This phase II trial studies how well nivolumab works when given alone and in combination with ipilimumab or chemotherapy in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin, docetaxel, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with ipilimumab or chemotherapy may work better in treating patients with non-small cell lung cancer compared to chemotherapy alone.
PRIMARY OBJECTIVE: I. To determine the major pathologic response rate (MPRR) in patients treated with induction nivolumab, nivolumab plus ipilimumab, and nivolumab plus platinum-based chemotherapy. SECONDARY OBJECTIVES: I. Toxicity (assessed by the National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 4). II. Peri-operative morbidity and mortality. III. CD8 positive (+) tumor infiltrating lymphocytes (TILs) in resected tumor tissues of patients treated with nivolumab alone and nivolumab plus ipilimumab and nivolumab plus platinum-based chemotherapy. IV. Quantification of CD8+ TILs will be assessed by counting the cells positive for staining with an anti-CD8 antibody by immunohistochemistry in five random square areas (1 mm\^2 each) in both intratumoral and peritumoral compartments using the automated Aperio system. V. Response rates to induction treatment (by Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1). VI. Recurrence-free survival. VII. Overall survival. VIII. To correlate major pathologic response with recurrence-free and overall survival. IX. Complete resection (R0) rate. X. Pathologic complete response (pCR) in resected tumor specimens. XI. To correlate response assessed by imaging studies with outcomes (both major pathologic response to treatment and long-term recurrence-free survival). XII. To correlate blood, tissue, and stool-based biomarkers with efficacy and toxicity. EXPLORATORY OBJECTIVES: I. To identify novel prognostic and predictive markers present at diagnosis. II. To determine modulation of markers by induction immunotherapy and/or immunotherapy plus platinum-based chemotherapy in order to inform future translational studies. OUTLINE: Patients are randomized to Arms A and B and enrolled in Arm C or D after completion of enrollment to Arms A and B. ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive nivolumab as in Arm A and receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive ipilimumab IV over 90 minutes on day 1, nivolumab IV over 30 minutes on days 1, 22, and 43, and cisplatin (or carboplatin) IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. After completion of study treatment and surgery, patients are followed up at 8 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
101
Given IV
Given IV
Given IV
Given IV
Given IV
Given IV
M D Anderson Cancer Center
Houston, Texas, United States
Major Pathologic Response (mPR)
The percentage of viable tumor cells was averaged across all reviewed tumor slides from the lung resection specimen. The specimen was reviewed by two pathologists and average score was used. Tumors with ≤ 10% of viable tumor cells were considered to have undergone MPR. Patients who did not have surgery was considered to be no MPR.
Time frame: The lung resection specimen was collected at surgery.
Pathologic Complete Response (pCR)
The percentage of viable tumor cells was averaged across all reviewed tumor slides from the lung resection specimen. The specimen was reviewed by two pathologists and average score was used. Tumors with 0% of viable tumor cells were considered to have undergone pCR. Patients who did not have surgery was considered to be no pCR.
Time frame: The lung resection specimen was collected at surgery.
Radiographic Response
Radiographic response to induction treatment was assessed by RECIST version 1.1
Time frame: Reassessment after induction therapy
Overall Survival (OS)
Overall survival was defined as the time from randomization (in Arm A and Arm B) or treatment initiation (in Arm C and Arm D) to the time of death from all causes or to the time of last follow-up.
Time frame: In Arms A and B, the cutoff date was 2020-2-25. The median follow-up time frame was 22.2 months. In Arms C and D, the cutoff date was 2022-7-18. The median follow-up time frames were 39.2 and 24.0 months respectively
Event-free Survival (EFS)
EFS was defined as the time from randomization (in Arm A and Arm B) or treatment initiation (in Arm C and Arm D) to any progression of primary lung cancer precluding planned surgery, any progression or recurrence (as assessed by imaging and/or histopathologically) of primary lung cancer after surgery, any progression of primary lung cancer in patients without surgery or death from all causes or to the time of last imaging.
Time frame: In Arms A and B, the cutoff date was 2020-2-25. The median follow-up time frame was 22.2 months. In Arms C and D, the cutoff date was 2022-7-18. The median follow-up time frames were 39.2 and 24.0 months respectively.
Residual Tumor Classification
The residual tumor (R) classification measures how well the lung tumor was removed by surgery in the anatomic extent. R0 means a complete resection. R1 means a macroscopically complete resection but with microscopic tumor at the surgical margin. R2 means a resection that leaves gross tumor behind. R0 resection is a better surgical outcome than R1, R2 resections and R2 is the worst surgical outcome. The number of R0, R1 and R2 resections were reported among the patients who underwent surgery.
Time frame: At surgery
30-day Postoperative Complication
The number of patients who had complications including pulmonary, cardiac, gastrointestinal, genitourinary, neurological, and wound within 30 days after surgery
Time frame: Within 30 days after surgery
90-day Mortality
The number of patients who died within 90 days after surgery
Time frame: Within 90 days after surgery
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