We know that mTOR is a critical node in an important signaling pathway in most cancers.
William Gradishar, MD
For the treatment of endocrine-sensitive metastatic breast cancer, the combination of an mTOR inhibitor and an endocrine agent represents a promising new option. At the 2012 Breast Cancer Symposium, the 18-month update of BOLERO-2, which tested therapy with everolimus (Afinitor) plus exemestane, confirmed a more than doubling in progression-free survival, with a 62% reduction in risk.1 Exploratory analyses also suggested that everolimus has positive effects on bone markers and prevents disease progression in the bone.2
With FDA approval of this combination for patients whose disease progresses on letrozole or anastrozole, the regimen is gaining traction in the clinic. The optimal use of everolimus, however, is an evolving scenario, and the next generation of trials seeks to answer several important questions.
“The everolimus approval is likely to be only the beginning in a new phase of outcome improvements for estrogen receptor–positive, HER2-negative disease based on PI3-kinase pathway inhibition in combination with endocrine agents,” predicted Matthew J. Ellis, MB, PhD, of Washington University, St. Louis.
Why the Excitement?
In a lecture about mTOR inhibition, William Gradishar, MD, of Northwestern University Feinberg School of Medicine, Chicago, said, “We know that mTOR is a critical node in an important signaling pathway in most cancers.”
In breast cancer, the currently available mTOR inhibitors appear to enhance endocrine responsiveness where endocrine resistance has taken hold. In both preclinical and phase II clinical studies, the combination of everolimus plus letrozole suppressed tumor cell proliferation more potently than letrozole alone.
Early hints of clinical activity culminated in the promising results of BOLERO-2, in which progression-free survival was 7.8 months with everolimus/exemestane vs 3.2 months with exemestane alone in the 18-month update; by central review, the difference was 11.0 months vs 4.1 months, respectively (P < .0001 for both).
Long-term Estrogen Deprivation
“The interesting thing is that the same was not seen with temsirolimus (Torisel) in a large randomized trial,” he added. The phase III trial included 1,112 patients with metastatic breast cancer who had not received prior hormonal therapy for metastasis.3 Progression-free survival was approximately 9 months in each arm, and the study was closed due to futility.
“It may be that the absence of an activated pathway in the largely endocrine-untreated population may be responsible for the lack of benefit with the combination,” Dr. Gradishar said.
This, he added, is in keeping with a preclinical discovery made a decade ago in Dr. Mitch Dowsett’s laboratory: the finding that PI3K/Akt/mTOR intracellular signaling can be activated during long-term estrogen deprivation.4
“This is a situation that may be replicated in a treated estrogen receptor–positive breast cancer that develops acquired resistance to long-term aromatase inhibitor treatment,” he suggested. “This supports the idea that priming the survival pathway may be important in order to derive an effect from an mTOR inhibitor.”
In other words, mTOR inhibitors may work best in combination with an endocrine agent among patients who develop resistance to endocrine agents. This was implied in the BOLERO-2 trial, as well as in a smaller phase II French study, TAMRAD, which demonstrated greater clinical benefit with everolimus plus tamoxifen (61%) vs tamoxifen alone (42%).5 An exploratory analysis demonstrated benefits in terms of time to progression and overall survival.
The effect in TAMRAD was greater among patients with secondary hormone resistance, in whom progression-free survival was 17.4 months with the combination vs 5.0 months with tamoxifen alone (HR = 0.38), than among those with primary hormone resistance (HR = 0.74).
While this suggests patients with hormone-sensitive disease may derive greater benefit, BOLERO-2 actually showed no difference between this subset (86% of the population) and those with primary resistance (16%), said Hope S. Rugo, MD, of the University of California, San Francisco. Dr. Rugo argued that the TAMRAD subsets were likely too small to be reliable; therefore, one cannot conclude that patients with primary endocrine resistance do not benefit.
Best Partner for Everolimus?
Considering the negative findings for temsirolimus plus exemestane, can one conclude that everolimus is a superior mTOR inhbitor? Probably not, according to Dr. Gradishar.
