MK-8242 Is Active in Patients with p53 Wild-Type Advanced Solid Tumors

MDM2, a negative regulator of p53, is amplified in multiple tumor types, including a large majority of liposarcomas. Thus, targeting MDM2 is a potential therapeutic strategy for p53 activation. MK-8242 is a potent, orally bioavailable, small-molecule inhibitor of the MDM2–p53 interaction. In a phase I dose-ranging study, Wagner and colleagues evaluated MK-8242 in 47 patients with TP53–wild-type advanced solid tumors, 27 of whom had liposarcoma. The primary endpoints were to identify dose-limiting toxicities and establish the recommended phase II dose, and secondary endpoints included determination of the objective radiologic response rate (ORR). In total, 46 of 47 (98%) patients had at least one drug-related adverse event, including 4 (8.5%) who experienced serious drug-related adverse events, and 12 patients (26%) discontinued treatment as a result of adverse events. In patients receiving 300 mg, 400 mg, or 500 mg MK-8242, expression of the p53 target gene PHLDA3 increased, suggesting that MK-8242 treatment results in p53 activation. The recommended phase II dose was determined to be 400 mg. The ORR was 6.4%, with an ORR of 11.1% in patients with liposarcoma. Three patients achieved partial responses and 31 showed stable disease. The median progression-free survival was 3.4 months overall and 7.8 months in patients with liposarcoma. Taken together, the results of this phase I trial indicate that MK-8242 has an acceptable safety profile at the determined recommended dose, and may have antitumor activity in patients with p53–wild-type tumors, particularly those with liposarcoma. These findings support further investigation of MDM2 inhibitors including MK-8242 as a strategy to activate or reactivate p53, alone or in combination with conventional chemotherapy for the treatment of cancer.

Wagner AJ, Banerji U, Mahipal A, Somaiah N, Hirsch H, Fancourt C, et al. Phase I trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors. J Clin Oncol 2017 Feb 27 [Epub ahead of print].

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