Purpose: Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity. Experimental design: This first-in-human dose escalation study (NCT02152943) enrolled patients with hormone receptor-positive, HER2-positive (defined by amplification, overexpression or mutation)treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21) and intravenous trastuzmab (day 1) every 21 days todetermine dose-limiting toxicities (DLTs) and maximum tolerated dose or recommended phase 2 dose (RP2D). Results: Total of 32 patients with hormone receptor-positive, HER2-positive (amplification, n=27; overexpression, n=1; mutation, n=4) advanced breast cancer (n=26) or other cancers (n=6) were enrolled. The most frequent grade greater than or equal to 3 adverse eve nts included hyperglycemia (n=4), anemia (n=3), thrombocytopenia (n= 2) and mucositis (n=2).DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8-mg/kg loading dose on day 1 of cycle 1 followed by a 6-mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five breast cancer patients (4 with HER2amplification and 1 with HER2mutation) had partial responses. HER2amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P<0.05). Conclusions: Everolimus, letrozole, and trastuzumab has a favorable safety profile and elicits encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor-and HER2-positive advanced cancers.
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