Neoadjuvant Immunotherapy in Resectable Non-Small Cell Lung Cancer

Methodology and Study Progress

An uncontrolled pilot study was conducted in a total of 22 adult patients with previously untreated, surgically resectable early-stage NSCLC (stage I, II or IIIA) at 2 oncology centers in the USA. The primary objective of the study was safety and feasibility. Also assessed were tumor pathological response, expression of the PD-1 receptor ligand (PD-L1), mutational load, and mutation-related neoantigen-specific T-cell response.

Nivolumab was administered intravenously at a dose of 3 mg/kg body weight once every 2 weeks, and surgical tumor resection was planned approximately 4 weeks after the first dose.

Results

Neoadjuvant nivolumab had an acceptable side-effect profile and its administration did not lead to delays in surgical procedures. Of the 21 tumors removed, 20 were completely resected.

Significant response confirmed by a pathologist, i.e., the presence of < 10% viable tumor cells in the tumor tissue sample, was observed in 9 out of 20 resected tumors (45%). Responses occurred in both PD-L1 positive and negative tumors. There was a significant correlation between the extent of tumor mutational load and a good response confirmed by a pathologist.

Systemic increases in T lymphocyte clones were observed both in the tumor and peripheral blood after PD-1 blockade in 8 out of 9 evaluated patients. In patients with a primary tumor showing complete response, a rapid expansion of mutation-associated neoantigen-specific T lymphocyte clones originating from the primary tumor was observed in peripheral blood 2-4 weeks after treatment administration. Some of these clones were not detected before nivolumab administration.

Combined Neoadjuvant Therapy

Based on the promising results of this study, the investigative team decided to test a combination of nivolumab and ipilimumab, which had shown good results in clinical studies in patients with advanced NSCLC. The evaluation was to include 15 previously untreated patients with histologically confirmed resectable NSCLC in stages IB-IIIA, who were to receive ipilimumab in combination with nivolumab approximately 6 weeks before the planned tumor resection, as well as 2 doses of nivolumab (approximately 4 and 2 weeks before the procedure). Therapy was administered to 9 patients, 6 of whom experienced treatment-related adverse events. Researchers decided to terminate the study prematurely due to excessive toxicity.

Tumor resection was performed in 6 patients, 2 of whom achieved complete response to treatment according to pathological evaluation and were disease-free 24 months post-surgery. Tumor pathological response correlated with PD-L1 expression but not with tumor mutational load.

Conclusion

Neoadjuvant nivolumab exhibited a good safety profile in patients with early-stage NSCLC and induced a good pathological response in 45% of resected tumors. Tumor mutational load was a predictive factor of response to nivolumab monotherapy.

Addition of ipilimumab to the neoadjuvant regimen was feasible according to the proposed protocol. Long-term outcomes for patients who achieved complete pathological response appear promising; however, the safety profile of the combined treatment was not favorable. The potential use of this therapy thus depends on finding reliable biomarkers to identify patients who will benefit from this modality.

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Sources:
1. Forde P. M., Chaft J. E., Smith K. N. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018; 378 (21): 1976−1986, doi: 10.1056/NEJMoa1716078.
2. Reuss J. E., Anagnostou V., Cottrell T. R. et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J Immunother Cancer 2020; 8 (2): e001282, doi: 10.1136/jitc-2020-001282.