Limited Stage Lung Small Cell Carcinoma, Stage III Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Stage I Lung Cancer AJCC v8
Conditions
Brief summary
This phase III trial studies how well chemotherapy and radiation therapy (chemoradiation) with or without atezolizumab works in treating patients with limited stage small cell lung cancer. Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving chemoradiation with or without atezolizumab may work better in treating patients with limited stage small cell lung cancer.
Detailed description
PRIMARY OBJECTIVE: I. To compare overall survival (OS) for patients with LS-SCLC treated with chemoradiation +/- atezolizumab. SECONDARY OBJECTIVES: I. To compare progression free survival (PFS) for patients with limited stage small cell lung cancer (LS-SCLC) treated with chemoradiation +/- atezolizumab. II. To determine overall response rate (ORR), rates of local control, and distant metastases free survival with chemoradiation +/- atezolizumab. III. To characterize immune mediated and non-immune mediated toxicity from chemoradiotherapy plus atezolizumab. IV. To compare quality of life, as measured by the Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI), for patients undergoing chemoradiation +/- atezolizumab. V. To evaluate the quality-adjusted survival, using scores from the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L), of chemoradiation +/- atezolizumab for patients with LS-SCLC. VI. To characterize fatigue, as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS), following chemoradiation +/- atezolizumab. VII. To determine the association of small cell lung cancer (SCLC) molecular subtypes with clinical outcomes. EXPLORATORY OBJECTIVES: I. To collect biospecimens at baseline, day 1 and 3 months after the end of chemoradiotherapy, to allow for future analyses. II. To characterize patient-reported symptomatic toxicities measured by the Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). III. To characterize the concordance between tumor and circulating cell-free deoxyribonucleic acid (cfDNA)-determined molecular subtypes. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive etoposide intravenously (IV) on days 1-3 and cisplatin IV or carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) twice daily (BID) for approximately 3 weeks or once daily (QD) for approximately 6-7 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial. ARM II: Patients receive treatment as in Arm I. Patients also receive atezolizumab IV over 30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
DRUGAtezolizumab
Given IV
PROCEDUREBiospecimen Collection
Correlative studies
DRUGCarboplatin
Given IV
DRUGCisplatin
Given IV
DRUGEtoposide
Given IV
RADIATIONIntensity-Modulated Radiation Therapy
Undergo IMRT
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer \[AJCC\] staging, 8th edition \[Ed.\]), within 60 days prior to registration * Patients must have received one cycle of platinum/etoposide chemotherapy pre-registration (prior to study entry). Study registration must be within 21 days from day 1 of the pre-registration cycle of chemotherapy. * Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors \[RECIST\], version 1.1) prior to the required pre-registration cycle of platinum/etoposide chemotherapy * Minimal staging requirements include: * History/physical examination within 30 days prior to registration * Positron emission tomography (PET)/computed tomography (CT) scan for staging within 60 days prior to registration * CT chest and CT abdomen with IV contrast (unless contraindicated based on kidney function) within 60 days prior to registration; magnetic resonance imaging (MRI) abdomen with IV contrast allowed in place of CT abdomen * Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy * MRI scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration * Age \>= 18 * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration * Absolute neutrophil count (ANC) \>= 1,500/cells/mm\^3 (prior to pre-registration cycle) * Platelet count \>= 100,000 cells/mm\^3 (prior to pre-registration cycle) * Hemoglobin \>= 9 g/dL (prior to pre-registration cycle) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) (prior to pre-registration cycle) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.0 x ULN (prior to pre-registration cycle) * Adequate renal function within 30 days prior to registration defined as follows: Creatinine clearance \>= 30 mL/min by the Cockcroft-Gault (C-G) equation * Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging * Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential * The patient or a legally authorized representative must provide study-specific informed consent prior to study entry * Hepatitis B/C testing prior to enrollment for patients that have not been tested before. Note: This is required even if the patient has never shown or had symptoms of hepatitis * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Exclusion criteria
