Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 8, Issue 2, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2020-001282
Keywords
immunotherapy; lung neoplasms; tumor microenvironment; clinical trials as topic; tumor biomarkers
Categories
Funding
- National Institutes of Health [CA121113, CA006973, CA180950, CA233259, T32 CA193145, T32 CA009071-38, R01 CA142779]
- Stand Up To Cancer - CRI Immunology Dream Team [SU2C-AACR-DT1012]
- Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team
- Bristol-Myers Squibb International Immuno-Oncology Network
- Conquer Cancer: The ASCO Foundation - Young Investigator Award [90083528]
- LUNGevity Foundation
- V Foundation
- Lung Cancer Foundation of America
- MacMillan Foundation
- Eastern Cooperative Oncology Group-American College of Radiology Imaging Network
- Swim Across America
- Allegheny Health Network - Johns Hopkins Research Fund
- Maryland Department of Health and Mental Hygiene Cigarette Restitution Fund Program
- Commonwealth Foundation
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Memorial Sloan Kettering Cancer Center [P30 CA008748]
- Johns Hopkins University Cancer Center [P30 CA006973]
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Background We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Methods Patients with resectable stage IB (>= 4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naive NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. Results While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade >= 3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. TumorKRAS/STK11co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumorKRAS/STK11/KEAP1co-mutations. Conclusions Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.
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