MA25.02 Arrangement and Architecture of Tumor-Infiltrating Lymphocyte on H&E Slides Predict OS in Nivolumab Treated Non-Small Cell Lung Cancer

Immune checkpoint inhibitors (ICI) are a promising and novel approach to treating chemotherapy refractory advanced NSCLC as well as first-line combination therapy in certain NSCLC. Nivolumab, a PD-L1 inhibitor is a promising ICI showing durable benefit with low toxicity in these patients. While PD-L1 positivity is an established tissue based biomarker for response to Nivolumab, studies have shown response rates ranging from 20-50%. Recent research has shown that TILs have been implicated in cancer aggressiveness as well as immune response. In this work, we go beyond simply counting TILs, and apply novel computer-extracted features characterizing the interaction and spatial co-localization of TILs and cancer nuclei (SpaTIL) in stratifying patients based on OS following nivolumab therapy. H&E tissue slides obtained from pre-treatment biopsies of 96 NSCLC patients treated with nivolumab were digitized and included for this study from 3 different institutions with the tumor region annotated by pathologists. Then 85 SpaTIL features related to TIL density, architecture and co-localization with tumor cells have been extracted to represent each patient. The most discriminative and uncorrelated features were selected by Elastic-Net regularized Cox-regression model to predict OS. The model was trained on D1 (n=25) and independently validated in D2 (n=32) and D3 (n=64). Multivariate analysis with clinico-pathologic factors was also performed. The top features consisted of the abundance of TILs around tumor cells and the distribution of the TILs. On the validation set, SpaTIL classifier yielded a HR=3.03 (95%CI=1.1 -8.35; p=0.042) on D2 and HR=4.12 (95%CI=1.87-9.09; p=0.02) on D3 by a log-rank test. On multivariate analysis with stage, smoking, histologic type, total lymphocyte count (See Table 1) SpaTIL was independently prognostic of OS (HR=7.88; 95%CI=1.66 – 37.216; p=0.009).Table 1Multivariate analysis for overall survival on the validation sets D2 and D3VariablesHR(95% CI)p valueAge (>65 vs <=65 yrs)0.99(0.97-1.03)0.67Gender (Male vs Female)1.05(0.75-2.79)0.88Smoking Status (Former vs Never smoker)3.19(0.92-11.061)0.07Histological Subtypes (Adeno vs Squamous)11.06(0.13-8.54)0.95EGFR status1.32(0.49-3.52)0.58ALK status0.63(0.36-1.10)0.10Total lymphocyte count0.99(0.99-1.00)0.33SpaTIL Classifier7.88(1.66-37.216)0.009CI = confidence interval; HR = Mantel-Haenszel Hazard ratio. Values in bold are statistically significant, p<=0.05. Open table in a new tab CI = confidence interval; HR = Mantel-Haenszel Hazard ratio. Values in bold are statistically significant, p<=0.05. Spatial interaction of TILs and cancer are independently prognostic of OS in nivolumab treated NSCLC. Further validation needs to be done to evaluate its utility.