Purpose

This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed by pemetrexed and carboplatin with or without pembrolizumab after disease progression is superior to induction with pembrolizumab, pemetrexed and carboplatin followed by pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. It is not yet known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or without pembrolizumab works better in treating patients with non-squamous non-small cell cancer.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer (NSCLC) (includes M1a, M1b, and M1c stage disease, American
Joint Committee on Cancer [AJCC] 8th edition). Patients with stage IIIB and IIIC
disease are eligible if they are not candidates for combined chemotherapy and
radiation. Prior chemo-radiation therapy (RT) for stage III with recurrence is allowed

- Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells.
If PD-L1 expression TPS is unevaluable or the testing could not be completed, the
patients are not eligible. 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. The presence of malignant
pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline
imaging assessments and measurements used to evaluate all measurable or non-measurable
sites of disease must be done within 4 weeks prior to study registration

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

- NOTE: An additional 15 days is allowed to account for any infection/exposure
related logistical delays

- Patients must be >= 18 years of age

- 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 metastatic lung cancer
are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy)
or immunotherapy for locally advanced stage III disease, or treated with
neoadjuvant IO is allowed if at least 6 months have elapsed between the last dose
of the prior therapy and study registration. Local therapy, e.g. palliative
radiation, is allowed as long as a period of 14 days has passed between
completion of local therapy and the start of protocol treatment. Registration
during the 14 days is allowed. Palliative radiation must be to non-target
lesions. Palliative radiation to pre-existing lesions while on protocol treatment
is allowed as long as these areas have not grown to RECIST defined progression.
Development of any new metastasis is considered progression. Concurrent radiation
and protocol treatment is not allowed; protocol treatment may resume after
completion of radiation as long as patient does not have greater than grade 2
side effects from radiation per physician discretion.

- 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

- Palliative radiation to non-target lesions (bone metastasis) is allowed if the
patient develops symptoms

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

- Patients with treated brain metastases are eligible if follow-up brain imaging
obtained at least 14 days after central nervous system (CNS)-directed therapy shows no
evidence of progression. CNS progression counts as progression and patients must move
on to the next phase after CNS treatment. Patients with asymptomatic new (at
screening) or progressive brain metastases (active brain metastases at screening) are
eligible if the treating physician determines that immediate CNS specific treatment is
not required and is unlikely to be required during the first cycle of therapy

- Patients are eligible if off steroids for at least 14 days prior to protocol
treatment

- Anticonvulsants are allowed

- Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion
of investigators do not need immediate CNS directed therapies are eligible

- Patients with prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial

- 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 (including Guillain-Barre
Syndrome or Multiple Sclerosis) requiring ongoing or intermittent systemic treatment
in the past 2 years prior to registration (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 with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better

- 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

- Patients must not be pregnant or breast-feeding due to potential harm to the fetus or
infant from cytotoxic chemotherapy and the unknown risk of pembrolizumab (MK-3475).
All patients of childbearing potential must have a blood test or urine study within 72
hours prior to registration to rule out pregnancy. A patient of childbearing potential
is anyone, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has achieved menarche at some point; 2)
has not undergone a hysterectomy or bilateral oophorectomy; or 3) 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)

- Patients must use accepted and effective method(s) of contraception or by abstaining
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 prior to randomization)

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

- Prothrombin time (PT)/international normalized ratio (INR) (only if on active
anticoagulation with warfarin or any formulations of heparin) =< 3.0 (within 14 day
prior to randomization)

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

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

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

- Calculated creatinine clearance >= 45 ml/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.
Patients are permitted to receive inactivated vaccines and any non-live vaccines
including those for the seasonal influenza and COVID-19 (Note: intranasal influenza
vaccines, such as Flu-Mist [registered trademark] are live attenuated vaccines and are
not allowed). If possible, it is recommended to separate study drug administration
from vaccine administration by about a week (primarily, in order to minimize an
overlap of adverse events)

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable or on suppressive therapy, if indicated. Patients with a
history of hepatitis C virus (HCV) infection must have been treated and cured. For
patients with HCV infection who are currently on treatment, they are eligible if they
have an undetectable HCV viral load

