Novartis has presented results from a pivotal phase III trial of a treatment regimen including Afinitor (everolimus) tablets in women with human epidermal growth factor receptor-2 positive (HER2 positive) advanced breast cancer who received prior taxane therapy and whose disease is resistant to prior trastuzumab (Herceptin) treatment. This findings showed that adding everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine significantly extended progression-free survival (PFS) when compared to treatment with placebo plus trastuzumab and vinorelbine, meeting the study's primary endpoint.

The BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) findings were presented at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO). Final PFS results showed that adding everolimus to the standard treatment of trastuzumab and vinorelbine reduced the risk of disease progression by 22 per cent (hazard ratio=0.78 [95 per cent confidence interval (CI): 0.65 to 0.95]; p<0.01). Median time to progression was 7.0 months in the everolimus combination arm and 5.8 months in the placebo combination arm. All patients were resistant to trastuzumab-containing regimens and 27 per cent of the patient population was pretreated with a lapatinib-containing regimen. Findings on overall survival, the key secondary endpoint of the trial, are not yet mature.

"These encouraging data demonstrate that everolimus has a meaningful impact in heavily pretreated HER2 positive advanced breast cancer patients," said Ruth O'Regan, professor and vice-chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University School of Medicine and lead study author. "Everolimus works differently than available treatment options for HER2 positive advanced breast cancer by inhibiting mTOR, and may offer an important new option for physicians and their patients."

Adverse events were consistent with the known safety profile of everolimus. The most common all-grade adverse reactions (incidence >=30 per cent) were neutropenia, stomatitis, anaemia, leukopenia, fatigue, pyrexia, diarrhoea, nausea, decreased appetite and constipation. The most common Grade 3-4 adverse reactions (incidence >= two per cent) were neutropenia, leukopenia, anemia, stomatitis, fatigue, febrile neutropenia, diarrhea, pyrexia, nausea, hyperglycemia and thrombocytopenia.

The number of on-treatment deaths (2.5 per cent per arm) and the number of deaths due to adverse events (0.7 per cent per arm) were similar across treatment groups.

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism. Previously released data indicate that the mTOR inhibitor everolimus can provide significant benefit when added to certain existing advanced breast cancer treatments.

"Our previous advanced breast cancer studies have proven that everolimus plays a key role in treating women with hormone-receptor positive, HER2 negative advanced breast cancer, and now we know it may have a substantial impact in HER2 positive advanced breast cancer," said Alessandro Riva, global head, Oncology Development & Medical Affairs, Novartis Oncology. "We plan to share the BOLERO-3 data with regulatory health authorities worldwide."

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor. The specific indications vary by country. HR+/HER2 negative advanced breast cancer is the most common form of the disease. Approximately 70 per cent of all invasive breast cancers are positive for HR expression at the time of diagnosis.

BOLERO-3 is a phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m IV and weekly trastuzumab 2 mg/kg IV following a loading dose of 4 mg/kg.

The primary endpoint of the trial is PFS. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics.

Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III). 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. 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.

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer. Eighty per cent of advanced breast cancer is either HR+ and/or HER2 positive.

HR+ advanced breast cancer is the most common type of advanced breast cancer, and is characterized by hormone receptor-positive tumours, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones.

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer.

Everolimus is approved as Afinitor in the European Union for the treatment of hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative 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.

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