Phase 1 Study Of The P53-Mdm2 Inhibitor Amg 232 Combined With Trametinib Plus Dabrafenib Or Trametinib In Patients (Pts) With Tp53 Wild Type (Tp53wt) Metastatic Cutaneous Melanoma (Mcm).

2575Background: Large sequencing studies in MCM have shown a TP53WT incidence of approximately 80%. In preclinical TP53WT melanoma models, the oral p53-MDM2 inhibitor AMG 232 exhibited synergistic, cytotoxic-type antitumor activity when combined with MAPK inhibitors. This phase 1 study assessed the toxicity (CTCAE 4.03), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity (RECIST 1.1) of AMG 232 plus trametinib (T) and dabrafenib (D) (BRAFV600-mutant) or T (BRAFV600-WT) in pts with TP53WT MCM. Methods: Using 3+3 dose escalation design, pts with advanced TP53WT (using a CLIA-approved assay) MCM received AMG 232 PO QD for seven days of each 3-week cycle (7/21) at 120, 240, or 480 mg plus either T 2 mg PO QD and D 150 mg PO BID (Arm 1; BRAFV600-mutant) or T 2 mg QD (Arm 2; BRAFnonV600-mutant). Results: At the time of this analysis, 21 pts (median age, 58 y [range 24–76]; male, n = 11; at least 2 systemic treatments, n = 15) were treated. Arm 2 enrolled first: AMG 232 120 m...