Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy

J Immunother Cancer. 2019 May 6;7(1):121. doi: 10.1186/s40425-019-0589-x.

Abstract

Background: 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), 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.

Methods: Archival 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.

Results: For 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.

Conclusions: An 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 registration: ClinicalTrials.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).

Keywords: Biomarker; CD8; Cancer immune checkpoint therapy; Image analysis; Immunohistochemistry; NSCLC; PD-L1.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • CD8 Antigens / analysis
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Female
  • Humans
  • Image Processing, Computer-Assisted*
  • Immunohistochemistry
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Prognosis
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CD8 Antigens
  • durvalumab

Associated data

  • ClinicalTrials.gov/NCT01693562