Combination treatment with everolimus and the aromatase inhibitor exemestane extended progression-free survival (PFS) by more than four months in postmenopausal women with hormone receptor-positive metastatic breast cancer whose disease had continued to spread while on or following initial hormonal treatment, researchers reported here at the CTRC-AACR San Antonio Breast Cancer Symposium.
Gabriel N. Hortobagyi, MD, Chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, presented the results of the Phase III BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial (Abstract S3-7), updating an earlier preplanned interim analysis that appeared online the same day of the presentation in The New England Journal of Medicine (2011 Dec 7, 2011; 10.1056/NEJMoa1109653).
"For postmenopausal patients with hormone receptor-positive metastatic breast cancer, the addition of everolimus to exemestane markedly improved the duration of disease control. These results establish a new standard of care for this group of patients," he said.
BOLERO-2 was stopped early due to the benefits observed in the everolimus arm.
In a second trial presented at the conference, however, adding everolimus to a paclitaxel-containing neoadjuvant chemotherapy regimen did not appear to benefit women with primary HER2-negative breast cancer.
The BOLERO-2 trial involved 724 postmenopausal women with hormone receptor-positive metastatic breast cancer and evidence of recurrence or progressive disease while on anastrozole or letrozole in the adjuvant or advanced setting, or both.
A total of 485 patients were randomly assigned to treatment with exemestane plus everolimus, and 239 were assigned to treatment with exemestane plus placebo.
"Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. Everolimus is a sirolimus derivative that inhibits mTOR. In preclinical and early human studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity," said Hortobagyi, explaining the rationale for the trial.
The median age of the women was 62, and they had undergone a median of three previous therapies. In addition to letrozole or anastrozole, earlier therapies included tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%).
Study Results
The median progression-free survival time was 7.4 months for patients on exemestane plus everolimus versus 3.2 months for women on exemestane plus placebo.
The response rate was 12.0% in the everolimus arm, compared with 1.3% in the placebo arm. The clinical benefit rate-the complete and partial response rate plus the stable disease rate - was 50.5% in the everolimus arm and 25.5% in the placebo arm.
The most common adverse effects in the everolimus and placebo groups, as reported in the NEJM article, were stomatitis (8% and 1%, respectively), anemia (5% and 1%), dyspnea (4% and 1%), hyperglycemia (4% and less than 1%), fatigue (3% and 1%), and pneumonitis (3% and 0%).
One of the co-investigators, Jennifer K. Litton, MD, Assistant Professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, told OT- that the biggest concern with everolimus is stomatitis. "But you can control it with medication or with different delivery systems-putting the medication in a marshmallow, for example," she said.
The overall survival data are not yet mature, she added.
'Data Provide Long-Term Evidence'
Hortobagyi noted that once patients stop responding to hormonal treatment, their options are limited.
"These data provide longer-term evidence of the benefit of adding everolimus to hormonal therapy in patients whose disease progressed while on or following initial hormonal treatment, representing a major paradigm shift in the management of estrogen receptor-positive, HER2-negative breast cancer," he said.
"In this group of heavily pretreated patients, all of whom progressed on prior endocrine therapy, the addition of this mTOR inhibitor resulted in significant prolongation of progression-free survival and an improved response rate, with only a modest addition of toxicity."
Commenting on the updated results, Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, who served on the independent monitoring committee overseeing the trial, said, "This is the first study ever to show any significant benefit in [patients who progress on hormonal therapy]."
And Minetta C. Liu, MD, Director of Translational Breast Cancer Research at Georgetown Lombardi Comprehensive Cancer Center, said that the immediate benefit to the patient is the ability to delay the time to chemotherapy without exposing her to a significant increase in toxicity.
"We don't yet know if [everolimus] will extend overall survival. But it offers patients an option to extend endocrine therapy," she said.
Novartis, which funded the trial, said that it will be submitting the data for approval of a new indication for everolimus. Several oncologists who spoke with OT said they were not in favor of prescribing the combination off-label in the interim.
Everolimus Falls Short
In a second trial of women who failed to respond to four cycles of initial chemotherapy, those who received paclitaxel plus everolimus had lower pathologic complete response (pCR) rates and lower clinical response rates at surgery, compared with patients treated with paclitaxel alone (Abstract S3-6), reported Jens B. Huober, MD, PhD, Professor of Gynecologic Oncology at Kantonsspital in St. Gallen, Switzerland.
The addition of everolimus, however, did bring added toxicity, he said, adding that in preclinical studies, everolimus showed synergistic activity with some chemotherapy drugs, including paclitaxel.
The new study, also funded by Novartis, involved 403 women whose tumors failed to shrink by at least 50% after four cycles of epirubicin and cyclophosphamide with or without bevacizumab. The patients were randomly assigned to either paclitaxel at 80 mg/m2 weekly for 12 weeks, or the same schedule of paclitaxel plus everolimus starting at 2.5 mg every other day and increasing to 5 mg every day after two weeks.
In the paclitaxel group, 11.6% of patients dropped out (2.5% due to adverse events, 5.1% based on the investigator's decision, 2.5% based on the patient's decision, and 1.5% because of progressive disease). In the paclitaxel plus everolimus group, 22.1% dropped out (6.2% due to adverse events, 6.2% based on the investigator's decision, 5.1% based on the patient's decision, 4.1% because of progressive disease, and 0.5% for other reasons). Another 7.2% of patients discontinued everolimus but continued on paclitaxel.
Among the 395 patients with available data, 5.6% of the paclitaxel group had a pCR (using the strictest definition of no invasive or noninvasive residuals in breast and nodes), compared with 3.6% of the paclitaxel plus everolimus group, a nonsignficant difference.
When the University of Texas MD Anderson Cancer Center's definition (no invasive residuals in breast and nodes) or the National Surgical Adjuvant Breast and Bowel Project definition (no invasive residuals in the breast) of pCR were applied, there was still no significant difference between the two arms. And the paclitaxel-only group still had a higher pCR rate numerically.
Similarly, the combined clinical complete and partial response rates at the time of surgery were 62.1% in the paclitaxel group, compared with 52.2% in the paclitaxel plus everolimus group, a nonsignificant difference.
Side Effects
Side effects that were reported significantly more frequently in the paclitaxel-plus-everolimus group than in the paclitaxel-only group included Grade 3 or higher neutropenia (17.8% vs 9.5%); thrombocytopenia of any grade (15.9% vs 5.1%); any grade liver of enzyme abnormalities (47.6% vs 32.2%); any grade of fever (13.8% vs 3.6%); any diarrhea (32.7% vs 16.3%); any grade of infection (38.3% vs 23.0%); any grade of stomatitis; any grade of mucositis and/or esophagitis (66.8% vs 54.1%); and any grade of bleeding (25.5% vs 12.8% ).
Huober said, though, that he is not ready to give up: "It could be that pCR is not the appropriate endpoint in this patient population. Before drawing definite conclusions, [we should wait for] disease-free survival and overall survival results."