Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

Phase II

To evaluate the impact of adding local consolidative therapy (LCT) to maintenance systemic
therapy versus maintenance systemic therapy alone on progression-free survival for patients
with metastatic non-small cell lung cancer (NSCLC) with no evidence of progression and
limited metastatic sites after first-line systemic therapy.

Phase III

To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance
systemic therapy alone on overall survival for patients with metastatic NSCLC with no
evidence of progression and limited metastatic sites after first-line systemic therapy.

SECONDARY OBJECTIVES:

I. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance
systemic therapy alone on in-field local failure.

II. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance
systemic therapy alone on the time to development of new lesions.

III. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance
systemic therapy alone on toxicity.

IV. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance
systemic therapy alone on duration of maintenance systemic therapy usage.

V. To evaluate the effect of adding LCT to systemic therapy in limited stage IV NSCLC on
Quality of Life (QOL) VI. To collect biospecimens and evaluate the correlation between
clinical outcomes and circulating tumor DNA (ctDNA).

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM 1 (CHEMOTHERAPY ALONE): ): Patients may receive docetaxel intravenously (IV) over 60
minutes on Day 1, erlotinib hydrochloride orally (PO) once daily (QD), or gemcitabine IV over
30 minutes on Days 1 and 8. Patients with non-squamous non-small cell lung cancer may receive
pemetrexed disodium IV over 10 minutes on Day 1 alone or in combination with pembrolizumab IV
over 30 minutes. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

ARM 2 (SBRT AND CHEMOTHERAPY): Patients undergo LCT over 2-4 weeks. If LCT cannot be used to
treat primary disease sites, patients also undergo intensity-modulated radiation therapy
(IMRT) or 3-dimensional conformal radiation therapy (3DCRT) over 3-5 weeks. Within 2 weeks
after completion of radiation therapy, patients receive chemotherapy as in Arm 1. Patients
may possibly undergo surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, then annually thereafter.

Inclusion Criteria:

- Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up

- Women of childbearing potential and men who are sexually active should be willing and
able to use medically acceptable forms of contraception during the trial and for up to
180 days after completion of all treatment to prevent pregnancy or fathering a child.

- Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present
prior to registration; this includes patients newly diagnosed with metastatic disease
or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop
metastases

- Appropriate stage for study entry based on the following diagnostic workup:

- History/physical examination within 30 days prior to registration

- Imaging proof of limited metastatic disease and response to therapy/stable
disease, by at least CT chest through the adrenals or PET/CT within 30 days prior
to registration

- Zubrod performance status 0, 1, or 2 within 30 days prior to registration

- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of
normal (ULN) or ≤ 5 × ULN with metastatic liver disease

- Total bilirubin ≤ 1.5 × ULN

- Absolute neutrophil count (ANC) ≥ 500 cells/mm^3

- Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Platelets ≥ 50,000 cells/mm^3

- Negative serum pregnancy test within one week prior to registration for females of
childbearing potential

- Patients must have received first-line/induction chemotherapy (4 cycles) and achieved
stable disease or a partial response

- Prior systemic chemotherapy as part of concurrent treatment approach for previously
diagnosed stage III NSCLC, as adjuvant therapy for previously resected NSCLC, or for
other previous cancers is permitted

- Prior radiotherapy for patients with brain metastases prior to enrollment is
acceptable

- Patients must have measurable disease at baseline and 3 or fewer discrete,
extracranial metastatic disease sites that are technically amenable to SBRT

- For de novo stage IV NSCLC patients (patients with metastatic disease at first
presentation), primary disease must be treatable with local therapy in the form of
SBRT or hypofractionated radiation; if the primary disease is found in the peripheral
or central lung parenchyma without nodal disease for instance, SBRT may be employed;
if primary disease is more advanced with involvement of the mediastinum (T4 tumor,
N1-N3 disease, etc.), these volumes should be technically treatable with
hypofractionated radiation

- If primary disease in the thoracic cavity was previously treated with local therapy in
the form of surgery, any local/regional disease recurrence should be technically
treatable with SBRT or hypofractionated radiation after induction systemic therapy

- Patients must be registered within 35 days of administration of the last dose of
first-line/induction systemic therapy

- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry

- Patients with brain metastases are eligible if these lesions have been previously
treated and the patients have no clinical or radiographic evidence of progression
prior to enrollment

Exclusion Criteria:

- Clinical or radiologic evidence of untreated and/or progressive brain metastases

- Cutaneous metastasis of NSCLC

- Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph
nodes if not a candidate for surgery for these lesions

- Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate
risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix)
unless disease free for a minimum of one year

- Metastases located within 3 cm of previously irradiated (< 3Gy per fraction)
structures if if not a candidate for surgery for these lesions and if:

- Spinal cord previously irradiated to > 40 Gy

- Brachial plexus previously irradiated to > 50 Gy

- Small intestine, large intestine, or stomach previously irradiated to > 45 Gy

- Brainstem previously irradiated to > 50 Gy

- Lung previously irradiated with prior V20 Gy > 35%

- Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the
first-line setting

- If a patient has progressed in previous areas of primary disease that received
definitive doses of radiation, these patients would require re-irradiation in previous
high dose anatomic areas and are not eligible for this study

- Patients with malignant pleural effusions that do not resolve after first-line
systemic therapy; patients with pleural effusions that have become too small for
thoracentesis at the time of registration would be permitted on study, indicating a
significant response to first-line chemotherapy

- Patients with more than 3 discrete locations of extra-cranial metastatic disease after
first-line systemic therapy requiring more than 3 SBRT plans to cover these distinct
metastatic disease entities

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration

- Patients who are pregnant or nursing

- Participation in any investigational drug study (excluding non-oncology and/or symptom
management studies) within 4 weeks prior to registration

- Known human immunodeficiency virus (HIV) positive with cluster of differentiation 4
(CD4) count < 200 cells/microliter; note that patients who are HIV positive are
eligible, provided they are under treatment with highly active antiretroviral therapy
(HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to
registration; note also that HIV testing is not required for eligibility for this
protocol

- Patients who received prior non-induction pembrolizumab, patients on chronic steroids
or who have active autoimmune disease for which they received systemic treatment in
the previous 2 years with corticosteroids, disease modifying agents, or
immunosuppressive drugs. Replacement therapy (thyroxine, insulin or physiological
corticosteroid replacement for adrenal or pituitary insufficiency) is allowed.
Patients with active interstitial lung disease or who have a history of pneumonitis
for which they had received glucocorticoids are not eligible

- Prior bevacizumab therapy