Everolimus (Afinitor) added to tamoxifen delayed tumor progression in patients with hormone receptor (HR)-positive, HER2-negative, advanced metastatic breast cancer (MBC), according to results of the phase II TAMRAD (Tamoxifen and RAD001) study. At 6 months' follow-up, 61% of patients who received the combination had not experienced any tumor progression compared with 42% of patients given tamoxifen alone. Additionally, the median time to disease progression was almost twice as long for the everolimus group.
"The almost doubling 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 principal investigator Thomas Bachelot, MD, Centre Leon Berard, Lyon, France, at a press conference.
Everolimus is an oral inhibitor of mTOR, a protein in cancer cells that regulates tumor cell division, blood vessel growth, and cell metabolism. It is approved in several countries as a second-line therapy for advanced kidney cancer, but its use in breast cancer is investigational. The phase III BOLERO (Breast Cancer Trials of Oral Everolimus) trial is evaluating the safety and efficacy of everolimus in women with advanced breast cancer who become resistant to hormonal therapies.
TAMRAD enrolled 111 patients with HR-positive, HER2-negative MBC who had previously received adjuvant therapy with an aromatase inhibitor. Patients were randomized to 20 mg per day of tamoxifen alone (n = 57) or in combination with 10 mg daily of everolimus (n = 54). Both arms were comparable in terms of disease characteristics, although the median age of patients in the tamoxifen arm was slightly higher than the age of patients in the everolimus arm (66 y vs 62.5 y, respectively). The primary endpoint of the trial was clinical benefit rate (CBR), defined as complete response plus partial response plus stable disease at 6 months.
An exploratory analysis showed a superior CBR for the combination arm versus the tamoxifenonly arm at 13 months (61.1% vs 42.1%, respectively; P
= .045). The addition of everolimus improved the CBR across all predefined subgroups, regardless of the presence of visceral metastases, regardless of whether the patient had taken prior adjuvant tamoxifen or received chemotherapy for metastatic disease, and irrespective of primary or secondary hormone resistance.
Median time to disease progression, a secondary endpoint of the study, reached 4.5 months for the tamoxifen-only arm versus 8.4 months for the everolimus group, representing a 47% reduction in disease progression for patients who took everolimus (P = .0026). As of October 2010, overall survival was significantly superior in the tamoxifen plus everolimus arm, with 80% of women receiving combination therapy alive at 30 months versus ~40% of women taking only tamoxifen (P = .0019). At the time of the analysis, investigators said 17 patients treated with tamoxifen alone had died compared with 5 patients given tamoxifen and everolimus together; none of these deaths was attributable to toxicity.
Adverse effects in both arms were generally manageable, although 15 patients (28%) taking everolimus required dose reductions. Only 3 patients receiving everolimus plus tamoxifen and 4 taking only tamoxifen discontinued because of adverse events. Toxicities of any grade that occurred at higher rates in the everolimus-treated group than in the tamoxifen-only arm included fatigue, stomatitis, rash, anorexia, and diarrhea. Grade 3 and 4 adverse events observed in >10% of patients included stomatitis, which developed in 11% of patients taking everolimus and none of the patients given tamoxifen only; pain, experienced by 9% of patients who received everolimus compared with 19% of patients on tamoxifen alone; and fatigue, which was reported by 6% of patients in the combination arm compared with 11% of patients in the monotherapy group.
Improvement in disease progression favored the everolimus arm for patients with secondary hormone resistance (defined as late relapse or prior response and subsequent progression to metastatic disease on an aromatase inhibitor) versus primary hormone resistance. In the subgroup of patients with secondary hormone resistance (n = 56), median time to progression was 5 months in the tamoxifen-only arm versus 17.4 months in the tamoxifen plus everolimus group. Less disparity was observed in time to progression for patients with primary hormone resistance; median time to progression was 3.9 months with tamoxifen monotherapy versus 5.4 months when everolimus was added to tamoxifen.
Based on these results, Bachelot said the investigators plan to conduct additional studies evaluating the combination of everolimus and hormonal therapy as a second-line option for women with HR-positive, HER2-negative breast cancer.
_______________________________________Abstract S1-6. Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: A Gineco Randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patents with hormone-receptor positive, HER2 negative metastatic breast cancer with prior exposure to aromatase inhibitors. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.