Chapter 2 30 Methods Patient enrollment and study endpoints In this study, 164 stage IV NSCLC patients were identified from two independent cohorts who started second or later line monotherapy with nivolumab (n=128) or pembrolizumab (n=36) between March 2015 and April 2018 at the Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), The Netherlands. All patients had pathologically confirmed stage IV NSCLC. Absence of sensitizing EGFR mutations or ALK translocations was confirmed in 145 patients, while in 19 patients the mutation status was unknown. Patients received single agent nivolumab 3 mg/ kg, administered as an IV infusion, every two weeks for at least one dose or single agent pembrolizumab 200 mg as an IV infusion every 3 weeks. Nivolumab was provided within the Expanded Access Programme (EAP) from Bristol Myers Squibb or in regular care after the drug was registered. Pembrolizumab treated patients were part of the control arm in the PEMBRO-RT study (NCT02492568)17. Patients were randomized into a training and validation set. Randomization was stratified by type of treatment (nivolumab vs pembrolizumab) and treatment outcome at 6 months. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used to assess efficacy. Patients with progressive disease (PD) who were not evaluable for response by RECIST were determined by the treating physician as PD. Disease Control (DC) (complete response (CR)/partial response (PR) or stable disease (SD)) at 6 months following initiation of treatment was used as the primary clinical outcome measure. We assessed DC at 12 months (CR/PR/SD that lasted ≥12 months), progression-free survival (PFS) and overall survival (OS) as secondary outcome measures to predict long-term efficacy to PD-1 blockade. PFS and OS were defined as the time from the date of initiation of treatment with PD-1 blockade to the date of progression or death (for PFS) or death (for OS). Patients who had not progressed or died were censored at the date of their last follow-up. Pretreatment formalin-fixed paraffin embedded (FFPE) tumor tissue samples were collected from all patients. Written informed consent was obtained from all patients 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 Research Board of NKI (CFMPB586). 44 patients (27%) were excluded based on the following criteria: samples contained less than 10,000 cells in the tumor area on a single cross-sectional slide (n=15), were obtained more than 2 years before start of PD-1 blockade (n=14), were obtained from endobronchial lesions (n=8), contained normal lymphoid
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