Serum test identifies patients deriving benefit from CPIs 175 5 Methods Patient cohorts and sample sets Pretreatment serum samples, collected within one month of immunotherapy initiation, were available from four cohorts of patients. The development set consisted of 116 samples from patients treated at the Netherlands Cancer Institute between May 2015 and March 2017. Validation set 1 consisted of 98 samples from patients treated at Vrije Universiteit Medical Center or Netherlands Cancer Institute between June 2015 and July 2018. Validation set 2 comprised samples from 75 patients treated at Erasmus University Medical Centre in Rotterdam between April 2016 and July 2017. Patients, identified according to criteria established in the phase 3 trials demonstrating benefit for nivolumab over docetaxel10,11, received nivolumab 3mg/kg, administered as an intravenous infusion, every 2 weeks, for advanced NSCLC after platinum containing chemotherapy as part of routine clinical care. Patients in the development cohort and validation set 2 were treated in second line. Validation set 1 contained 58 patients treated in second line and 40 patients treated in higher lines. The cohorts comprised all patients in the respective institutions who provided pretreatment serum samples available for analysis, were eligible for immunotherapy as routine care, and who received at least one dose of nivolumab. Response to treatment was evaluated according to RECIST v1.1 every 6 weeks for the first 12 weeks and every three months thereafter. In addition, a fourth cohort of pretreatment serum samples (chemotherapy cohort) had been collected from patients with advanced NSCLC treated in second line with chemotherapy while enrolled in a clinical trial (NCT00989690)12. Samples were available for 68 of the 74 patients who received docetaxel (75mg/m2 every 21 days) in this study. Trial inclusion and exclusion criteria have been published elsewhere12. All samples were obtained in the context of biobanking protocols or a clinical trial for which institutional review board approval was sought and obtained. All patients provided written informed consent according to local ethical standards and adhered to standards set out in the Declaration of Helsinki. Progression free survival (PFS) was measured from start of treatment until progression of disease, death or loss to follow up. Overall survival (OS) was defined as time from start of therapy until death or loss to follow up. PD-L1 immunohistochemistry Tumor PD-L1 expression scoring was performed according to the instruction manual of the qualitative immunohistochemical assay developed as a complementary diagnostic tool for nivolumab (PD-L1 IHC 22C3 pharmDx, Dako, Carpinteria, CA). PD-L1 expression levels were determined by observing complete circumferential or partial linear expression (at any intensity) of PD-L1 on the plasma cell membrane of
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