Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors.

Abstract

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. 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 trastuzumab (day 1) every 21 days to determine dose-limiting toxicities (DLT) and MTD or recommended phase II dose (RP2D). A total of 32 patients with hormone receptor-positive, HER2-positive (amplification, <i>n</i> = 27; overexpression, <i>n</i> = 1; and mutation, <i>n</i> = 4) advanced breast cancer (<i>n</i> = 26) or other cancers (<i>n</i> = 6) were enrolled. The most frequent grade ≥3 adverse events included hyperglycemia (<i>n</i> = 4), anemia (<i>n</i> = 3), thrombocytopenia (<i>n</i> = 2), and mucositis (<i>n</i> = 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 patients with breast cancer (four with <i>HER2</i> amplification and one with <i>HER2</i> mutation) had partial responses. <i>HER2</i> amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (<i>P</i> < 0.05). Everolimus, letrozole, and trastuzumab have a favorable safety profile and elicit encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor- and HER2-positive advanced cancers.