is required to begin treatment in this trial. Patients who are never smoker wild-types
must be treatment naïve
- All patients must be chemotherapy, VEGF therapy, and immunotherapy naive, with the
exception of prior oral TKIs which are required for EGFR mutated patients. The number
of prior oral TKIs and duration of use is neither specified nor limited.
- Patients with a history of treated asymptomatic CNS metastases are eligible, provided
they meet all of the following criteria:
- Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
midbrain, pons, medulla or spinal cord)
- No ongoing requirement for corticosteroids as therapy for CNS disease
- No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to randomization
- No evidence of interim progression between the completion of CNS-directed therapy
and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan must receive
radiation therapy and/or surgery for CNS metastases. Following treatment, these patients
may then be eligible without the need for an additional brain scan prior to randomization,
if all other criteria are met
- Age > 18 years
- ECOG performance status 0 or 1
- Patients must have normal organ and marrow function as defined below. The use of G-CSF
should follow standard recommendations and physician discretion. If blood transfusion
is performed for achieving hemoglobin levels, the levels should stay at ≥ 9.0 mg/ml
for at least a week after transfusion.
Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL Total
bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) < 3 times
institutional normal limits, or up to 5 times institutional normal limits if the patient
has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR > 40 Ml/min/1.73 m2
for patients with creatinine levels above institutional normal as per Cockcroft-Gault
formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) <1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants Thyroid stimulating hormone (TSH)
Within normal limits a
a: If TSH is not within normal limits at baseline, the subject will still be eligible if
total T3 or free T4 are within normal limits.
- 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
clinically significant active bleeding (with 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).
- Ability to understand and willingness to sign a written informed consent and HIPAA
consent document.
- A core biopsy must be available for the study. The biopsy sample must be adequate for
analyses. If the sample is not adequate, the patient must agree to provide a fresh
biopsy specimen before the start of treatment. Any available archival tissue will also
be collected.
- Urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; 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 the protocol).
- Female subjects of child-bearing potential must be willing to use an effective method
of contraception, for the course of the study through at least 6 months after the last
dose of study medication.
- Male patients who have WOCBP partners must agree to use effective method of
contraception for the course of the study through 8 months after the last dose of
study medication.
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Exclusion Criteria:
- Patients currently receiving any other investigational agents, immunomodulatory
agents, chemotherapy, or TKIs. EGFR mutation-positive patients must have received
prior TKI treatment
- The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first
dose of protocol therapy.
- The patient has a 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 the first dose of protocol therapy.
- Subjects with untreated CNS metastases are excluded, even if they are asymptomatic.
Patients with treated brain metastases will be allowed if brain imaging obtained
within 28 days of trial enrollment reveals stable disease.
- Cirrhosis at a level of Child-Pugh B or worse, or cirrhosis of any degree and a
history of hepatic encephalopathy, or clinically meaningful ascites resulting from
cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis
requiring diuretics or paracentesis.
- The patient has experienced 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.
- The patient has uncontrolled or poorly-controlled hypertension (>150 mmHg systolic or
> 100 mmHg diastolic for >4 weeks) despite standard medical management
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to randomization
- Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
anticoagulation)
- History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
6 months prior to randomization
- Clinical signs of gastrointestinal obstruction or requirement for routine parenteral
hydration, parenteral nutrition, or tube feeding
- Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure
- Serious, non-healing wound, active ulcer, or untreated bone fracture within 28 days
prior to first dose of protocol therapy
- Subjects with a history of smoking greater than a 100 cigarettes in a lifetime, unless
their tumor has an EGFR exon 19 or exon 21 mutation.
- Patients with active, suspected, or known autoimmune disease that has required
systemic treatment in the past one year (i.e., with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Hormone 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.
- Patients with a history of hemoptysis (defined as bright red blood or ≥1/2 teaspoons)
within 1 month prior to first dose of protocol therapy or with radiographic evidence
of major blood vessel invasion or encasement by cancer.
- The patient has undergone major surgery within 28 days prior to first dose of study
treatment, or minor surgery/ subcutaneous venous access device placement within 7 days
prior to first dose of protocol therapy. The patient has elective or planned major
surgery to be performed during the course of the clinical trial.
- The patient is receiving chronic anti-platelet therapy other than aspirin, including
non-steroidal 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. Occasional use of NSAIDs is allowed (for
example daily use for less than a week; treating physician discretion is permitted to
differentiate between occasional vs chronic use)
- Patients who have not recovered from adverse events due to agents administered earlier
except neuropathy and alopecia. Physician's discretion is allowed to decide which
unresolved adverse events from previous therapy (for NSCLC) prohibit patient
participation in this study.
- Patients requiring more than 10 mg prednisolone (or its equivalent) per day are
excluded.
- Patients with any evidence of interstitial lung disease (ILD) or pneumonitis or a
prior history of ILD or pneumonitis requiring oral or IV glucocorticoids. History of
radiation pneumonitis in the radiation field (fibrosis) is permitted
- Patients with active tuberculosis infection are excluded.
- Patients who have received a live vaccine within 30 days prior to cycle 1 Day 1.
- Uncontrolled illness including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
(significant), cirrhosis, or psychiatric illness/ social situations that would limit
compliance with the study requirements.
- Known history of testing positive for immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS).
- Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
indicating chronic infection that is not cured.
- Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
cancers, such as, bladder, gastric, colon, cervical/ dysplasia, melanoma, or breast)
are excluded unless a complete remission was achieved at least 2 years prior to study
registration and no additional therapy is required or anticipated to be required
during the study period.
- Leptomeningeal disease
- Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic
lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing
nerve impingement) should be treated prior to randomization. Patients should be recovered
from the effects of radiation. There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits
or intractable pain (e.g., epidural metastasis that is not currently associated with spinal
cord compression) should be considered for locoregional therapy, if appropriate, prior to
randomization.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
Patients with indwelling catheters (e.g., PleurX®) are allowed.
- Ca > 12 mg/dl or corrected serum calcium > ULN
Patients who are receiving denosumab prior to randomization must be willing and eligible to
receive a bisphosphonate instead while in the study
- Pregnant or breast feeding
- Prior allogeneic bone marrow transplantation or solid organ transplant
- Known hypersensitivity to Chinese hamster ovary cell products or any of the study
drugs.
- Clear tumor infiltration into the thoracic great vessels is seen on imaging
- Clear cavitation of pulmonary lesions is seen on imaging
- Subjects with squamous cell carcinoma of the lung.
- Subjects with a lung tumor with a known ALK or ROS1 rearrangement or an EGFR mutation
other than in exon 19 or exon 21.
