This phase III trial compares standard therapy given after surgery (adjuvant) to standard therapy given before and after surgery (perioperative) in treating patients with stage II-IIIB non-small cell lung cancer (NSCLC) that can be removed by surgery (resectable). The usual approach for patients with resectable NSCLC is chemotherapy and/or immunotherapy before surgery, after surgery, or both before and after surgery. This study is being done to find out which approach is better at treating patients with lung cancer. Treatment will be administered according to the current standard of care at the time of enrollment. Chemotherapy options may include cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and vinorelbine at standard doses according to the treating physician. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. 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 tumor cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Docetaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Other chemotherapy drugs, such as vinorelbine, 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 . Immunotherapy with monoclonal antibodies, such as nivolumab, pembrolizumab, and atezolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with chemotherapy and immunotherapy prior to surgery and continuing treatment after surgery may be a more effective treatment option than adjuvant therapy alone in patients with stage II-IIIB resectable NSCLC.
Histologically or cytologically confirmed surgically resectable stage IIA to IIIB NSCLC according to the American Joint Committee on Cancer (AJCC) 9th edition (stage IIA to IIIB NSCLC up to single station N2, according to the AJCC 8th edition)
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (or Karnofsky ≥ 60%)
No prior systemic treatment for NSCLC within 5 years except stage 1 and 2 cancers treated with curative intent
None
Parallel
Surgical Procedure
Procedure/Surgeryundergo surgery
Cisplatin
DrugGive cisplatin
Carboplatin
DrugGive Carboplatin
Pemetrexed
DrugGive Pemetrexed
Gemcitabine
DrugGive Gemcitabine
Docetaxel
DrugGive Docetaxel
Vinorelbine
DrugGive Vinorelbine
Nivolumab
DrugGive Nivolumab
Pembrolizumab
DrugGive Pembrolizumab
Atezolizumab
DrugGive Atezolizumab
Computed Tomography
Procedure/SurgeryUndergo CT and/or PET/CT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
3-year real-world event-free survival (rwEFS)
Time to event analyses will be summarized using the Kaplan-Meier method, where both the stratified and unstratified log-rank test will be used to compare the distributions across the treatment arms. For the primary analysis of 3-year rwEFS rate, we will compare the rwEFS curves at 3 years, using the difference in Kaplan-Meier estimates for the survival functions. The test statistic will be derived from the difference in the estimated Kaplan-Meier values between two arms at 3 years, using the Greenwood estimate of the variances. rwEFS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. The comparison of the rwEFS post 3-years between the two arms among patients who do not experience an event by 3 years, will involve assessing the probability of a longer rwEFS on the perioperative arm. Non-parametric estimation and inference methods will be used for analysis.
Overall survival (OS)
Time to event analyses will be summarized using the Kaplan-Meier method, where both the stratified and unstratified log-rank test will be used to compare the distributions across the treatment arms. OS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals.
Rates of surgical resection
Rates of resection will be tabulated and compared between the arms using chi-square tests or Fisher's exact tests. Univariable Cox models stratified by the stratification factors used in the randomization will be used to understand the impact of baseline covariates, resection status and systemic treatments on outcomes.
Rates of complete resection (R0)
Rates of R0 resection will be tabulated and compared between the arms using chi-square tests or Fisher's exact tests. Univariable Cox models stratified by the stratification factors used in the randomization will be used to understand the impact of baseline covariates, resection status and systemic treatments on outcomes.
Incidence of adverse events (AEs)
Adverse events will be recorded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for each patient. Frequency tables and summary statistics will be used to determine the overall patterns within and across the arms.
Pathological complete response (pCR)
Pathologic complete response is defined as having no viable invasive cancer in the lung and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) based on guidelines published by National Comprehensive Cancer Network and International Association for the Study of Lung Cancer. Cox regression models will be used to evaluate the association between pCR and rwEFS in perioperative arm (arm 2). The hazard ratio and corresponding 95% confidence interval will be reported. Multivariable landmark and time dependent models will be subsequently explored.
Estimates of treatment effect by sex
Estimates of 3-year rwEFS rates and hazard ratio for OS and the corresponding 95% confidence intervals (CIs) will be evaluated by sex.
Estimates of treatment effect by race
Estimates of 3-year rwEFS rates and hazard ratio for OS and the corresponding 95% confidence intervals (CIs) will be evaluated by race.
Estimates of treatment effect by ethnicity
Estimates of 3-year rwEFS rates and hazard ratio for OS and the corresponding 95% confidence intervals (CIs) will be evaluated by ethnicity.
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Alliance for Clinical Trials in Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
