Afinitor (Everolimus) has been approved by the US Food and Drug Administration (FDA) as the first oral, daily therapy (5 mg and 10 mg tablets) to treat advanced kidney cancer after failure of treatment with sunitinib or sorafenib. Trastuzumab or lapatinib resistance may be related to loss/deregulation of PTEN or activating mutations in the PI3K/AKT pathway. Everolimus (E), an oral inhibitor of mTOR, enhances efficacy and reverses resistance to H, and demonstrates synergistic activity with paclitaxel (T).
Two phase I studies that tested this hypothesis have been published, one with lapatinib and one with Herceptin. We await farther developments in this area.
C. J. Hoban, A. Hoering, T. W. Synold, V. Chung, D. R. Gandara, A. F. Schott, L. Kingsbury, D. Lew, P. M. LoRusso, S. M. Gadgeel; Southwest Oncology Group/University of Michigan, Ann Arbor, MI; Cancer Research and Biostatistics, Seattle, WA; City of Hope Comprehensive Cancer Center, Duarte, CA; UC Davis Cancer Center, Sacramento , CA; University of Michigan, Ann Arbor, MI; Wayne State University/Karmanos Cancer Institute, Detroit, MI Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528. J Clin Oncol 27:15s, 2009 (suppl; abstr 3553)
M. Campone, R. O’Regan, S. Hurvitz, M. Naughton, C. Manlius, L. Vittori, P. Mukhopadhyay, C. Massacesi, T. Sahmoud, F. André; CLCC René Gauducheau, Nantes, France; Emory Winship Cancer Institute, Atlanta, GA; UCLA Medical Center, Los Angeles, CA; Washington University, St Louis, MO; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals, Florham Park, NJ; Institut Gustave Roussy, Villejuif, France Everolimus plus weekly paclitaxel and trastuzumab in patients (pts) with HER-2+ metastatic breast cancer (MBC) with prior resistance to trastuzumab: A phase I clinical trial 2009 Breast Cancer Symposium, #218