Carboplatin Plus Pemetrexed Plus Atezolizumab Plus Bevacizumab in Chemotherapy and Immunotherapy-naïve Patients With Stage IV Non-squamous Non-small Cell Lung Cancer

The hypothesis of this study is that the addition of Atezolizumab (an anti-PD-L1 antibody),
to the combination of Carboplatin plus Pemetrexed plus Bevacizumab, a vascular endothelial
growth factor (VEGF) inhibitor, for the treatment of patients with stage IV non-squamous,
non-small cell lung cancer (NSCLC) will improve progression free survival (PFS) compared with
a historical control of carboplatin plus pemetrexed plus bevacizumab.

Inclusion Criteria:

- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.

- Age ≥ 18 years at the time of consent.

- ECOG Performance Status of 0-1 within 28 days prior to registration.

- Must have life expectancy of > 3 months at time of consent

- Histological or cytological confirmation of non-squamous NSCLC.

- Must have known PD-L1 status using the Dako 22C3 antibody (+ vs. -) OR must have at
least 5 unstained slides to perform prospective PD-L1 testing. PD-L1 positive is
defined as a tumor proportion score (TPS) ≥ 1%. PD-L1 negative is defined as a TPS
<1%.

- Patients with known targetable mutations in EGFR or BRAF or known translocations in
ALK or ROS1 are eligible if they have received FDA approved targeted therapy first.

- Stage IV disease or recurrent disease

- Measurable disease according to RECIST v1.1 criteria within 28 days prior to
registration with either PET/CT scan, CT scan of chest and abdomen, or CT chest
including upper abdomen and adrenal glands which define stage IV disease.

- Patients who had disease progression greater than 1 year after completing prior
adjuvant therapy for stage I - III are eligible as long as no systemic therapy was
given for recurrence.

- No prior immunotherapy or antiangiogenic therapy.

- Prior platinum therapy or pemetrexed are permissible if previously given in the
adjuvant setting for stage I-III disease and disease recurrence is > 1 year from
completion of therapy.

- If subject received major surgery or radiation therapy of > 30 Gy, they must have
recovered from the toxicity and/or complications from the intervention.

- Demonstrate adequate organ function as defined below, with all screening labs to be
obtained within 28 days prior to registration

- Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 100 K/mm3

- Calculated Creatinine Clearance ≤1.5 X upper limit of normal (ULN) OR ≥ 45 cc/min
using the Cockcroft-Gault formula

- Bilirubin ≤ 1.5 × upper limit of normal (ULN)

- Aspartate aminotransferase (AST) ≤ 1.5 × ULN or < 5x ULN if the transferase
elevation was due to liver metastases

- Alanine aminotransferase (ALT) ≤ 1.5 × ULN or <5x ULN if the transferase
elevation was due to liver metastases

- International Normalized Ratio (INR) or Prothrombin Time (PT) & aPTT ≤ 1.5 × ULN
(unless subjects is receiving anticoagulant therapy, as long as PT or PTT is
within therapeutic range of intended use of anticoagulants)

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to registration. NOTE: A woman is considered to be of childbearing
potential if she is postmenarcheal, has not reached a postmenopausal state (> 12
continuous months of amenorrhea with no identified cause other than menopause), and
has not undergone surgical sterilization (removal of ovaries and/or uterus).

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use two non-hormonal methods of contraception, including
at least one method with a failure rate of < 1% per year, during the treatment period
and for 5 months after the last dose of atezolizumab or 120 days after the last dose
of any study drug, whichever is later;

- examples of non-hormonal contraceptive methods with a failure rate of < 1% per
year include bilateral tubal ligation, male sterilization, hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices. Must use "estrogen-free" hormonal method if this
is chosen contraception method.

- A barrier method may be used as the second contraceptive method. The reliability
of sexual abstinence should be evaluated in relation to the duration of the
clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)
and withdrawal are not acceptable methods of contraception.

- Contraception method must begin starting from the time of informed consent until 120
days after treatment discontinuation.

- For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom, and agreement to refrain from donating sperm, as defined below:

- With female partners of childbearing potential or pregnant female partners, men must
remain abstinent or use a condom during the treatment period and for 120 days after
the last dose of study treatment to avoid exposing the embryo. Men must refrain from
donating sperm during this same period.

- The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

- Active infection requiring systemic therapy

- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

- Active secondary cancers.

- Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases. Brain imaging with either MRI or CT with contrast must be performed on all
subjects at screening to evaluate for the presence of brain metastases. Patients with
a history of treated CNS lesions are eligible, provided that all of the following
criteria are met:

- Measurable disease, per RECIST v1.1, must be present outside the CNS.

- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

- Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metastases to the midbrain, pons, medulla, or spinal cord).

- The patient has not received stereotactic radiotherapy within 14 days prior to
initiation of study treatment or whole-brain radiotherapy within 21 days prior to
initiation of study treatment

- The patient has no ongoing requirement for corticosteroids as therapy for CNS
disease and off steroid therapy for at least 14 days. Anticonvulsant therapy at a
stable dose is permitted.

- Asymptomatic patients with CNS metastases newly detected at screening are
eligible for the study after receiving radiotherapy or surgery, with no need to
repeat the screening brain scan.

- Major surgery within 3 weeks of the first dose of trial treatment.

- Completed palliative radiotherapy within 7 days of the first dose of trial treatment.

- The patient had a history of uncontrolled hereditary or acquired thrombotic disorder.

- Patients with a history of gross hemoptysis (defined as bright red blood or ≥1/2
teaspoon) within 2 months prior to enrollment.

- The patient had clinically relevant congestive heart failure (CHF; NYHA II-IV) or
symptomatic or poorly controlled cardiac arrhythmia.

- The patient had experienced any arterial thrombotic event, including myocardial
infarction, unstable angina, cerebrovascular accident, or transient ischemic attack,
within 6 months prior to enrollment.

- The patient had uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard
medical management.

- The patient has had a serious or non-healing wound, ulcer, or bone fracture within 28
days prior to enrollment.

- Patients with ≥ 2 + protein on dipstick urinalysis. All patients with ≥ 2 + protein on
dipstick urinalysis at baseline must undergo a 24-hour urine collection and must
demonstrate ≤ 1 g of protein in 24 hours to be eligible.

- Clear cavitation of pulmonary lesions seen on imaging.

- The patient had significant bleeding disorders, vasculitis, or experienced Grade 3-4
gastrointestinal (GI) bleeding within 3 months prior to enrollment.

- History of GI perforation and/or fistulae within 6 months prior to enrollment.

- Evidence of tumor invading or abutting major blood vessels.

- The patient had a bowel obstruction, history or presence of inflammatory enteropathy
or extensive intestinal resection (hemicolectomy or extensive small intestine
resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic
diarrhea.

- Has received a live-virus vaccination within 30 days of planned treatment start.
Seasonal flu vaccines that do not contain live virus are permitted.

- Previously had a severe hypersensitivity reaction to treatment with another monoclonal
antibody (mAb).

- Has active autoimmune disease that has required systemic treatments in the past 2
years, including but not limited to cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-TNF-α agents; chronic or occasional use of low-dose steroid
therapy can be still be considered eligible as long as no greater than the daily
equivalent of 5mg oral prednisone.

- Exceptions to excluding patients with active autoimmune disease include the following:

- Patients with a history of autoimmune-related hypothyroidism who are on thyroid
replacement hormone are eligible for the study.

- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.

- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations are eligible for the study provided all of following
conditions are met:

- Rash must cover < 10% of body surface area

- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids

- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids
within the previous 12 months

- Subjects with asthma that require intermittent use of bronchodilators, inhaled
steroids, or local steroid injections would not be excluded from the study. Subjects
on chronic systemic steroids would be excluded from the study.

- Had prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
(whichever is longer) prior to initiation of study treatment

- Treatment with systemic immunosuppressive medication (including, but not limited to
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during the course of
the study, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for the study.

- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
for the study.

- Treatment with denosumab (a RANKL inhibitor) within 4 weeks prior to initiation of
study treatment. Patients receiving denosumab prior to enrollment must be willing and
eligible to receive a bisphosphonate during atezolizumab treatment.

- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins

- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation

- Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive
HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and
known quantitative HCV RNA results greater than the lower limits of detection of the
assay. For patients with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is
only eligible if they are negative for HBV DNA.

- Active tuberculosis

- Has a 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.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Has known interstitial lung disease or history of idiopathic pulmonary fibrosis,
organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed
tomography (CT) scan; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted. Lymphangitic spread of the NSCLC is not exclusionary.