The two mTOR inhibitors do have pharmacokinetic differences, but the discrepancy in outcome is more likely related to the difference in the trial populations. While temsirolimus was given to endocrine therapy-naive patients, everolimus was given to patients with prior exposure to endocrine agents in the metastatic setting. This likely activates the survival pathways and creates a setting where mTOR inhibition is apt to have an impact, the researchers said.
It is also possible that the disappointing results with temsirolimus were due to an inadequate dose or schedule, Dr. Rugo added, or to the possible dilution of benefit in the 55% of patients without previous exposure to adjuvant hormone therapy (and presumably reduced activation of resistance pathways).
According to Dr. Ellis, even better outcomes might be achieved if everolimus were not paired with exemestane, but with a stronger agent. “Exemestane is a very weak endocrine agent in the setting of nonsteroid aromatase inhibitor resistance,” Dr. Ellis pointed out. “Tamoxifen is actually more active in this setting.”
Notably, an exploratory analysis of TAMRAD showed an overall survival benefit with everolimus plus tamoxifen. In the most recent analysis, median overall survival was 32.9 months with tamoxifen alone but had not yet been reached with the combination, representing a 55% reduction in risk (P = .007), he emphasized.
“Exemestane plus tamoxifen achieved a survival effect in a relatively small study,” Dr. Ellis noted. “Perhaps we would have seen an even greater effect in BOLERO-2 if a more effective endocrine agent had been chosen. Everolimus should probably be tested in combination with potentially more active endocrine agents, such as tamoxifen, high-dose toremifene (Fareston), fulvestrant (Faslodex), or the fulvestrant/aromatase inhibitor combination, with exemestane/everolimus as the control arm.”
Who Should Receive Everolimus?
Meanwhile, BOLERO-2 is having an impact on clinical practice. “With the new data, and the recently updated guidelines, we have a variety of choices for postmenopausal patients, and everolimus plus exemestane is a reasonable consideration for women who fit the eligibility profile of BOLERO-2,” Dr. Gradishar said. “But while there is a role for this combination, we do not have sufficient data to say that we should be using this in every endocrine-responsive patient or in the first-line setting.”
Dr. Rugo added that the expected benefit of this regimen should be weighed against the potential risks in an individual patient. “If well tolerated, a more than doubling of progression-free survival certainly seems to be worthwhile.” She urged caution in patients with primary hormone resistance, but said there are no convincing data that these patients should be excluded.6
In the first-line setting, the phase II BOLERO-4 trial will evaluate the addition of everolimus to letrozole. e who have had disease progression on an aromatase inhibitor, BOLERO-6 will compare everolimus with and without exemestane vs capecitabine (Xeloda), while the phase II PrECOG study will evaluate fulvestrant plus everolimus. The Southwest Oncology Group (SWOG) 2107 trial will move everolimus into the adjuvant setting, evaluating 5 years of endocrine therapy with and without everolimus in high-risk patients.
Clinical trials of eight dual mTOR inhibitors (primarily mTOR/PI3K inhibitors) are underway, and six pan-mTOR inhibitors are in development. “We are awaiting trials that will inform us not only about efficacy with these combinations but also toxicity,” Dr. Gradishar said. ■
Disclosure: Dr. Ellis has served in a consulting or advisory role for GlaxoSmithKline, Novartis, and Pfizer, and has received honoraria or research funding from AstraZeneca, Merck, and Novartis. Dr. Gradishar has served in a consulting or advisory role for Novartis. Dr. Rugo receives research funding through the University of California from Novartis, Pfizer, and Merck.
1. Arena FP, Noguchi S. Pritchard KI, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2012 Breast Cancer Symposium. Abstract 99. Presented September 13, 2012.
2. Hart LL, Baselga J, Rugo HS, et al: Effects of everolimus on disease progression in bone and bone markers in patients with bone metastases. 2012 Breast Cancer Symposium. Abstract 102. Presented September 14, 2012.
3. Chow LWC, Sun Y, Jassem J, et al: Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 100(suppl 1):Abstract 6091, 2006.
4. Martin LA, Farmer I, Johnston SR, et al: Enhanced estrogen receptor alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 278:30458-30468, 2003.
5. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30:2718-2724, 2012.
6. Rugo HS, Keck S: Reversing hormone resistance: Have we found the golden key? J Clin Oncol 30:2707-2709, 2012.