Results from the secondary endpoint of the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) study of Afinitor® (everolimus) trial were presented today at the 9th European Breast Cancer Conference (EBCC-9) in Glasgow, Scotland. A median overall survival duration of 31 months was seen in the combination arm versus 26.6 months for those on exemestane monotherapy, a difference of 4.4 months (hazard ratio=0.89 [95% CI: 0.73 to 1.10]; p=0.1426)[1],[2]. This secondary endpoint did not reach the threshold of statistical significance[1]. The median overall survival is the longest reported to date in a Phase III hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer trial following prior treatment with a non-steroidal aromatase inhibitor (NSAI)[2].
"The BOLERO-2 trial shows that treatment with Afinitor in combination with exemestane works against multiple target pathways to slow the progression of hormone receptor-positive advanced breast cancer, even among patients who have progressed while on or within 12 months of completing adjuvant non-steroidal aromatase inhibitor therapy," said Gabriel Hortobagyi, MD, professor, Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. "This dual approach both extends the benefits of endocrine therapy while delaying the time until the patient needs chemotherapy, which can have an important impact on patients living with this disease."
The final overall survival results were assessed as part of a prospectively planned secondary endpoint analysis. Previously reported progression-free survival (PFS) results found that treatment with everolimus plus exemestane more than doubled median PFS to 7.8 months, compared to 3.2 months with exemestane alone, meeting the study's primary endpoint (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), confirmed by central assessment (11 months versus 4.1 months PFS)[3]. The most common adverse reactions (incidence >= 30%) were stomatitis, infections, rash, fatigue, diarrhea and decreased appetite[2],[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[2],[3].
"These data, along with experience from more than 18 months of real-world use, add to the growing body of evidence regarding the use of Afinitor plus exemestane in patients with hormone receptor-positive, HER2 negative advanced breast cancer after they progress on a non-steroidal aromatase inhibitor," said Alessandro Riva, MD, President Novartis Oncology ad interim and Global Head, Oncology Development and Medical Affairs. "We continue to research the role of Afinitor in advanced breast cancer and are committed to developing other novel therapies, such as those targeting the PI3K/AKT/mTOR and CDK 4/6 pathways."
Everolimus is the first and only mTOR inhibitor approved for the treatment of HR+/HER2- advanced breast cancer[2],[4]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[5]. Additional data presented at the meeting provide continued evidence on the important role of dual hormone receptor and mTOR inhibition in the treatment of HR+/HER2- advanced breast cancer upon NSAI failure[2].
Everolimus is approved as Afinitor in more than 80 countries to treat women with HR+/HER2- advanced breast cancer, including the most recent approval in Japan this week[2]. The specific indications vary by country.
Study design
BOLERO-2 involved more than 700 patients at more than 195 sites worldwide. Patients in the trial were randomized (2:1) to receive continuous therapy with everolimus 10 mg/day orally or placebo, plus oral exemestane 25 mg/day[5]. Patients who had received more than one prior chemotherapy regimen for advanced breast cancer were excluded from enrollment[5]. The primary endpoint was PFS[5]. Secondary endpoints included overall survival, overall response rate, incidence of adverse events, patient reported outcomes and clinical benefit rate[5].
About advanced breast cancer
Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[6]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[6]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[6].
It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[7],[8]. Hyperactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4].
Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[9]. HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[2],[10]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone[11]. Cancer cell growth can be driven by these hormones[11].
About Afinitor® (everolimus)
Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.
Afinitor (everolimus) tablets is approved in more than 100 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.
Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.
Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.
About the Novartis breast cancer pipeline
Novartis is currently investigating PI3K inhibitors buparlisib (BKM120) and BYL719, and CDK 4/6 inhibitor LEE011, in the treatment of drug-resistant breast cancer in combination with other targeted therapies[2].
The PI3K/AKT/mTOR pathway regulates cell metabolism, proliferation and survival, and abnormal activation of this pathway has been shown to be important in initiation and maintenance of human tumors[4]. Cyclin-dependent kinases (CDKs) drive cell cycle progression and control transcriptional processes, and the deregulation of multiple CDK proteins, including CDK 4 and 6, occur commonly in cancer[12]. Targeting these pathways could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies[2],[4],[12].
Because they are investigational compounds, the safety and efficacy profile of BKM120, BYL719 and LEE011 have not yet been established[2]. Access to these investigational compounds is available only through carefully controlled and monitored clinical trials designed to better understand their potential benefits and risks. Because of the uncertainty of clinical trials, there is no guarantee that BKM120, BYL719 and LEE011 will ever be commercially available anywhere in the world.
About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 136,000 full-time-equivalent associates and operate in more than 140 countries around the world.
1. Piccart M, et al. Everolimus plus exemestane for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (BC): overall survival results from BOLERO-2. Oral Presentation Abstract #LBA1. European Breast Cancer Conference (EBCC-9), 2014, Glasgow, Scotland.
2. Novartis Data on File.
3. Piccart M, et al. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Abstract #559. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
4. Advani SH. Targeting mTOR Pathway: A New Concept in Cancer Therapy. Indian Journal Medical Pediatric Oncology. Oct-Dec 2010: 1-10.
5. Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. December 2011.
6. American Cancer Society. How Do You Determine the Stage of Breast Cancer? http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-staging. Accessed February 19, 2014.
7. Eniua A, Palmierib F and Perez E. Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist. 2005.
8. Giordano, S. Update on Locally Advanced Breast Cancer. The Oncologist. 2003.
9. Dobrescu A, et al. Study of Estrogen Receptor and Progesterone Receptor Expression in Breast Ductal Carcinoma In Situ by Immunohistochemical Staining in ER/PgR-Negative Invasive Breast Cancer. International Scholarly Research Network. 2011;2011:1-5.
10. Buckley N, Isherwood A. Breast Cancer. Decision Resources. March 2011: 1-301.
11. Redmond C. Breast Cancer Hormone Therapy Options. http://christineredmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed February 19, 2014.
12. Shapiro J. Cyclin-Dependent Kinase Pathways as Targets for Cancer Treatment. Journal of Clinical Oncology. January 2006.