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Neoadjuvant PD-1 Blockade in Resectable Lung Cancer
Patrick M Forde1, Jamie E Chaft1, Kellie N Smith1
1From the Bloomberg-Kimmel Institute for Cancer Immunotherapy and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (P.M.F., K.N.S., V.A., T.R.C., M.Z., S.C.Y., S.B., R.J.B., J.N., K.A.M., F.V., H.G., J.Z., J.X.C., H.Y.C., J.-W.S., R.B.S., J.W., E.G., H.W., G.L.R., J.M.T., V.E.V., S.L.T., J.R.B., D.M.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (J.E.C., M.D.H., D.R.J., M.J.V., N.R., Z.O., V.R., J.D.W., T.M.) and the Ludwig Collaborative (J.D.W., T.M.) - all in New York; the Parker Institute for Cancer Immunotherapy, San Francisco (J.D.W., T.M.); and Swim Across America Laboratory, Charlotte, NC (J.D.W., T.M.).
Background:
Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.
Methods:
In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.
Results:
Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.
Conclusions:
Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).
Insights
Neoadjuvant nivolumab shows promise for early non-small-cell lung cancer (NSCLC). This treatment was safe, feasible, and induced significant pathological responses in 45% of patients, regardless of PD-L1 status.
Area of Science:
- Oncology
- Immunotherapy
- Surgical Oncology
Background:
- Programmed death 1 (PD-1) inhibitors improve survival in advanced non-small-cell lung cancer (NSCLC).
- Limited progress has been made in treating resectable NSCLC over the past decade.
- The efficacy of PD-1 blockade in resectable NSCLC has not been previously investigated.
Purpose of the Study:
- To assess the safety and feasibility of neoadjuvant PD-1 inhibitor nivolumab in patients with resectable NSCLC.
- To evaluate the pathological response to neoadjuvant nivolumab.
- To explore the relationship between tumor mutational burden, PD-L1 expression, and T-cell responses following PD-1 blockade.
Main Methods:
- Pilot study administering two preoperative doses of nivolumab (3 mg/kg) every 2 weeks to adults with resectable early-stage NSCLC.
- Surgery was planned approximately 4 weeks after the first dose.
- Evaluated safety, feasibility, tumor pathological response, PD-L1 expression, mutational burden, and T-cell responses.
Main Results:
- Neoadjuvant nivolumab demonstrated an acceptable side-effect profile and did not delay surgery.
- A major pathological response was observed in 45% (9 of 20) of resected tumors, irrespective of PD-L1 expression.
- A significant correlation was found between pathological response and pretreatment tumor mutational burden.
- PD-1 blockade led to systemic expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.
Conclusions:
- Neoadjuvant nivolumab is safe and feasible for resectable NSCLC, inducing significant pathological responses.
- Tumor mutational burden is a predictive biomarker for pathological response to PD-1 blockade.
- Nivolumab treatment stimulates systemic T-cell responses against neoantigens.
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