Everolimus, Letrozole, and Trastuzumab in Hormone Receptor–Positive, HER2+/Amplified or Mutant Metastatic Cancer

Combinations of HER2 and aromatase or mTOR inhibitors have demonstrated activity in the clinical setting.1 Thus, the authors hypothesized that the triple combination of HER2-targeted therapy, aromatase, and mTOR inhibitor would have increased anticancer activity. In this regard, they designed a 3 + 3 dose-escalation phase 1 study of letrozole 2.5 mg orally daily, everolimus 2.5 to 10 mg orally daily, and trastuzumab (4-mg to 8-mg loading dose followed by a 2-mg to 4-mg maintenance dose intravenously on day 1 of a 21-day cycle), in patients with hormone receptor–positive, HER2+ or mutant advanced cancers. HER2 and hormone receptor status were confirmed by immunohistochemistry and/or fluorescence in situ hybridization and/or next-generation sequencing. There was a preplanned expansion cohort for patients with metastatic breast cancer to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), dose-limiting toxicities (DLTs), overall safety, and response. The results of this study were presented at SABCS 2019.2

A total of 32 patients (1 man, 31 women; 28 with HER2 amplification, 4 with HER2 mutation, 26 with breast cancer, and 6 with other cancers), with a median of 5 prior therapies (including letrozole or other aromatase inhibitor, everolimus, trastuzumab, or other HER2-targeted therapy) were enrolled in the planned 6 dose levels. The MTD has not been reached and letrozole 2.5 mg PO daily, everolimus 10 mg PO daily, and trastuzumab 8-mg loading dose followed by a 4-mg maintenance dose intravenously on day 1 of a 21-day cycle was declared as RP2D. DLTs included grade 3 mucositis at dose level 3 and grade 3 thrombocytopenia and neutropenia at dose level 4. Other grade 3 or grade 4 treatment-related toxicities included hyperglycemia, anemia, thrombocytopenia, transaminitis, mucositis, and headache. Of 32 patients, 5 (16%) had a partial response (all with heavily pretreated breast cancer with HER2/neu amplification), 23 (72%) patients showed stable disease (SD), including 5 (16%) patients with SD >12 months (all with heavily pretreated breast cancer) and 4 (13%) patients progressed. The median change in size of target lesions per RECIST 1.1. was –5%. Median time to treatment failure (TTF) was 4.3 months and median overall survival was 13.9 months. A total of 14 patients had serial plasma collection to assess dynamics of circulating tumor DNA and clonal evolution; HER2/neu amplification in circulating tumor (ct)DNA was detected in 8 (57%).

The authors concluded that the combination of letrozole, everolimus, and trastuzumab is well tolerated with early signals of encouraging clinical activity in heavily pretreated patients with HER2/neu-amplified or mutant advanced breast cancer. HER2/neu amplification can be detected in ctDNA and patients with high amounts of HER2/neu ctDNA before therapy had inferior TTF.


  1. Jones KL, Buzdar AU. Lancet Oncol. 2009;10:1179-1187.
  2. Ballhausen A, et al. SABCS 2019. Abstract P1-19-18.

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