Age Is Associated With Response To Immune Checkpoint Blockade In Advanced Urothelial Carcinoma

Introduction Urothelial cancer patients treated with immune checkpoint inhibitor (ICI) therapy have varied response and survival. It has been shown that older age is associated with ICI response and survival in melanoma but a prior analysis of the Keynote-052 trial did not demonstrate significant differences in response or survival by age. Age and other biomarkers could help predict ICI response and survival to inform decisions about patient selection for ICI treatment. Methods The association of age with response and survival was analyzed in a set of 347 urothelial cancer patients treated with ICI from the IMvigor210 study (Mariathasan 2018). Data were divided into discovery (2/3) and validation (1/3) sets. From clinical metadata, elastic net modeling was used to assess the predictive value of age for response and survival. Results In urothelial cancer patients treated with ICI, the optimal age cut-point for analyses of both survival and response was calculated to be 72 years. Patients over 72 years old have significantly higher rates of response (p = 0.024) and survival (p = 0.043). In univariate analysis with age as a continuous variable, age is significantly correlated with response (p = 0.032) but not survival (p = 0.066). In multivariable analysis encompassing clinical metadata, age is selected by the final elastic net model of response (βage = 0.0184 [95% CI 0.0154,0.0213], AUC p_AUC = 0.0145). A model built using all clinical metadata including age did not show significantly improved fit in prediction of response compared to a model built with age omitted as a predictor variable (likelihood ratio test: p = 0.538). In multivariable analysis encompassing clinical metadata, age is not selected by the final elastic net model of survival (c-index_model = 0.658, p_c-index = 0.00592). Common predictive biomarkers of response, including tumor mutational burden, IFNG expression, and F-TBRS score (Mariathasan 2018) are not correlated with age, suggesting age\u0027s association with clinical benefit is independent of these features. Conclusions Among urothelial cancer patients treated with ICI, older patients have better response and survival. Age helps predict response to ICI, and age may be an important feature in a model of response from clinical metadata. We propose that age could serve as an important predictor of ICI response to better inform treatment selection in UC.