PMID- 24615500 OWN - NLM STAT- MEDLINE DCOM- 20141121 LR - 20240229 IS - 1569-8041 (Electronic) IS - 0923-7534 (Print) IS - 0923-7534 (Linking) VI - 25 IP - 4 DP - 2014 Apr TI - Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. PG - 808-815 LID - S0923-7534(19)36498-1 [pii] LID - 10.1093/annonc/mdu009 [doi] AB - BACKGROUND: In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS: Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS: The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS: Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER: NCT00863655. FAU - Rugo, H S AU - Rugo HS AD - University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, USA. Electronic address: hrugo@medicine.ucsf.edu. FAU - Pritchard, K I AU - Pritchard KI AD - Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Canada. FAU - Gnant, M AU - Gnant M AD - Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. FAU - Noguchi, S AU - Noguchi S AD - Department of Breast and Endocrine Surgery, Osaka University, Osaka, Japan. FAU - Piccart, M AU - Piccart M AD - Institut Jules Bordet, Brussels, Belgium. FAU - Hortobagyi, G AU - Hortobagyi G AD - The University of Texas MD Anderson Cancer Center, Houston. FAU - Baselga, J AU - Baselga J AD - Memorial Sloan-Kettering Cancer Center, New York. FAU - Perez, A AU - Perez A AD - Memorial Cancer Institute, Hollywood, USA. FAU - Geberth, M AU - Geberth M AD - Praxisklinic am Rosengarten Mannheim, Schwerpunktpraxis fur Gynaekologische Onkologie, Mannheim, Germany. FAU - Csoszi, T AU - Csoszi T AD - Department of Medical Oncology, Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Szolnok, Hungary. FAU - Chouinard, E AU - Chouinard E AD - Cambridge Memorial Hospital, Cambridge, Canada. FAU - Srimuninnimit, V AU - Srimuninnimit V AD - Siriraj Hospital, Mahidol University, Bangkok. FAU - Puttawibul, P AU - Puttawibul P AD - Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand. FAU - Eakle, J AU - Eakle J AD - Florida Cancer Specialists, Ft Myers. FAU - Feng, W AU - Feng W AD - Novartis Pharmaceuticals Corporation, East Hanover, USA. FAU - Bauly, H AU - Bauly H AD - Novartis Pharma AG, Basel, Switzerland. FAU - El-Hashimy, M AU - El-Hashimy M AD - Novartis Pharmaceuticals Corporation, East Hanover, USA. FAU - Taran, T AU - Taran T AD - Novartis Pharmaceuticals Corporation, East Hanover, USA. FAU - Burris, H A 3rd AU - Burris HA 3rd AD - Sarah Cannon Research Institute, Nashville, USA. LA - eng SI - ClinicalTrials.gov/NCT00863655 GR - P30 CA016672/CA/NCI NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140310 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - Ann Oncol. 2014 Sep;25(9):1861. PMID: 24875799 CIN - Ann Oncol. 2014 Oct;25(10):2096-8. PMID: 25085504 CIN - Ann Oncol. 2014 Oct;25(10):2096. PMID: 25085505 MH - Adult MH - Aged MH - Aged, 80 and over MH - Breast Neoplasms/*drug therapy/genetics/pathology MH - Disease-Free Survival MH - Drug-Related Side Effects and Adverse Reactions/classification/*pathology MH - Everolimus MH - Female MH - Humans MH - Middle Aged MH - Neoplasm Staging MH - Postmenopause MH - Sirolimus/administration & dosage/adverse effects/*analogs & derivatives MH - TOR Serine-Threonine Kinases/genetics PMC - PMC3969554 OTO - NOTNLM OT - advanced breast cancer OT - everolimus OT - mammalian target of rapamycin (mTOR) OT - safety EDAT- 2014/03/13 06:00 MHDA- 2014/12/15 06:00 PMCR- 2014/03/10 CRDT- 2014/03/12 06:00 PHST- 2014/03/12 06:00 [entrez] PHST- 2014/03/13 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2014/03/10 00:00 [pmc-release] AID - S0923-7534(19)36498-1 [pii] AID - mdu009 [pii] AID - 10.1093/annonc/mdu009 [doi] PST - ppublish SO - Ann Oncol. 2014 Apr;25(4):808-815. doi: 10.1093/annonc/mdu009. Epub 2014 Mar 10.