A new study shows that the addition of everolimus (Afinitor® tablets) to the hormonal therapy tamoxifen in patients with hormone-receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer who have been previously treated with an aromatase inhibitor (AI) delays disease progression compared to tamoxifen alone. These results were presented today at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium in San Antonio, Texas(1).
Findings from a randomized, Phase II study of 111 patients showed the proportion of metastatic breast cancer patients without tumor progression at six months was 61.1% for those taking everolimus plus tamoxifen (95% confidence interval [CI], 46.9 to 74.1) versus 42.1% for patients treated with tamoxifen alone (95% CI, 29.1 to 55.9); p=0.045(1).
Disease progression was delayed by a median of 8.6 months in patients treated with the combination versus 4.5 months in patients treated with tamoxifen alone, with everolimus in combination with tamoxifen providing a statistically significant reduction in the risk of disease progression by 47% (hazard ratio=0.53 [95% CI, 0.35 to 0.81]; log-rank test: p=0.0026, exploratory analysis). Side effects were generally manageable in both study arms. As of October 2010, there were 25 patient deaths in the tamoxifen arm versus nine in the everolimus plus tamoxifen arm (hazard ratio=0.32 [95% CI, 0.15 to 0.68]; log-rank test: p=0.0019)(1).
This Phase II trial is conducted by the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du sein (the French GINECO Group).
Everolimus is an investigational agent for the treatment of patients with breast cancer. Everolimus targets mTOR in cancer cells, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism(7,8).
“The almost doubling of time to disease progression seen in the everolimus plus tamoxifen treatment arm reinforces the potential benefit of inhibiting mTOR to help overcome endocrine therapy resistance,” said Thomas Bachelot, MD, from Centre Leon Berard in Lyon, France, and principal investigator of the study. “Based on these results, additional studies will evaluate the combination of everolimus with hormonal therapies as a second-line treatment for patients with HR+/HER2- metastatic breast cancer.”
Breast cancer patients with advanced disease who become resistant to hormonal therapies have limited treatment options(2). Prior to these study findings, Novartis Pharmaceuticals Corporation (“Novartis”) initiated a Phase III trial program called BOLERO (Breast cancer trials of OraL EveROlimus), which is the largest international Phase III clinical trial program to study an mTOR inhibitor in patients with locally advanced or metastatic breast cancer(4,5,6).
“These results are encouraging because if everolimus is approved for this indication, it could offer physicians a new strategy to treat patients with metastatic breast cancer whose disease progresses or becomes resistant to traditional hormonal therapies,” said Herve Hoppenot, President, Novartis Oncology. “Novartis has a Phase III study underway researching the potential of everolimus for this patient population, which currently has limited treatment options.”
Study Details
This randomized Phase II trial evaluated the efficacy and safety of everolimus in 111 patients with HR+/HER2- metastatic breast cancer with prior exposure to AI treatment (in adjuvant and/or metastatic setting). Patients were randomized 1:1 to receive everolimus plus tamoxifen (10 mg/day plus 20 mg/day, respectively) [N=54] or tamoxifen alone (20 mg/day) [N=57]. The primary endpoint was clinical benefit rate, defined as complete response, partial response and stable disease (CR+PR+SD) at six months in the everolimus plus tamoxifen arm. For the intent-to-treat analysis, a gain in clinical benefit of at least 20 percent was needed to warrant further study of the combination regimen, which was met in this trial(1).
For patients receiving everolimus plus tamoxifen, time to disease progression, a secondary endpoint, was almost twice as long as it was for patients receiving tamoxifen alone (8.6 months in patients treated with the combination versus 4.5 months in patients treated with tamoxifen alone). Everolimus in combination with tamoxifen provided a statistically significant reduction in the risk of disease progression by 47% (hazard ratio=0.53 [95% CI, 0.35 to 0.81]; log-rank test: p=0.0026, exploratory analysis)(1).
Side effects were generally manageable in both arms of the study. Everolimus had to be decreased for 15 patients (28%). Treatment was stopped due to toxicities in three patients in the everolimus plus tamoxifen arm and in four patients in the tamoxifen-only arm. Grade 3-4 adverse events (>10%) were stomatitis (11% in the everolimus plus tamoxifen arm and 0% in the tamoxifen-only arm), pain (9% in the everolimus plus tamoxifen arm and 19% in the tamoxifen-only arm) and fatigue (6% in the everolimus plus tamoxifen arm and 11% in the tamoxifen-only arm)(1).
Source: Novartis