Phase I study of everolimus, letrozole, and trastuzumab in patients with hormone receptor-positive metastatic breast cancer or other solid tumors

Alexej Ballhausen, Jennifer J. Wheler, Daniel D. Karp, Sarina A. Piha-Paul, Siqing Fu, Shubham Pant, Apostolia M. Tsimberidou, David S. Hong, Vivek Subbiah, Veronica R. Holley, Helen J. Huang, Abenaa M. Brewster, Kimberly B. Koenig, Nuhad K. Ibrahim, Funda Meric-Bernstam, Filip Janku

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 events 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.

Original languageEnglish (US)
Pages (from-to)1247-1255
Number of pages9
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume27
Issue number5
Early online dateOct 28 2020
DOIs
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Clinical and Translational Research Center
  • Precision Oncology Decision Support
  • Clinical Trials Office

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