A PD-1T signature as clinical applicable biomarker in NSCLC 133 4 Methods Patient cohorts and study endpoints In this study, 152 stage IV NSCLC patients were included that all started second or later line monotherapy with nivolumab. Patients with tumors harboring known sensitizing EGFR mutations or ALK translocations were excluded. A total of 115 patients received PD-1 blockade therapy since March 2015 at the Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), The Netherlands, and were split in a training (n=94) and validation cohort (n=21). 37 patients from the CERTIM (Immunomodulatory Therapies Multidisciplinary Study Group) treated since July 2015 at Cochin University hospital, France13 were pooled with the validation cohort (Fig. 1). All patients received nivolumab, administered per label as a single agent. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used to determine the objective response. Patients treated at NKI-AVL, who were not evaluable for response assessment according to RECIST, were determined as progressive disease (PD) by the treating physician. Disease Control (DC) status (complete response (CR)/ partial response (PR) or stable disease (SD)) at 12 months after treatment initiation was used as the primary clinical outcome measure. Progression-free survival (PFS) and overall survival (OS) were used as secondary outcome measures. PFS and OS were defined as the time from the date of initiation of PD-1 blockade treatment to the date of progression (for PFS) or death (for OS). Patients who had not progressed or died were censored at the date of their last follow-up. RNA or gene expression data derived from pretreatment archival formalin-fixed paraffin embedded (FFPE) tumor tissue samples were collected from the cohorts. Written informed consent was obtained from all patients treated at NKI-AVL for research usage of material not required for diagnostic use by institutionally implemented opt-out procedure. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of NKI (CFMPB586). Gene expression data of the CERTIM cohort was used from Damotte et al., a study that was previously approved by the ethics committee (CPP Ile de France II, no. 2008-33, 2012 06-12, 2018 MS1) in agreement with article L.1121-1 of the French law13. In the NKI-AVL training cohort (n=94), 28 samples were excluded based on low RNA yield and/or low RNA quality. Eight additional samples were excluded due to quality control failure in the Nanostring nCounter profiling assay (Nanostring) (Fig. 1). Eight samples in the NKI-AVL validation cohort and 6 samples in the CERTIM cohort were excluded because these were obtained 2 years or more before start of PD-1 blockade. Two additional samples in the NKI-AVL validation cohort were
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