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Currently, more and more patients receive first-line treatment with immunotherapy combinations and not all patients respond in metastatic renal cell carcinoma. After IO-IO progression, we don't have a standard of treatment because it is not available prospective data on this setting. We present the case of a patient with metastatic renal cell carcinoma who suffered hyperprogression with IO-IO combination in first line. Second line with cabozantinib results in a deep response of the disease. We performed a Foundation One testing to the patient which showed a mutation in NOTCH. The molecular mechanism to explain patient's response, it's the probably crosstalk between MET and NOTCH pathway. Nowadays, there is not clear the subsequent treatment in those patients who progress to IO-IO first line. More efforts in biomarkers development should be made to better selection of patients treatment along the disease.

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Hyperprogression to a dual immune blockade followed by subsequent response with cabozantinib in metastatic poor-risk clear cell renal cell carcinoma with NOTCH mutation