Non-Small Cell Lung Cancer
Conditions
Keywords
Lung Cancer, NSCLC, Nivolumab
Brief summary
Patients with Stage III unresectable non-small cell lung cancer will receive thoracic radiation, cisplatin and etoposide followed by nivolumab or placebo given every 2 weeks for a year.
Detailed description
PRIMARY OBJECTIVES: I. To compare the Overall Survival (OS) for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation. II. To compare Progression-Free Survival (PFS) according to RECIST 1.1 criteria for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation.
Interventions
DRUGEtoposide
Concurrently with radiation, 40 mg/m2, IV, on days 1-5 and 29-33, to begin with day 1 of radiation therapy.
DRUGNivolumab
Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks.
RADIATIONRadiation Therapy (RT)
2 Gy fractions once a day, 5 days per week, for a total of 60 Gy in 30 fractions.
DRUGCisplatin
Concurrently with radiation therapy, 50 mg/m2, IV, on days 1, 8, 29, and 36, to begin with day 1 of radiation therapy.
OTHERPlacebo
Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks.
Sponsors
Bristol-Myers Squibb
RTOG Foundation, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer (NSCLC) with unresectable, medically inoperable disease, or patients who refuse resection stage IIIA or stage IIIB disease (AJCC 7th edition) * History/physical examination within 30 days prior to registration * Computed tomography (CT) scan with IV contrast (CT scan without contrast acceptable if IV contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands within 60 days prior to registration (recommended within 30 days prior to registration) * Magnetic resonance imaging (MRI) of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 60 days prior to registration; note: the use of intravenous contrast is required for the MRI or CT (unless medically contra-indicated). * Whole-body fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT within 60 days prior to registration; Note: patients do not need to have a separate CT of chest and upper abdomen with contrast if PET/CT imaging includes a high quality CT chest with contrast. * Age ≥ 18 years * The trial is open to both genders * Zubrod Performance status of 0-1 * Forced Expiratory Volume at one second (FEV1) \> 1.2 liters; Diffusion Capacity of Lung for Carbon Monoxide (DLCO) ≥ 50% predicted * Patients must be at least 3 weeks from prior thoracotomy (if performed); if prior thoracotomy then measurable disease on imaging must be present * Negative serum pregnancy test within three days prior to registration for women of childbearing potential * An archived tumor block or punches instead block must be available for submission for programmed death-ligand 1 (PD-L1) analysis. If an archived tumor block sample cannot be shipped for this study, then two 3mm punches from the core needle biopsy blocks may be provided for analysis. Note: core or excisional biopsy is required for this study. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis. * Agreement of women of childbearing potential to use highly effective contraception during receipt of study drug and up to 161 days (23 weeks) from the last dose of nivolumab/placebo and men receiving nivolumab/placebo who are sexually active with women of childbearing potential to use highly effective contraception during receipt of study drug for 31 weeks from the last dose of nivolumab/placebo.
Exclusion criteria
* Definitive clinical or radiological evidence of metastatic disease * Prior or current invasive malignancy (except non-melanomatous skin cancer, localized bladder and prostate cancer) unless disease free for a minimum of 2 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) * Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. For example, patients with prior breast radiotherapy treatments would likely be excluded. * Prior systemic treatment with and anti-programmed cell death protein 1 (PD1), anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways * Known immunosuppressive disease, for example HIV infection or history of bone marrow transplant or chronic lymphocytic leukemia (CLL) * Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration. COPD requiring chronic oral steroid therapy * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * History of symptomatic or p previously established interstitial lung disease * Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection; * History of severe hypersensitivity reaction to any monoclonal antibody or allergy to study drug components * As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen * Pregnancy, nursing females or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From registration to study termination. Maximum follow-up was 14.9 months. | Survival time is defined as time from registration to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported and no statistical testing was done. |
