Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and

MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.