Abstract P1-19-18: Everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic cancer: Evaluating synergy and overcoming resistance
Authors: Ballhausen Alexej , Wheler Jennifer J , Karp Daniel D , Piha-Paul Sarina A , Fu Siqing , Pant Shubham , Tsimberidou Apostolia M , Hong David S , Subbiah Vivek , Holley Veronica R , Huang Helen J , Brewster Abeena M , Koenig Kimberly H , Ibrahim Nuhad K , Meric-Bernstam Funda , Janku Filip 
Published: March 2020

Abstract
Background: Combinations of HER2 and aromatase or mTOR inhibitors demonstrated activity in the clinical setting. We hypothesized that the triple combination of HER2 targeted therapy, aromatase and mTOR inhibitor has increased anticancer activity.
Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing) with preplanned expansion cohort at for patients with metastatic breast cancer to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), dose limiting toxicities (DLT), overall safety and response (NCT02152943).
Results: A total of 32 patients (men, 1; women, 31; HER2 amplification, 28; HER2 mutation, 4; breast cancer, 26; other cancers, 6), median age 55.5 years, median of 5 prior therapies (including letrozole [13] or other aromatase inhibitor [10]; everolimus [3]; trastuzumab [25] or other HER2 targeted therapy [2]) were enrolled in the planned 6 dose levels. The MTD has not been reached and letrozole 2.5mg PO daily, everolimus 10mg PO daily and trastuzumab 8mg loading dose followed by 4mg maintenance dose IV on day 1 of 21-day cycle was declared as RP2D. DLTs included grade 3 (G3) mucositis (1 patient) at dose level 3, and G3 thrombocytopenia, neutropenia (1 patient) at dose level 4. Other G3 or G4 treatment-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G4 anemia in 1 patient, G3 anemia in 2 patients, G3 thrombocytopenia in 1 patient, G3 transaminitis in 1 patient, G3 mucositis in 1 patient and G3 headache in 1 patient. Of 32 patients, 5 (16%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [4] or HER2A775_G776insYVMA mutation [1]), 23 (72%) stable disease (SD) including 5 (16%) patients with SD &gt; 12 months (all with heavily-pretreated breast cancer) and 4 (13%) progressed. The median change in size of target lesions per RECIST 1.1. was -5% (-91% to +47%). Median time to treatment failure (TTF) was 4.3 months (95% CI 0.0-9.6). A total of 14 patients had serial plasma collection to assess dynamics of circulating tumor DNA and clonal evolution and the data will be presented at the meeting.
Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer.
Citation Format: 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, Abeena M Brewster, Kimberly H Koenig, Nuhad K Ibrahim, Funda Meric-Bernstam, Filip Janku. Everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic cancer: Evaluating synergy and overcoming resistance [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-18.