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm A (pembrolizumab, pemetrexed, carboplatin)
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. Within 6 weeks 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. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Drug: Carboplatin
    Given IV
    Other names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • JM8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Computed Tomography
    Undergo CT scan
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Biological: Pembrolizumab
    Given IV
    Other names:
    • BCD-201
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • Pembrolizumab Biosimilar BCD-201
    • Pembrolizumab Biosimilar QL2107
    • QL2107
    • SCH 900475
  • Drug: Pemetrexed
    Given IV
    Other names:
    • MTA
    • Multitargeted Antifolate
    • Pemfexy
  • Procedure: Positron Emission Tomography
    Undergo PET scan
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
Experimental
Arm B (pembrolizumab, pemetrexed, carboplatin)
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. Within 6 weeks 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. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Drug: Carboplatin
    Given IV
    Other names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • JM8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Computed Tomography
    Undergo CT scan
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Biological: Pembrolizumab
    Given IV
    Other names:
    • BCD-201
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • Pembrolizumab Biosimilar BCD-201
    • Pembrolizumab Biosimilar QL2107
    • QL2107
    • SCH 900475
  • Drug: Pemetrexed
    Given IV
    Other names:
    • MTA
    • Multitargeted Antifolate
    • Pemfexy
  • Procedure: Positron Emission Tomography
    Undergo PET scan
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
Active Comparator
Arm C (pembrolizumab, pembrolizumab, carboplatin)
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. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Drug: Carboplatin
    Given IV
    Other names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • JM8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Computed Tomography
    Undergo CT scan
    Other names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • Computerized Tomography (CT) scan
    • CT
    • CT Scan
    • tomography
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other names:
    • Magnetic Resonance
    • Magnetic Resonance Imaging (MRI)
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • MRIs
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
    • sMRI
    • Structural MRI
  • Biological: Pembrolizumab
    Given IV
    Other names:
    • BCD-201
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • Pembrolizumab Biosimilar BCD-201
    • Pembrolizumab Biosimilar QL2107
    • QL2107
    • SCH 900475
  • Drug: Pemetrexed
    Given IV
    Other names:
    • MTA
    • Multitargeted Antifolate
    • Pemfexy
  • Procedure: Positron Emission Tomography
    Undergo PET scan
    Other names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT

More Details

Status
Active, not recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

Detailed Description

PRIMARY OBJECTIVE: 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 OBJECTIVE: I. To collect and bank tissue and blood for future research studies, including potential development of a prognostic and predictive signature for pembrolizumab (MK-3475) in combination with chemotherapy versus pembrolizumab (MK-3475) alone. EXPLORATORY IMAGING OBJECTIVES: I. To collect and bank standard of care computed tomography (CT) imaging at baseline and first three follow-up post-treatment scans on first line treatment for validating the radiomic risk score with the following exploratory objectives: Ia. To determine the negative predictive value (NPV) by validating the Radiomic Risk score on pre-treatment scans as well as compute differences between pre- and post- treatment scans (delta features) in determining which patients will benefit from first line pembrolizumab in the metastatic setting in both low (< 50%) and high (> 50%) PD-L1 cohorts using patients in Arm 1 and Arm 2 of the trial where pembrolizumab is used as first line treatment. Ib. To determine the positive predictive value (PPV) by validating the Radiomic Risk score in order to predict which patients would benefit from combination pembrolizumab and subsequent chemotherapy vs. immunotherapy alone in both low (< 50%) and high (> 50%) PD-L1 cohorts using patients who went on to receive chemotherapy as second line and stratifying the patients based on those who received benefit from pembrolizumab plus chemotherapy versus (vs.) 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. Within 6 weeks 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. Within 6 weeks 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 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. Patients undergo magnetic resonance imaging (MRI) during screening, CT scan and blood sample collection throughout the study, and may undergo position emission tomography (PET) scan throughout the study. After completion of study treatment, patients are followed up for 5 years.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.