Firstline Pembrolizumab Alone or in Combination With Pemetrexed and Carboplatin in Induction/Maintenance or Postprogression in Treating Patients With Stage IV Non-squamous Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate overall survival (OS) in each of the 2 experimental arms (Arms A and B) to
control (Arm C).

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 for Arm C versus each of Arms A and B.

II. To evaluate best objective response rates per RECIST 1.1 for Arm C versus each of Arms A
and B.

III. To estimate toxicity within each of the treatment arms via the Common Terminology
Criteria for Adverse Events (CTCAE) criteria.

IV. To compare outcomes between Arms A and B. V. To compare outcomes by treatment arm within
subgroups defined by a cutpoint of PD-L1 expression at >= 50%.

BIOMARKER OBJECTIVES:

I. To collect and bank tissue and blood for future research studies, including potential
development of a prognostic and predictive signature for MK-3475 (pembrolizumab) in
combination with chemotherapy versus MK-3475 (pembrolizumab) alone.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles
repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable
toxicity. At time of disease progression, patients receive pemetrexed IV over 10 minutes and
carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles
in the absence of disease progression or unacceptable toxicity. Patients then may receive
pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21
days for up to 2 years in the absence of disease progression or unacceptable toxicity. At
time of disease progression, patients receive pembrolizumab IV over 30 minutes, pemetrexed IV
over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days
for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients
then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1.
Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease
progression or unacceptable toxicity and until to disease progression for pemetrexed.

ARM C: Patients receive patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over
10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for
up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then
receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles
repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease
progression or unacceptable toxicity and until to disease progression for pemetrexed.

After completion of study treatment, patients are followed up for 5 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage IV non-squamous
non‐small cell lung cancer (NSCLC) (includes M1a, M1b stage disease, American Joint
Committee on Cancer [AJCC] 8th edition). Patients with T4NX disease (stage IIIB) with
nodule in ipsilateral lung lobe are eligible if they are not candidates for combined
chemotherapy and radiation

- Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells.
The assay must have been performed by a Clinical Laboratory Improvement Act (CLIA) (or
equivalent) certified laboratory

- Patients must have measurable or non-measurable disease. Presence of malignant pleural
fluid alone is allowed as study eligibility.

- NOTE: If patient receives pemetrexed, follow institutional guidelines to drain
fluids

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1

- Patients must NOT have received the following:

- Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC.
Patients treated with any prior checkpoint inhibitors for lung cancer are
ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or
immunotherapy for locally advanced stage III disease is allowed if at least 6
months have elapsed since the prior therapy and registration. Local therapy, e.g.
palliative radiation, is allowed as long as a period of 14 days has passed since
completion

- Methotrexate (MTX) given in low doses for non-malignant conditions with last dose
at least 14 days prior to date of registration will be allowed. Other low dose
chemotherapeutics for non-malignant conditions will be considered, but review by
the study chair is required

- Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600)
or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors
are excluded

- Patients with symptomatic brain metastases are excluded. Patients with treated or
asymptomatic brain metastases are eligible if off steroids for at least 14 days prior
to protocol treatment. Anticonvulsants are allowed

- Patients with another active malignancy within the last 2 years are excluded.
Adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
adequately treated stage I or II cancer from which the patient is currently in
complete remission, or any other cancer from which the patient has been disease free
for five years are permitted

- Patients must not have known pre-existing and clinically active interstitial lung
disease, or a known history of (non infectious) pneumonitis that required steroids, or
current pneumonitis

- Patients must not have significant gastrointestinal disorders with diarrhea as a major
symptom (e.g. Crohn's disease, malabsorption, etc.)

- Patients must not have history of auto-immune condition requiring ongoing or
intermittent 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

- Patients must not have history of clinically relevant cardiovascular abnormalities
such as uncontrolled hypertension, congestive heart failure, New York Heart
Association (NYHA) classification of 3, unstable angina or poorly controlled
arrhythmia, or myocardial infarction within 6 months prior to registration

- Patients must not have any other concomitant serious illness or organ system
dysfunction that in the opinion of the investigator would either compromise patient
safety or interfere with the evaluation of the safety of the study drug

- Patients must not receive any other investigational agents during the course of
therapy

- Women must not be pregnant or breast-feeding due to potential harm to the fetus or
infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab).
Patients must also not expect to conceive or father children from the time of
registration, while on study treatment, and continue for 120 days after the last dose
of study treatment

- All females of childbearing potential must have a blood test or urine study
within 72 hours prior to registration to rule out pregnancy

- A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
has achieved menarche at some point; has not undergone a hysterectomy or
bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea
following cancer therapy does not rule out childbearing potential) for at least
24 consecutive months (i.e., has had menses at any time in the preceding 24
consecutive months)

- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception or abstain from sexual intercourse from time of
registration, while on study treatment, and continue for 120 days after the last dose
of study treatment

- Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of randomization)

- Platelets >= 100,000/mm^3 (within 14 days of randomization)

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 Or if patient on
therapeutic anticoagulation, PT/INR =< 3.0 (within 14 days of randomization)

- Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if
patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN (within 14 days of
randomization)

- Total bilirubin =< 1.5 mg/dL (obtained within 14 days of randomization)

- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5
x upper limit of normal (ULN) (obtained within 14 days of randomization)

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x
upper limit of normal (ULN) (obtained within 14 days of randomization)

- Calculated creatinine clearance >= 45ml/min to be eligible to receive pemetrexed
(obtained within 14 days prior to randomization)

- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (obtained within
14 days prior to randomization)

- Patients must not have a known history of active tuberculosis (TB)

- Patients must not have a diagnosis of immunodeficiency or receive systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of protocol treatment

- Patients must not have received a live vaccine within 30 days prior to randomization.
Seasonal flu vaccines that do not contain live virus are permitted

- Patients who are known to be human immunodeficiency virus (HIV) positive are eligible
if they meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective

- They must have a CD4+ T-cell count 250 cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

- Patients must not have known active hepatitis B (e.g., hepatitis B virus surface
antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C Virus [HCV] ribonucleic
acid [RNA] [qualitative] is detected)