Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial.
Authors: F. Dalenc, M. Campone, P. Hupperets, R. O'Regan, C. Manlius, L. Vittori, P. Mukhopadhyay, C. Massacesi, T. Sahmoud, F. Andre
Journal: Journal of Clinical Oncology (2010)

1013^ Background: Resistance to trastuzumab (H) may be associated with deregulation of PTEN or mutations in PI3K/AKT pathway. Preclinically, everolimus (E), an oral inhibitor of mTOR, enhances activity, reverses resistance to H and demonstrates synergistic activity with paclitaxel (T). The objective of this phase II study was to evaluate the efficacy of E combined with T and H in heavily pretreated HER2-positive MBC pts. Methods: A multicenter, Novartis sponsored, phase II trial was conducted using: T 80mg/m2, IV on days 1, 8 and 15 q4w; H 4mg/kg IV loading dose, then weekly 2mg/kg; E daily 10mg in patients whose disease is resistant to both H (progression on or within 3 months of the end of H therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant H) and taxanes (progression on or within 4 months of the end of taxane therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant therapy.) Treatment continued until progression or unacceptable toxicity. Results: The study completed enrollment (n=55). Analyses were performed on 37 evaluable pts. Median treatment duration is 12 weeks (2-43) with19 pts still on treatment and 6 beyond 6 cycles. Pt characteristics were median age 56 y; visceral disease in 33 pts (89%) with lung and liver involvement in 18 pts (49%) and 21 pts (57%), respectively; median no. of prior chemo lines for metastatic disease 3 (range 0-8); prior anthracyclines in 25 pts (68%); prior lapatinib in 23 pts (62%). Twenty-five pts were evaluable for efficacy. We observed 5 (20%) confirmed PRs, 14 (56%) SDs and 6 (24%) PDs. Treatment was well tolerated. G3-4 neutropenia occurred in 12 pts (32%) with 1 case of febrile neutropenia, G3 stomatitis in 5 pts (13%) and G3 asthenia/fatigue in 2 pts (5%). Conclusions: These preliminary results confirm a previous phase I study showing that E in combination with T and H has an acceptable safety profile and promising anticancer activity in HER2-positive MBC pts pretreated with trastuzumab and taxanes. Updated safety, efficacy, and PFS results will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis, Pfizer Novartis Novartis, Pfizer Genentech, Novartis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.