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The standard assessment of response to cancer treatments is based on gross tumor characteristics, such as tumor size or glycolysis, which provide very indirect information about the effect of precision treatments on the pharmacological targets of tumors. Several advanced imaging modalities allow for the visualization of targeted tumor hallmarks. Descriptors extracted from these images can help establishing new classifications of precision treatment response. We propose a machine learning (ML) framework to analyze metabolic–anatomical–vascular imaging features from positron emission tomography, ultrafast Doppler, and computed tomography in a mouse model of paraganglioma undergoing anti-angiogenic treatment with sunitinib. Imaging features from the follow-up of sunitinib-treated (n= 8, imaged once-per-week/6-weeks) and sham-treated (n= 8, imaged once-per-week/3-weeks) mice groups were dimensionally reduced and analyzed with hierarchical clustering Analysis (HCA). The classes extracted from HCA were used with 10 ML classifiers to find a generalized tumor stage prediction model, which was validated with an independent dataset of sunitinib-treated mice. HCA provided three stages of treatment response that were validated using the best-performing ML classifier. The Gaussian naive Bayes classifier showed the best performance, with a training accuracy of 98.7 and an average area under curve of 100. Our results show that metabolic–anatomical–vascular markers allow defining treatment response trajectories that reflect the efficacy of an anti-angiogenic drug on the tumor target hallmark.