* Definitive clinical or radiologic evidence of metastatic disease * Definitive surgical resection of small cell lung cancer * Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible) * More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable * Any prior atezolizumab or other immunotherapy agent * Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs) * Patients with cytologically positive pleural or pericardial fluid are not eligible * An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) * History of allogeneic organ transplant * History of primary immunodeficiency * Severe, active co-morbidity defined as follows: * Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications * Active tuberculosis * Active hepatitis B (chronic or acute) or hepatitis C infection. Note that if hepatitis status is unknown, hepatitis B/C testing is required * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen \[HBsAg\]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test.) * Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL) * Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of \> 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary * Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months * Transmural myocardial infarction within the last 3 months * Clinically significant interstitial lung disease * A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease * Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Randomization to date of death due or last follow-up. Median follow-up at the time of analysis was 23.8 months. | Survival rates and median survival time are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From randomization to progression or death due to any cause, whichever occurs first, or last tumor assessment if alive. MMedian follow-up at the time of analysis was 23.8 months. | PFS failure event is defined as progressive disease (PD) determined by investigator per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause. PD is defined as at least a 20% increase in the sum of longest diameters of target lesions, and an absolute increase of at least 5 mm. The appearance of any new lesions is also considered progression. PFS rates and median PFS time are estimated using the Kaplan-Meier method, censoring participants alive without progression at the date of their last evaluable radiographic tumor assessment. |
| Number of Participants by Highest Grade Adverse Event Reported | Randomization to last follow-up. Median follow-up at the time of analysis was 23.8 months. | Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Percentage of Participants With Confirmed Objective Response (Objective Response Rate (ORR)) | Randomization to last radiographic tumor assessment. Median follow-up at the time of analysis was 23.8 months. | Objective response rate (ORR) is defined as the proportion of subjects whose best overall response (BOR) is a confirmed complete or partial response as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 on two consecutive occasions ≥4 weeks apart. |
| Percentage of Participants With Local Progression | From randomization to local progression, other progression, or death, whichever occurs first, or last tumor assessment if alive. Median follow-up at the time of analysis was 23.8 months. 1-, 2-, and 3-year rates are reported. | Local progression is defined as intrathoracic tumor progression (failure in the lobe of the primary tumor or mediastinal lymph nodes) by RECIST 1.1 criteria determined by the investigator. Local progression rates are estimated by the cumulative incidence method, treating non-local progression (i.e., distant metastasis or failure in a different lung) and death without local progression as competing risks, and otherwise censoring participants alive at last tumor assessment. Treatment effect comparisons will utilize a cause-specific hazard function in which competing risks are censored. |
| Distant Metastases-free Survival (DMFS) | Randomization to DMFS event or local progression, whichever occurs first, or last tumor assessment if alive. Median follow-up at the time of analysis was 23.8 months. | DMFS failure event is defined as first date of documented distant metastases (or failures in a different lung lobe) or death due to any cause, whichever occurs first. Participants with local progression prior to such an event are censored on the date of local progression. Participants with no post-baseline tumor assessment and alive at last follow-up are censored on the date of randomization. Participants alive without distant metastasis, failures in a different lung lobe, or local progression are censored on the date of their last evaluable radiographic tumor assessment. DMFS rates and median DMFS time are estimated using the Kaplan-Meier method. |
