Adding everolimus to exemestane for the treatment of estrogen receptor–positive advanced breast cancer that is refractory to nonsteroidal aromatase inhibitors has beneficial effects on bone turnover and breast cancer progression in bone, according to an exploratory analysis of data from the BOLERO-2 trial.
Additional exploratory analyses demonstrate that everolimus (Afinitor) is well tolerated among postmenopausal women – including the elderly.
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been implicated in resistance to standard endocrine therapy for estrogen receptor–positive breast cancer. Previously reported data from the double-blind, placebo-controlled phase III BOLERO-2 trial showed a significant clinical benefit with respect to the primary end point of progression-free survival when everolimus was added to the steroidal aromatase inhibitor exemestane (Aromasin).
The new findings were presented during poster sessions at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.
To evaluate the bone-related effects of everolimus, investigators analyzed bone turnover marker levels and breast cancer progression in bone in BOLERO-2 patients who had bone metastases at baseline, including 184 patients who received placebo and 370 who received exemestane.
They found that active treatment with everolimus and exemestane was associated with improved levels of bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen at 6- and 12-week follow-up.
The levels of each of these markers had increased at both time points in those receiving placebo, but had decreased in those receiving everolimus, Dr. Lowell L. Hart, a hematologist/oncologist in group practice in Fort Myers, Fla., and his colleagues reported (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102]).
Also, the cumulative incidence rate of breast cancer progressive disease in bone was lower in those who received everolimus, compared with those who received placebo (3.03% vs. 6.16% at day 60), they said, noting that this trend continued beyond 6 months.
Bone-related adverse events among the patients included in this analysis were grade 1/2, and occurred at a similar frequency in both groups (2.9% for the placebo group and 3.8% for the treatment group).
The safety and tolerability of everolimus were also evaluated in two additional exploratory analyses. In one, everolimus treatment was shown at a median of 12.5 months’ follow-up to be generally well tolerated among 492 postmenopausal women in the treatment group for the study.
Notable adverse events of all grades in those patients, compared with the 238 patients in the placebo group, included stomatitis (59% vs. 12%), rash (39% vs. 7%), pneumonitis (16% vs. 0%), and hyperglycemia (14% vs. less than 1%). Notable grade 3/4 events were stomatitis (8% vs. less than 1%), anemia (7% vs. less than 1%), hyperglycemia (5% vs. less than 1%), pneumonitis (3% vs. 0), and rash (1% vs. 0), reported Dr. Alejandra T. Perez, director of the breast cancer center at Memorial Cancer Institute in Hollywood, Fla.
The adverse events were manageable when patients were treated appropriately, Dr. Perez said (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103]).
For example, the study protocol permitted dose reduction or interruptions for the management of adverse events, and a look at the antitumor effects of treatment showed that results were consistent in those who received time-averaged doses less than 7.5 mg/day and those who received time-averaged doses greater than 7.5 mg/day (hazard ratios, 0.4 vs. 0.45, respectively). Those who developed stomatitis were treated with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics, and those with noninfectious pneumonitis were treated using a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment.
Among the subset of study participants aged 65 years and older, the incidences of adverse events were similar or marginally lower than in the entire population, according to Dr. Hope S. Rugo of the University of California, San Francisco, and her colleagues.
For example, stomatitis occurred in 52% of those aged 65 and older who received everolimus, rash occurred in 32%, pneumonitis occurred in 15%, and hyperglycemia occurred in 13%. Grade 3/4 adverse events among those aged 70 years or older and reported only in those receiving everolimus included fatigue in 10%, anemia in 10%, hyperglycemia in 9%, stomatitis in 8%, dyspnea in 7%, pneumonitis in 5%, neutropenia in 3%, and hypertension in 3% (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104]).
Adding everolimus to exemestane was well tolerated both in the overall population and among elderly patients, and grade 3/4 adverse events were uncommon and manageable, Dr. Rugo noted. No new safety signals emerged.
Dr. Perez added that knowledge of adverse event management strategies is essential for optimizing tolerability and patient outcomes.