San Antonio, TX—The addition of the mTOR inhibitor everolimus (Afinitor) to the antiestrogen chemotherapy fulvestrant (Faslodex) led to a 2-fold increase in progression-free survival (PFS) in patients with advanced hormone receptor (HR)-positive breast cancer compared with fulvestrant alone, according to results of a randomized clinical trial presented at the 2016 San Antonio Breast Cancer Symposium.
In this study, the median PFS was 10.4 months with everolimus versus 5.1 months with fulvestrant alone, representing a 40% reduction in the hazard for disease progression or death for patients who received the combination.
Adding everolimus to the treatment regimen also added toxicity, but no new or unexpected adverse events were observed, reported Noah S. Kornblum, MD, Medical Oncologist, Montefiore Einstein Center for Cancer Care, Bronx, NY.
“This study provides additional evidence that adding everolimus to antiestrogen therapy in aromatase inhibitor–resistant disease improves clinical outcomes. My personal opinion is that this combination is likely to become a good treatment option for women with metastatic, endocrine-resistant breast cancer, but I don’t know if the pharmaceutical companies will apply for FDA approval for this indication,” said Dr Kornblum.
The findings are consistent with those of the 2013 BOLERO-2 clinical trial by Yardley and colleagues, in which the addition of everolimus to the steroidal aromatase inhibitor exemestane (Aromasin) doubled the median PFS to 7.8 months versus 3.2 months with exemestane alone.
These 2 combinations of everolimus plus an aromatase inhibitor represent ongoing efforts to develop strategies for managing advanced, endocrine-resistant breast cancer. Current strategies include the use of drugs that effect more complete inhibition of estrogen activity, such as a selective estrogen receptor downregulator or degrader.
Dr Kornblum reported findings from the phase 2 PrECOG-0102 clinical trial involving 130 postmenopausal women with progressive, locally advanced or metastatic HR-positive, HER2-negative breast cancer. All patients had previously received an aromatase inhibitor in the adjuvant or the metastatic setting. The primary end point was PFS. Treatment continued for a maximum of 48 weeks, at which point patients with progression-free disease could continue their assigned therapy.
The trial was powered to detect a 90% improvement in median PFS—from 5.4 months (as demonstrated in the 2010 CONFIRM trial of fulvestrant) to 9.2 months. The primary analysis showed an even greater improvement than projected, with a hazard ratio of 0.61 for the everolimus arm (P = .02).
Patients in the everolimus group had a 3-fold (48% vs 14%) increase in grade 3 adverse events. The most common grade 3 events were stomatitis (9%), pneumonitis (6%), hyperglycemia (6%), and fatigue (5%). Dr Kornblum noted that patients did not receive prophylactic corticosteroid mouthwash, which has been shown to reduce the risk for grade 1 or 2 stomatitis.
“In general, adverse events were manageable and consistent with the profile observed with everolimus in the BOLERO-2 trial,” said Dr Kornblum.
This study began before recent results with CDK4/CDK6 inhibitors—such as palbociclib (Ibrance) or ribociclib (Kisqali)—became available, showing unprecedented improvement in PFS and a survival advantage when used in combination therapy for advanced, hormone-responsive breast cancer. Nonetheless, the results of the PrECOG-0102 trial showed that everolimus offers another option for patients with advanced, HR-positive breast cancer, said Virginia G. Kaklamani, MD, DSc, Leader, Breast Cancer Program, Cancer Therapy & Research Center, UT Health Science Center San Antonio, TX. She also downplayed the need for phase 3 results to validate everolimus-containing combination therapy in this setting.
“What is important for clinicians is that, when we use combinations with our patients, there has been some kind of clinical trial that has validated that combination,” said Dr Kaklamani, who moderated the press briefing that included Dr Kornblum’s presentation.
“For CDK4/6 inhibitors and for everolimus, the sort of endocrine therapy we pair them with is not as important as the fact that we use the drugs,” she concluded.