| Percent of Participants With Deterioration in Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) | Baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization) | FACT-TOI is a measure of 21 items that sums 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) quality of life (QOL) instrument. The FACT-TOI total score ranges from 0 to 84 with higher scores indicating better quality of life and functioning. Clinically meaningful decline is defined as a decrease from baseline of at least 5 points. |
| Quality-adjusted Survival Months | Baseline to death, last follow-up or two years, whichever occurs first. | Quality-adjusted survival is calculated as the sum of weighted time intervals. Weight is the EuroQol 5-dimensional 5-level (EQ-5d-5L) index score, which measures health-related quality of life and ranges from 0 (death) to 1 (full health). |
| Change From Baseline in the 7 Item Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score | Baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization) | The PROMIS fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Change score is calculated by subtracting baseline from later score, with a positive change score indicating increased fatigue. |
| Molecular Subtyping | Up to 5 years | — |
Countries
Japan, United States
Contacts
PRINCIPAL_INVESTIGATORKristin A Higgins
NRG Oncology
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Chemotherapy, Radiation Therapy) Patients receive etoposide IV on days 1-3 and cisplatin IV or carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D-CRT or IMRT BID for approximately 3 weeks or QD for approximately 6-7 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial. | 270 |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) Patients receive treatment as in Arm I. Patients also receive atezolizumab IV over 30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial. | 274 |
| Total | 544 |
Baseline characteristics
| Characteristic | Arm I (Chemotherapy, Radiation Therapy) | Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Total |
|---|---|---|---|
| Age, Continuous | 67 years | 66 years | 66 years |
| Age, Customized ≤ 49 | 11 Participants | 5 Participants | 16 Participants |
| Age, Customized 50 - 59 | 49 Participants | 49 Participants | 98 Participants |
| Age, Customized 60 - 69 | 115 Participants | 127 Participants | 242 Participants |
| Age, Customized ≥ 70 | 95 Participants | 93 Participants | 188 Participants |
| American Joint Committee on Cancer (AJCC) Stage IA: T1, N0, M0 | 7 Participants | 7 Participants | 14 Participants |
| American Joint Committee on Cancer (AJCC) Stage IB: T2b, N0, M0 | 3 Participants | 4 Participants | 7 Participants |
| American Joint Committee on Cancer (AJCC) Stage IIA: T2b, N0, M0 | 2 Participants | 4 Participants | 6 Participants |
| American Joint Committee on Cancer (AJCC) Stage IIB: T1a-c or T2a-b, N1, M0; or T3, N0, M0. | 38 Participants | 34 Participants | 72 Participants |
| American Joint Committee on Cancer (AJCC) Stage IIIA: T1a-c or T2a-b, N2, M0; or T3, N1, M0; or T4, N0-1, M0. | 107 Participants | 112 Participants | 219 Participants |
| American Joint Committee on Cancer (AJCC) Stage IIIB: T1a-c or T2a-b, N3, M0; or T3, N2, M0; or T4, N2, M0. | 87 Participants | 77 Participants | 164 Participants |
| American Joint Committee on Cancer (AJCC) Stage IIIC: T3 or T4, N3, M0 | 26 Participants | 36 Participants | 62 Participants |
| Cigarette use Current | 78 Participants | 88 Participants | 166 Participants |
| Cigarette use Former | 185 Participants | 181 Participants | 366 Participants |
| Cigarette use Never | 7 Participants | 5 Participants | 12 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 121 Participants | 120 Participants | 241 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 136 Participants | 142 Participants | 278 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 13 Participants | 12 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 7 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 257 Participants | 261 Participants | 518 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 10 Participants |
| Forced Expiratory Volume in 1 second (FEV1) | 1.96 liters/second | 1.99 liters/second | 1.98 liters/second |
| N-Stage N0: No regional lymph node involvement. | 20 Participants | 26 Participants | 46 Participants |
| N-Stage N1: Cancer in nearby lymph nodes. | 43 Participants | 40 Participants | 83 Participants |
