December 7, 2011 (San Antonio, Texas) — Adding everolimus (Afinitor, Novartis), a mammalian target of rapamycin (mTOR) inhibitor, to exemestane (Aromasin) significantly improved progression-free survival of postmenopausal women with advanced estrogen receptor–positive breast cancer vs exemestane alone, according to updated findings from a randomized trial reported here at the 34th Annual San Antonio Breast Cancer Symposium.
Among 724 women, median progression-free survival (PFS) with the addition of everolimus to exemestane was 7.4 months, compared with 3.2 months for exemestane alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.36 - 0.53; P < .001), reported Gabriel N. Hortobagyi, MD, on behalf of investigators in the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) trial.
Results of an earlier preplanned interim analysis of the trial were reported at the 2011 European Multidisciplinary Cancer Congress (EMCC) in Stockholm, Sweden, in September and are published online December 7 in the New England Journal of Medicine. Dr. Hortobagyi is presenting updated data from the trial here on December 8.
BOLERO-2 was halted early because of the benefit observed.
"These results establish a new standard of care for this group of patients," Dr. Hortobagyi said.
"Everolimus is the most important advance in breast cancer since trastuzumab," said Fabrice André, MD, from the Institut Gustave Roussy, Paris, France, who acted as discussant during the presentation of the data at EMCC.
"The data are robust and are clinically relevant," he said, adding that "the efficacy is in the range of the most important recent advances in the field of medical oncology."
Commenting on the updated results, Harold Burstein, MD, from the Division of Breast Oncology at the Dana Farber Cancer Institute in Boston, Massachusetts, said that the findings are promising, but he stops short of calling them practice-changing.
"I think what's most exciting about this study is that it builds on some very elegant preclinical work and it provides clinical proof of principle. Secondly, it opens up a whole new pathway for discovery of drug products in breast cancer, and how we take advantage of that I think still remains to be seen," Dr. Burstein said in an interview with Medscape Medical News.
He pointed out, however, that the rate of response to the combination was low at 12% and that the rate of response to exemestane, at 1.3%, was "practically nonexistent."
A previous phase 3 study looking at a different combination of mTOR inhibitor and aromatase inhibitor (temsirolimus and letrozole) failed to find a similar benefit, Dr. Burstein noted.
"That study, in fairness, used a different drug and a patient population that had seen less in the way of hormone treatment, so there are reasons to imagine you could see different study results, but at the same time it's a little hard to immediately reconcile a strongly positive study with a previously negative outcome from a very similarly structured trial," he said.
Dr. Burstein was not involved in BOLERO-2.
Novartis has said that it will be submitting the data for approval of a new indication for everolimus. Clinicians should wait for registration before they incorporate this new drug combination into clinical practice, José Baselga, MD, from the Massachusetts General Hospital and Harvard Medical School, Boston, and BOLERO principal investigator, told Medscape Medical News in September.
However, because both drugs are already commercially available, they could be used off-label for this new indication. Everolimus has already been approved in the United States for the treatment of progressive neuroendocrine tumors of pancreatic origin and advanced renal cell carcinoma in certain patients. Exemestane is widely used as adjuvant therapy for estrogen receptor–positive breast cancer. Both drugs are taken orally.
Previous smaller studies and preclinical data support the use of an mTOR inhibitor to reverse the resistance to hormonal therapy that develops in estrogen receptor–positive breast cancer, Dr. Baselga noted. That resistance has been associated with an activation of the mTOR pathway, which is inhibited by drugs such as everolimus.
The results from this large phase 3 trial show that "everolimus is the first agent to enhance hormone therapy in refractory estrogen receptor–positive breast cancer patients," and they represent a "paradigm shift in the management of these patients," he told delegates.
The BOLERO-2 study was conducted in 724 postmenopausal women with estrogen receptor–positive but HER2-negative advanced breast cancer who had previously been treated with and had become refractory to the nonsteroidal aromatase inhibitors letrozole and anastrozole. Previous therapies included tamoxifen (in 48% patients), fulvestrant (in 16%), and chemotherapy (in 68%).
"When patients stop responding to hormonal therapy, the benefits from any secondary therapy are limited," Dr. Baselga explained.
All the women in the study received exemestane, which is a steroidal aromatase inhibitor with a slightly different profile than letrozole or anastrozole. In addition, women were randomly assigned in a 2:1 ratio to receive everolimus (10 mg/d orally).
The preplanned interim analysis found that everolimus significantly improved progression-free survival, the primary end point of the study. Median progression-free survival, assessed by local investigators, was longer with everolimus plus exemestane than with exemestane alone (6.9 vs 2.8 months; HR, 0.43; P ≤ .0001). These figures changed slightly after central assessment (10.6 vs 4.1 months; HR, 0.36; P < .0001).
With the additional 5 months of follow-up reported here (median follow-up duration, 17.5 months), the investigators found a similarly strong benefit for the combination; 12-month estimates for no disease progression were 31% among patients receiving exemestane plus everolimus and 10% of patients receiving exemestane alone.
In addition, an analysis of data based on independent central review of radiologic findings indicated a median progression-free survival of 11.0 months for exemestane/everolimus, compared with 4.1 months for exemestane alone (HR, 0.36; 95% CI, 0.28 - 0.45; P < .001).
The most recent data show a response rate of 12.% for exemestane/everolimus vs 1.3% for exemestane only, and a clinical benefit rate (combined complete and partial responses and stable disease) of 50.5% for the mTOR inhibitor and aromatase inhibitor combination vs 25.5% for exemestane and placebo (P < .001).
The most common adverse effects reported in the combination and exemestane-alone groups at EMCC were stomatitis (8% and 1%, respectively), anemia (5% and 1%), dyspnea (4% and 1%), hypoglycemia (4% and <1%), fatigue (3% and 1%), and pneumonitis (3% and 0%).
In a statement from the manufacturer, Novartis Oncology president Hervé Hoppenot said, "Despite the significant progress in treating women with breast cancer, there have been no new treatment advances for women living with estrogen receptor-positive, HER2-negative advanced breast cancer in more than 15 years. The results of BOLERO-2 are the first to show everolimus combined with hormonal therapy enabled women with this type of breast cancer to live significantly longer without their tumor progressing."
The BOLERO-2 trial was funded by Novartis. Dr. Hortobagyi has disclosed no relevant financial relationships. Dr. Baselga disclosed acting as a consultant for many pharmaceutical companies, including Novartis, Roche, Merck SA, and Bayer.
34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-7. Presented December 8, 2011.
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