Clinical Efficacy and Biomarker Analyses in Patients Receiving Adjuvant Checkpoint Blockade for Resected High-Risk Stages III/IV Melanoma
Jeffrey. S Weber1, David Woods1, Heinrich Roder2 1Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA; 2Biodesix, Inc., Boulder, CO, USA
PD-1 blocking antibodies were initially found effective for metastatic melanoma and are now approved for a variety of cancers. Recent data have shown that the PD-1 blocking antibody nivolumab is also effective as adjuvant treatment for resected high-risk melanoma, and prolonged relapse-free survival compared to the active control of ipilimumab. A variety of biomarkers in peripheral blood were tested to assess their utility to predict outcome in resected patients treated with adjuvant nivolumab. Non-relapsing resected melanoma patients treated with nivolumab had reduced Treg suppressive capacity post-treatment, but displayed an increase in the proportion of circulating Tregs. Differential changes in gene expression post-nivolumab were observed in Tregs versus conventional CD4+ T-cells and based on patient outcome; proliferation pathways were increased in non-relapsing but not in relapsing patient Tregs. Increased phosphorylated-STAT3 (pSTAT3) expression was also observed in Tregs from non-relapsing patients, but not in relapsing patients. Increased pSTAT3 was also observed in patients with metastatic disease responding to nivolumab therapy, and was positively associated with overall survival. A mass spectrometry analysis was also performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pre-treatment serum was obtained from melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for 'sensitive' relative to 'resistant' patients, HR = 0.15 (95% CI: 0.06-0.40), P < 0.001). Outcome was associated with acute phase reactant, complement and wound healing pathways. A pre-treatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies.
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