| N-Stage N2: Cancer in lymph nodes in the center of the chest (mediastinum). | 147 Participants | 148 Participants | 295 Participants |
| N-Stage N3: Cancer in lymph nodes on the opposite side of the chest or above the collarbone. | 58 Participants | 59 Participants | 117 Participants |
| N-Stage NX: Cannot be assessed | 2 Participants | 1 Participants | 3 Participants |
| Percentage of Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) | 67.5 percentage of predicted value | 66 percentage of predicted value | 66 percentage of predicted value |
| Percentage of Predicted FEV1 | 71 percentage of predicted value | 74 percentage of predicted value | 72 percentage of predicted value |
| Platinum regimen (as randomized) Carboplatin | 111 Participants | 111 Participants | 222 Participants |
| Platinum regimen (as randomized) Cisplatin | 159 Participants | 163 Participants | 322 Participants |
| Primary tumor location Carina | 4 Participants | 1 Participants | 5 Participants |
| Primary tumor location Left Lower Lobe | 29 Participants | 28 Participants | 57 Participants |
| Primary tumor location Left Upper Lobe | 61 Participants | 68 Participants | 129 Participants |
| Primary tumor location Lingula | 4 Participants | 5 Participants | 9 Participants |
| Primary tumor location Main Bronchus, Left | 2 Participants | 2 Participants | 4 Participants |
| Primary tumor location Main Bronchus, Right | 2 Participants | 0 Participants | 2 Participants |
| Primary tumor location Mediastinum | 20 Participants | 19 Participants | 39 Participants |
| Primary tumor location Multiple Sites | 7 Participants | 6 Participants | 13 Participants |
| Primary tumor location Other | 16 Participants | 17 Participants | 33 Participants |
| Primary tumor location Right Lower Lobe | 33 Participants | 35 Participants | 68 Participants |
| Primary tumor location Right Middle Lobe | 16 Participants | 13 Participants | 29 Participants |
| Primary tumor location Right Upper Lobe | 75 Participants | 80 Participants | 155 Participants |
| Primary tumor location Undetectable Primary | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 28 Participants | 47 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 24 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) White | 221 Participants | 215 Participants | 436 Participants |
| RT Schedule (as randomized) Daily (6.5 weeks) | 142 Participants | 145 Participants | 287 Participants |
| RT Schedule (as randomized) Twice a day (3 weeks) | 128 Participants | 129 Participants | 257 Participants |
| Sex: Female, Male Female | 137 Participants | 140 Participants | 277 Participants |
| Sex: Female, Male Male | 133 Participants | 134 Participants | 267 Participants |
| T-Stage T0 (No primary tumor) | 3 Participants | 2 Participants | 5 Participants |
| T-Stage T1 (Tumor ≤3 cm in size) | 96 Participants | 89 Participants | 185 Participants |
| T-Stage T2 (Tumor >3 cm but ≤5 cm or involves main bronchus, visceral pleura, or causes lung collapse.) | 58 Participants | 60 Participants | 118 Participants |
| T-Stage T3 (Tumor >5 cm but ≤7 cm or multiple tumors in the same lobe.) | 57 Participants | 62 Participants | 119 Participants |
| T-Stage T4 (Tumor >7 cm or invades nearby structures or has multiple tumors in different lobes.) | 46 Participants | 52 Participants | 98 Participants |
| T-Stage TX (Primary tumor cannot be assessed) | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 120 / 270 | 132 / 274 |
| other Total, other adverse events | 253 / 257 | 263 / 264 |
| serious Total, serious adverse events | 106 / 257 | 159 / 264 |
Outcome results
Primary
Overall Survival
Survival rates and median survival time are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis.
Time frame: Randomization to date of death due or last follow-up. Median follow-up at the time of analysis was 23.8 months.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Overall Survival | 36.1 months |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Overall Survival | 31.1 months |
Comparison: Assuming exponentially distributed survival times, 480 eligible patients accrued uniformly over 48 months months) with 26 months additional follow-up after the last accrued patient would provide at least 85% power to detect a hazard ratio of 0.71 (median survival times of 38 months \[Arm I\] vs. 27 months \[Arm II\]) at a one-sided significance level of 0.025, after adjusting for type 1 error using group sequential methods for two interim analyses.p-value: 0.581995% CI: [0.82, 1.34]Log Rank
Secondary
Change From Baseline in the 7 Item Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score
The PROMIS fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Change score is calculated by subtracting baseline from later score, with a positive change score indicating increased fatigue.
