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Afinitor Falls Short of Goal in HER+ Advanced Breast Cancer Trial

No significant improvement in progression-free survival

Adding everolimus (Afinitor, Novartis) to trastuzumab (Herceptin, Genentech) and paclitaxel did not significantly improve progression-free survival as a first-line treatment for women with human epidermal growth factor receptor-2 positive (HER2+) advanced breast cancer, according to the results of the BOLERO-1 trial. Novartis announced the results at the 2014 San Antonio Breast Cancer Symposium.

HER2+ breast cancer accounts for approximately 20% of advanced breast cancer cases and differs from the hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2–) advanced breast cancer patients for whom everolimus in combination with exemestane following a non-steroidal aromatase inhibitor is approved worldwide.

The study did not meet the threshold of statistical significance for the primary objectives of progression-free survival (PFS) among women with HER2+ advanced breast cancer or the predefined HR–/HER2+ subgroup.

The results of BOLERO-1, a phase III, randomized, double-blind, placebo-controlled multicenter trial of 719 patients with HER2+ locally advanced or metastatic breast cancer, showed that the median PFS with everolimus plus trastuzumab and paclitaxel was 15.0 months versus 14.5 months with placebo plus trastuzumab and paclitaxel, a difference of 0.5 months (hazard ratio, 0.89; 95% CI, 0.73–1.08; P = 0.1166).

In the HR– subgroup of women with HER2+ advanced breast cancer — a second primary objective — everolimus plus trastuzumab and paclitaxel treatment demonstrated benefit over the placebo arm, prolonging median PFS by 7.2 months. The median PFS was 20.3 months with everolimus plus trastuzumab and paclitaxel and 13.1 months with placebo plus trastuzumab and paclitaxel. While this difference was clinically relevant, the results did not demonstrate statistical significance. However, Novartis said this result supports continued research of the PI3K/AKT/mTOR pathway.

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division and blood vessel growth. Preclinical research has shown that activation of the PI3K/AKT/mTOR pathway is frequently a characteristic of worsening prognosis through increased aggressiveness of the tumor, resistance to treatment, and tumor progression. Overactivation of this pathway has also been associated with potential resistance to trastuzumab treatment and disease progression in women with HER2+ advanced breast cancer.

In BOLERO-1, the combination of everolimus, trastuzumab, and paclitaxel was generally well tolerated. Adverse events were consistent with the known safety profile of everolimus. The most common grade 3 or 4 adverse reactions were neutropenia, stomatitis, diarrhea, anemia, hypokalaemia, leukopenia, hyperglycemia, fatigue, pyrexia, and dyspnea.

In the United States, everolimus is approved for the treatment of postmenopausal women with advanced HR+/HER2– breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. HR+/HER2– advanced breast cancer is the most common form of the disease.

SOURCE: Novartis; December 12, 2014.

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