Comparing Impact of Treatment Before or After Surgery in Patients With Stage II-IIIB Resectable Non-small Cell Lung Cancer

Phase 3

Recruiting

• Conditions: Resectable Lung Non-Small Cell Carcinoma; Stage II Lung Cancer AJCC v8; Stage IIIA Lung Cancer AJCC v8; Stage IIIB Lung Cancer AJCC v8
• Interventions: Procedure: Surgical Procedure; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Drug: Gemcitabine; Drug: Docetaxel; Drug: Vinorelbine; Drug: Nivolumab; Drug: Pembrolizumab; Drug: Atezolizumab; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography

• Registration Number: NCT06632327
• Lead Sponsor: Alliance for Clinical Trials in Oncology

Brief Summary

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.

Detailed Description

The primary and secondary objectives of the study:

PRIMARY OBJECTIVE:

I. To compare the 3-year real-world event-free survival (rwEFS) rate and overall survival (OS) between perioperative and adjuvant immunotherapy-based treatment for patients with resectable non-small cell lung cancer (dual endpoints).

SECONDARY OBJECTIVES:

I. To compare the rates of surgical resection between the two arms. II. To compare the rates of complete resection (R0) between the two arms. III. To summarize and compare rates of adverse events (AEs) resulting in permanent treatment discontinuation, hospitalization, or death between the two arms.

IV. To evaluate the association between locally defined pathological complete response (pCR) and rwEFS in patients randomized to the perioperative arm (arm 2).

V. To compare the rwEFS post 3-years from randomization between the two arms among patients who do not experience an event by 3 years.

EXPLORATORY OBJECTIVES:

I. To compare outcomes according to the systemic therapy administered on each arm.

II. To compare the sites of relapse between the two treatment arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1:

SURGERY: Patients undergo surgery within 28 days of registration.

ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines.

ARM 2:

NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines.

SURGERY: Patients undergo surgery.

ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines.

Patients also undergo computed tomography (CT) throughout the study and may undergo magnetic resonance imaging (MRI) and/or positron emission tomography (PET)/CT at screening.

After completion of study treatment, patients are followed up every 6 months for up to 10 years.

Study Timeline

• Study First Submitted: 2024-10-07
• Study First Submitted QC: 2024-10-07
• Study First Posted: 2024-10-09
• Study Start: 2024-12-11
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-24
• Last Update Posted: 2025-06-27
• Primary Completion: 2029-04-30
• Study Completion: 2030-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1100

Inclusion Criteria

• 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)

  * Note: Patients with resectable stage N2a or T4 are eligible, but patients with stage N2b or N3 are not eligible. Patients with known EGFR or ALK alterations are excluded

• 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

• No treatment for another malignancy within 3 years prior to registration, except for stage 1 or 2 cancers treated for curative intent; patients must be disease free for one year prior to registration. Patients with non-melanoma skin cancer, urothelial carcinoma in situ (Tis), noninvasive papillary carcinoma of the urinary bladder (Ta), prostatic intraepithelial neoplasia (PIN), ductal carcinoma in situ (DCIS) of the breast, or cervical intraepithelial neoplasia (CIN) of the uterine cervix are also eligible

• No active autoimmune disease, interstitial lung disease, or transplant that precludes safe treatment with immune checkpoint inhibitors

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 (surgery, adjuvant therapy)	Surgical Procedure	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Cisplatin	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Carboplatin	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Computed Tomography	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Magnetic Resonance Imaging	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Positron Emission Tomography	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Surgical Procedure	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Computed Tomography	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Magnetic Resonance Imaging	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Positron Emission Tomography	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Gemcitabine	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Docetaxel	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Pemetrexed	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Vinorelbine	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Nivolumab	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Pembrolizumab	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 1 (surgery, adjuvant therapy)	Atezolizumab	SURGERY: Patients undergo surgery within 28 days of registration. ADJUVANT THERAPY: Patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles and immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Cisplatin	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Carboplatin	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Gemcitabine	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Docetaxel	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Vinorelbine	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Pemetrexed	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Nivolumab	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Pembrolizumab	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.
Arm 2 (neoadjuvant therapy, surgery, adjuvant therapy)	Atezolizumab	NEOADJUVANT THERAPY: Within 28 days of registration, patients receive platinum-based doublet chemotherapy (cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and/or vinorelbine) for up to 4 cycles in combination with immune checkpoint inhibitor (nivolumab, pembrolizumab, and/or atezolizumab) according to current approved guidelines. SURGERY: Patients undergo surgery. ADJUVANT THERAPY: Patients receive immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, and/or atezolizumab) for up to 1 year in the absence of disease progression or unacceptable toxicity according to current approved guidelines. Patients also undergo CT throughout the study and may undergo MRI and/or PET/CT at screening.

Primary Outcome Measures

Name	Time	Method
Overall survival (OS)	From randomization until death from any cause, assessed up to 10 years	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.
3-year real-world event-free survival (rwEFS)	From the date of randomization to the date of the first of the following events: failure to undergo resection for any reason, recurrence or progression at any time after surgery, or death from any cause, assessed at 3 years	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.

Secondary Outcome Measures

Name	Time	Method
Rates of surgical resection	Up to 10 years.	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)	Up to 10 years.	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)	Up to 10 years.	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)	Up to 10 years	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.

Trial Locations

Locations (327)

Cancer Center at Saint Joseph's; 🇺🇸 Phoenix, Arizona, United States

Mayo Clinic Hospital in Arizona; 🇺🇸 Phoenix, Arizona, United States

Mission Hope Medical Oncology - Arroyo Grande; 🇺🇸 Arroyo Grande, California, United States

Mercy Cancer Center - Carmichael; 🇺🇸 Carmichael, California, United States

Mercy San Juan Medical Center; 🇺🇸 Carmichael, California, United States

Mercy Cancer Center - Elk Grove; 🇺🇸 Elk Grove, California, United States

UC San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

Mercy Cancer Center; 🇺🇸 Merced, California, United States

Mercy Cancer Center - Rocklin; 🇺🇸 Rocklin, California, United States

Mercy Cancer Center - Sacramento; 🇺🇸 Sacramento, California, United States

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