Time frame: Baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization)
Population: Intent-to-treat participants with score at baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Change From Baseline in the 7 Item Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score | -2.0 score on a scale | Standard Deviation 9.9 |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Change From Baseline in the 7 Item Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form Score | -1.9 score on a scale | Standard Deviation 7.7 |
Secondary
Distant Metastases-free Survival (DMFS)
DMFS failure event is defined as first date of documented distant metastases (or failures in a different lung lobe) or death due to any cause, whichever occurs first. Participants with local progression prior to such an event are censored on the date of local progression. Participants with no post-baseline tumor assessment and alive at last follow-up are censored on the date of randomization. Participants alive without distant metastasis, failures in a different lung lobe, or local progression are censored on the date of their last evaluable radiographic tumor assessment. DMFS rates and median DMFS time are estimated using the Kaplan-Meier method.
Time frame: Randomization to DMFS event or local progression, whichever occurs first, or last tumor assessment if alive. Median follow-up at the time of analysis was 23.8 months.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Distant Metastases-free Survival (DMFS) | 13.0 months |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Distant Metastases-free Survival (DMFS) | 16.8 months |
95% CI: [0.76, 1.2]
Secondary
Molecular Subtyping
Time frame: Up to 5 years
Secondary
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: Randomization to last follow-up. Median follow-up at the time of analysis was 23.8 months.
Population: Adverse event population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | None reported | 4 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 1 | 3 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 2 | 8 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 3 | 56 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 4 | 182 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 5 | 4 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | None reported | 210 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 1 | 19 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 2 | 11 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 3 | 14 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 4 | 3 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 5 | 0 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | None reported | 4 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 1 | 3 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 2 | 8 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 3 | 57 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 4 | 181 Participants |
| Arm I (Chemotherapy, Radiation Therapy) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 5 | 4 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 1 | 0 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | None reported | 0 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 3 | 31 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 1 | 0 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 5 | 20 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 2 | 9 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 4 | 12 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 3 | 63 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 2 | 10 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 4 | 168 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 5 | 4 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Overall | Grade 5 | 24 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 4 | 168 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | None reported | 125 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | None reported | 0 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 1 | 29 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Non-Immune-Mediated | Grade 3 | 66 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Number of Participants by Highest Grade Adverse Event Reported | Immune-mediated | Grade 2 | 63 Participants |
Secondary
Percentage of Participants With Confirmed Objective Response (Objective Response Rate (ORR))
Objective response rate (ORR) is defined as the proportion of subjects whose best overall response (BOR) is a confirmed complete or partial response as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 on two consecutive occasions ≥4 weeks apart.
Time frame: Randomization to last radiographic tumor assessment. Median follow-up at the time of analysis was 23.8 months.
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Percentage of Participants With Confirmed Objective Response (Objective Response Rate (ORR)) | 59.6 percentage of participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Percentage of Participants With Confirmed Objective Response (Objective Response Rate (ORR)) | 60.2 percentage of participants |
Secondary
Percentage of Participants With Local Progression
Local progression is defined as intrathoracic tumor progression (failure in the lobe of the primary tumor or mediastinal lymph nodes) by RECIST 1.1 criteria determined by the investigator. Local progression rates are estimated by the cumulative incidence method, treating non-local progression (i.e., distant metastasis or failure in a different lung) and death without local progression as competing risks, and otherwise censoring participants alive at last tumor assessment. Treatment effect comparisons will utilize a cause-specific hazard function in which competing risks are censored.
Time frame: From randomization to local progression, other progression, or death, whichever occurs first, or last tumor assessment if alive. Median follow-up at the time of analysis was 23.8 months. 1-, 2-, and 3-year rates are reported.
