Abstract
BackgroundImmune checkpoint therapies (ICTs) targeting the programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) pathway have improved outcomes for patients with non-small cell lung cancer (NSCLC), particularly those with high PD-L1 expression. However, the predictive value of manual PD-L1 scoring is imperfect and alternative measures are needed. We report an automated image analysis solution to determine the predictive and prognostic values of the product of PD-L1+ cell and CD8+ tumor infiltrating lymphocyte (TIL) densities (CD8xPD-L1 signature) in baseline tumor biopsies.MethodsArchival or fresh tumor biopsies were analyzed for PD-L1 and CD8 expression by immunohistochemistry. Samples were collected from 163 patients in Study 1108/NCT01693562, a Phase 1/2 trial to evaluate durvalumab across multiple tumor types, including NSCLC, and a separate cohort of 199 non-ICT- patients. Digital images were automatically scored for PD-L1+ and CD8+ cell densities using customized algorithms applied with Developer XD™ 2.7 software.ResultsFor patients who received durvalumab, median overall survival (OS) was 21.0 months for CD8xPD-L1 signature-positive patients and 7.8 months for signature-negative patients (p = 0.00002). The CD8xPD-L1 signature provided greater stratification of OS than high densities of CD8+ cells, high densities of PD-L1+ cells, or manually assessed tumor cell PD-L1 expression ≥25%. The CD8xPD-L1 signature did not stratify OS in non-ICT patients, although a high density of CD8+ cells was associated with higher median OS (high: 67 months; low: 39.5 months, p = 0.0009) in this group.ConclusionsAn automated CD8xPD-L1 signature may help to identify NSCLC patients with improved response to durvalumab therapy. Our data also support the prognostic value of CD8+ TILS in NSCLC patients who do not receive ICT.Trial registrationClinicalTrials.gov identifier: NCT01693562.Study code: CD-ON-MEDI4736-1108.Interventional study (ongoing but not currently recruiting).Actual study start date: August 29, 2012.Primary completion date: June 23, 2017 (final data collection date for primary outcome measure).
Highlights
Immune checkpoint therapies (ICTs) targeting the programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) pathway have improved outcomes for patients with non-small cell lung cancer (NSCLC), those with high PD-L1 expression
Durvalumab-treated patients, training set At baseline, 31.0% of samples from patients enrolled in Study 1108 in the training set were CD8xPD-L1 signature-positive, 38.1% had high densities of Cluster of differentiation 8 (CD8)+ cells, 31.0% had high densities of PD-L1+ cells, and 58.3% had PD-L1 Tumor cell (TC) ≥25%
We evaluated the individual components in comparison to manual PD-L1 scoring and further investigated the prognostic value of these measures in patients with NSCLC treated with non-ICT, which further supported the predictive value of the CD8xPD-L1 signature
Summary
Immune checkpoint therapies (ICTs) targeting the programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) pathway have improved outcomes for patients with non-small cell lung cancer (NSCLC), those with high PD-L1 expression. Multiple cancer types, including non-small cell lung cancer (NSCLC), exploit this pathway through expression of PD-L1 on neoplastic cells or immune cells, primarily macrophages. Immune checkpoint therapy (ICT) targeting the PD1/PD-L1 pathway has greatly improved survival for NSCLC patients [3,4,5,6,7], leading to drug approvals across several countries. Multiple approaches to predict patient response to anti-PD1/PD-L1 therapies have been studied in recent years in the expanding field of precision medicine
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
