Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057.

Abstract

2662 Background: Immune checkpoint inhibitors (ICIs) are currently approved for use as therapy in advanced stage lung adenocarcinoma (LUAD). ICIs can decrease risk of progression by up to 60% when compared to chemotherapy, but only about 20% of patients (pts) show response. Given that high levels of tumor-infiltrating lymphocytes (TILs) have been shown to be associated with better prognosis, here, we assess whether computationally derived TIL density measures on digitized H&E images can predict RECIST derived response to nivolumab in LUAD in Checkmate 057 (CM057). CM057 is a clinical trial designed to compare the overall survival of metastatic non-squamous non-small cell lung cancer subjects treated with either nivolumab or docetaxel after failing platinum-based chemotherapy. Methods: H&E-stained samples of 683 LUAD pts were collected from TCGA (n = 421), University of Bern (UBern) (n = 100), and CM057 (n = 162). Tumor response was assessed using RECIST v1.1. Samples were digitized as whole slide images. 294 pts randomly selected from TCGA formed the training set. The remaining 389 pts were used for validation in response to nivolumab in CM057 and prognosticating overall survival (OS) in UBern and TCGA. Computerized algorithms automatically identified TILs and extracted features related to quantity and compactness of TILs with respect to other surrounding nuclei. The top 6 features, determined by least absolute shrinkage and selection operator, were used to train Cox regression models that assign a death risk score to each patient. Pts with risk scores higher than the training median score were considered “high risk” or “non-responders” while pts with lower scores were considered “low risk” or “responders”. Results: The classifier predicted objective response in CM057 with an AUC = 0.61. Additionally, survival analysis showed that the model was prognostic for OS with hazard ratios of 2.38 (confidence interval (CI): 1.32-4.29, p = 0.01, n = 127) in TCGA and 2.37 (CI: 1.32-4.25, p < 0.01, n = 100) in UBern. Conclusions: A computerized image analysis model based on measurements of TIL density showed association with response to treatment in LUAD pts who received nivolumab and was prognostic of OS. Although the AUC was not high, the results suggest analysis of TILs has potential to identify pts who will respond to treatment. Future work will include training a classifier using response to treatment as endpoint and combining the TIL measures with other biomarkers like TMB or PD-L1.