Simple SummaryLactate dehydrogenase (LDH) levels prior to treatment are a known biomarker to predict advanced melanoma’s response to immune checkpoint inhibitors (ICI). In this study, we evaluated the ability of machine learning-based models to predict responses to ICI and complement LDH for in predicting the outcomes of metastatic melanoma. A machine learning algorithm was developed using radiomics, and further analysis helped select the most important predictive features and variables. The machine learning model that combined both features extracted from images (radiomics) and pretreatment LDH levels resulted in better predictions of cancer response to ICI than models that only use radiomics features or LDH levels alone.AbstractPretreatment LDH is a standard prognostic biomarker for advanced melanoma and is associated with response to ICI. We assessed the role of machine learning-based radiomics in predicting responses to ICI and in complementing LDH for prognostication of metastatic melanoma. From 2008–2022, 79 patients with 168 metastatic hepatic lesions were identified. All patients had arterial phase CT images 1-month prior to initiation of ICI. Response to ICI was assessed on follow-up CT at 3 months using RECIST criteria. A machine learning algorithm was developed using radiomics. Maximum relevance minimum redundancy (mRMR) was used to select features. ROC analysis and logistic regression analyses evaluated performance. Shapley additive explanations were used to identify the variables that are the most important in predicting a response. mRMR selection revealed 15 features that are associated with a response to ICI. The machine learning model combining both radiomics features and pretreatment LDH resulted in better performance for response prediction compared to models that included radiomics or LDH alone (AUC of 0.89 (95% CI: [0.76–0.99]) vs. 0.81 (95% CI: [0.65–0.94]) and 0.81 (95% CI: [0.72–0.91]), respectively). Using SHAP analysis, LDH and two GLSZM were the most predictive of the outcome. Pre-treatment CT radiomic features performed equally well to serum LDH in predicting treatment response.