Abstract P4-13-11: Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance
Authors: Janku F , Hong DS , Atkins JT , Karp DD , Tsimberidou AM , Piha-Paul SA , Subbiah V , Naing A , Fu S , Moulder SL , Tripathy D , Meric-Bernstam F , Wheler JJ 
Published: May 2016

Abstract
Background
Combining anti-estrogen therapy with HER2 and mTOR inhibitors may be synergistic and overcome resistance to hormonal and anti-HER2 therapies in patients with estrogen receptor (ER)-positive and HER2 receptor amplified and/or mutant advanced cancers.
Patients and Methods
We evaluated the mTOR inhibitor everolimus, aromatase inhibitor letrozole and anti-HER2 antibody trastuzumab in patients with ER-positive, HER2-positive and/or mutant, solid tumors (confirmed by IHC, FISH, and/or HER2 sequencing). The primary objectives were to determine maximum tolerated dose (MTD) and toxicity and to evaluate response. Secondary objectives were to correlate activity with genomic and proteomic signatures. Next-generation sequencing (NGS) was performed either using a 50-gene panel or externally by Foundation Medicine (Cambridge, MA, USA).
Results
Nine of 10 patients enrolled are currently evaluable for toxicity and response including 7 patients with breast cancer, one patient with ovarian cancer, and one patient with cervical cancer. The median age was 57 years (range, 33-66 years) and the median number of prior therapies in the metastatic setting was 5 (range, 2-7). Of these nine patients, six were HER2+ (by IHC and/or FISH) and three had HER2 mutations (in the absence of HER2 overexpression or amplification). Dose Level (DL) 1 consisted of trastuzumab loading dose of 4mg/kg IV and maintenance dose of 2 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL2 consisted of trastuzumab loading dose of 6mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL3 consists of trastuzumab loading dose of 6 mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 7.5 mg PO daily and letrozole 2.5 mg PO daily. Currently patients are being enrolled in DL3 and no DLTs have been observed. Additional dose levels are planned with increased trastuzumab and everolimus to the FDA approved doses or until MTD is reached. The most common grade 1 and 2 treatment-related toxicities were fatigue (6 patients), anemia and constipation (2 patients each). No grade 3 or 4 toxicities have been reported. Median time to treatment failure (TTF) was 7.4 months (95% CI 5.2-9.6). One patient with breast cancer and a HER2 mutation experienced a partial response (PR) with a 32% decrease in measurable disease. This patient had no prior HER2-targeted therapy and previously progressed while on letrozole and while on exemestane and everolimus. Six additional patients experienced stable disease (SD) ≥ 6 months, 5 with breast cancer and 1 with cervical cancer. Of these 6 patients, 1 had a HER2 mutation and another had a PIK3CA mutation.
Conclusions
Combination treatment with everolimus, letrozole and trastuzumab is well tolerated and active in ER+, HER2+ and/or mutant solid tumors, including breast and cervical cancer. Clinical benefit (PR/SD≥6 months) was seen in 7 of 9 patients (78%), including patients with HER2 mutations in the absence of overexpression and/or amplification and patients with no genomic alterations in the PI3K/AKT/mTOR pathway. Enrollment is ongoing.
Citation Format: Janku F, Hong DS, Atkins JT, Karp DD, Tsimberidou AM, Piha-Paul SA, Subbiah V, Naing A, Fu S, Moulder SL, Tripathy D, Meric-Bernstam F, Wheler JJ. Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-11.