Population: Intent-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Percentage of Participants With Local Progression | 1 year | 10.1 percentage of participants |
| Arm I (Chemotherapy, Radiation Therapy) | Percentage of Participants With Local Progression | 2 years | 14.3 percentage of participants |
| Arm I (Chemotherapy, Radiation Therapy) | Percentage of Participants With Local Progression | 3 years | 14.3 percentage of participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Percentage of Participants With Local Progression | 1 year | 8.1 percentage of participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Percentage of Participants With Local Progression | 2 years | 12.8 percentage of participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Percentage of Participants With Local Progression | 3 years | 12.8 percentage of participants |
95% CI: [0.52, 1.41]
Secondary
Percent of Participants With Deterioration in Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI)
FACT-TOI is a measure of 21 items that sums 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) quality of life (QOL) instrument. The FACT-TOI total score ranges from 0 to 84 with higher scores indicating better quality of life and functioning. Clinically meaningful decline is defined as a decrease from baseline of at least 5 points.
Time frame: Baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization)
Population: Intent-to-treat participants with FACT-TOI at baseline and 15 months after completion of chemoradiation (approximately 18 months after randomization).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Percent of Participants With Deterioration in Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) | 33 Participants |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Percent of Participants With Deterioration in Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) | 39 Participants |
Secondary
Progression Free Survival (PFS)
PFS failure event is defined as progressive disease (PD) determined by investigator per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause. PD is defined as at least a 20% increase in the sum of longest diameters of target lesions, and an absolute increase of at least 5 mm. The appearance of any new lesions is also considered progression. PFS rates and median PFS time are estimated using the Kaplan-Meier method, censoring participants alive without progression at the date of their last evaluable radiographic tumor assessment.
Time frame: From randomization to progression or death due to any cause, whichever occurs first, or last tumor assessment if alive. MMedian follow-up at the time of analysis was 23.8 months.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Progression Free Survival (PFS) | 11.4 months |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Progression Free Survival (PFS) | 12.1 months |
95% CI: [0.8, 1.21]Log Rank
Secondary
Quality-adjusted Survival Months
Quality-adjusted survival is calculated as the sum of weighted time intervals. Weight is the EuroQol 5-dimensional 5-level (EQ-5d-5L) index score, which measures health-related quality of life and ranges from 0 (death) to 1 (full health).
Time frame: Baseline to death, last follow-up or two years, whichever occurs first.
Population: Eligible participants with baseline EQ-5D-5L index score and at least one follow-up EQ-5D-5L index score.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Chemotherapy, Radiation Therapy) | Quality-adjusted Survival Months | 16.9 months |
| Arm II (Chemotherapy, Radiation Therapy, Atezolizumab) | Quality-adjusted Survival Months | 17.3 months |
Other Pre-specified
Concordance Between Tumor and Circulating Cell Free Deoxyribonucleic Acid (cfDNA) Molecular Subtypes
The concordance between molecular subtypes obtained via ribonucleic acid sequencing (RNAseq) on tumor tissue and methylation analysis on cfDNA will be assessed among patients who have both evaluable RNAseq and methylation results, where Cohen's Kappa and corresponding 95% confidence interval will be reported. In addition, the sensitivity and specificity of dichotomized cfDNA molecular subtypes (considering RNAseq as reference standard), along with the associated 95% confidence intervals, will be reported. Spearman rank correlation and associated 95% confidence intervals based on bootstrap between RNAseq and methylation will be reported.
Time frame: Up to 5 years
Other Pre-specified
Patient-reported Symptomatic Toxicities
Will be measured by Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be summarized for the worst score experienced by the patient by treatment arm.
Time frame: Up to 15 months after completion of chemoradiation therapy
Other Pre-specified
Treatment Effect by Ethnicity
Estimates of the primary outcome treatment effect and the corresponding 95% CIs by ethnicity will be provided.
Time frame: Up to 5 years
Other Pre-specified
Treatment Effect by Race
Estimates of the primary outcome treatment effect and the corresponding 95% CIs by race will be provided.
Time frame: Up to 5 years
Other Pre-specified
Treatment Effect by Sex
Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals by sex will be provided.
Time frame: Up to 5 years