| Progression-Free Survival (PFS) | From registration to study termination. Maximum follow-up was 14.9 months. | Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression was to be determined by an independent radiology review committee using scans submitted to a central location. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored) and was to be estimated by the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3+ Adverse Events | From registration to study termination. Maximum follow-up was 14.9 months. | Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Percentage of Participants With Deterioration in Functional Assessment of Cancer Therapy - Trial Outcome Index for Lung Cancer (FACT-TOI) at 15 Months | Baseline and 15 months | FACT-TOI is a measure of 21 items that sum the functional well being (FWB), physical well being (PWB), and the lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy - Lung (FACT-L) QOL instrument, used for measuring QOL in patients with lung cancer. All items are rated on a 5 item (point) Likert Scale, from 0 (not at all) to 4 (very much). FACT-TOI is scored by summing the individual scale scores, with higher scores indicating better quality of life. Deterioration was defined as a decrease of 5 points or more from baseline. |
| Overall Survival by PD-L1 Status | From registration to study termination. Maximum follow-up was 14.9 months. | — |
| Progression-Free Survival by PD-L1 Status | From registration to study termination. Maximum follow-up was 14.9 months. | — |
Countries
United States
Participant flow
Pre-assignment details
Registered patients who submitted tissue for PD-L1 assessment and had no evidence of distant metastases or local disease progression at the second step registration were randomized. Of 20 registered patients, 8 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by nivolumab | 3 |
| Placebo 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by placebo | 5 |
| Total | 8 |
Baseline characteristics
| Characteristic | Placebo | Nivolumab | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 72 years | 67.5 years |
| Age, Customized 50-59 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized 60-69 years | 4 Participants | 0 Participants | 4 Participants |
| Age, Customized ≥ 70 years | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Histology Adenocarcinoma | 3 Participants | 2 Participants | 5 Participants |
| Histology Squamous cell carcinoma | 2 Participants | 1 Participants | 3 Participants |
| PD-L1 < 1% | 3 Participants | 0 Participants | 3 Participants |
| PD-L1 ≥ 1% | 1 Participants | 2 Participants | 3 Participants |
| PD-L1 Not Evaluable | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
| Zubrod Performance Status 0 | 1 Participants | 0 Participants | 1 Participants |
| Zubrod Performance Status 1 | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 2 / 3 | 1 / 5 |
Outcome results
Primary
Overall Survival (OS)
Survival time is defined as time from registration to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported and no statistical testing was done.
Time frame: From registration to study termination. Maximum follow-up was 14.9 months.
Population: Eligible participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab | Overall Survival (OS) | 2 Participants |
| Placebo | Overall Survival (OS) | 5 Participants |
Primary
Progression-Free Survival (PFS)
Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression was to be determined by an independent radiology review committee using scans submitted to a central location. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored) and was to be estimated by the Kaplan-Meier method.
Time frame: From registration to study termination. Maximum follow-up was 14.9 months.
Population: Central review of imaging to determine progression was not performed due to early study closure therefore progression (and hence progression-free survival) could not be determined.
Secondary
Number of Participants With Grade 3+ Adverse Events
Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From registration to study termination. Maximum follow-up was 14.9 months.
Population: Eligible participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab | Number of Participants With Grade 3+ Adverse Events | 3 Participants |
| Placebo | Number of Participants With Grade 3+ Adverse Events | 3 Participants |
Secondary
Overall Survival by PD-L1 Status
Time frame: From registration to study termination. Maximum follow-up was 14.9 months.
Population: Data is not reported because the primary endpoints were not determined to have positive results. \[Per the protocol, this subgroup analysis was to occur only if either of the primary endpoints were determined to have positive results.\]
Secondary
Percentage of Participants With Deterioration in Functional Assessment of Cancer Therapy - Trial Outcome Index for Lung Cancer (FACT-TOI) at 15 Months
FACT-TOI is a measure of 21 items that sum the functional well being (FWB), physical well being (PWB), and the lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy - Lung (FACT-L) QOL instrument, used for measuring QOL in patients with lung cancer. All items are rated on a 5 item (point) Likert Scale, from 0 (not at all) to 4 (very much). FACT-TOI is scored by summing the individual scale scores, with higher scores indicating better quality of life. Deterioration was defined as a decrease of 5 points or more from baseline.
Time frame: Baseline and 15 months
Population: No participants had a 15-month FACT-TOI assessment
Secondary
Progression-Free Survival by PD-L1 Status
Time frame: From registration to study termination. Maximum follow-up was 14.9 months.
Population: Data is not reported because the primary endpoints were not determined to have positive results. \[Per the protocol, this subgroup analysis was to occur only if either of the primary endpoints were determined to have positive results.\]