BOLERO-2 Trial Demonstrates Subgroup Benefits With Everolimus

Hope Rugo, MD

New analyses of the BOLERO-2 trial, presented at the 2013 Breast Cancer Symposium, held September 7-9 in San Francisco, California, indicate that everolimus and exemestane produced significantly longer progression-free survival (PFS) than placebo and exemestane in several previously unstudied patient subgroups.

The first analysis found that everolimus plus exemestane prolonged PFS in patients with hormone receptor-positive (HR+) advanced breast cancer who received treatment as first-line therapy for advanced breast cancer (patients received treatment immediately after recurrence during adjuvant therapy).¹Among 137 patients receiving everolimus plus exemestane (n = 100) or placebo plus exemestane (n = 37) in the advanced setting, 74% of the everolimus arm and 76% of the placebo arm had recurred after adjuvant endocrine therapy plus chemotherapy; 26% and 24%, respectively, had recurred after adjuvant endocrine therapy alone. The everolimus group had significantly longer PFS compared with the placebo group (11.50 vs 4.07 months, respectively; hazard ratio [HR] = 0.39; 95% CI, 0.25-0.62). Median PFS remained longer with everolimus versus placebo, regardless of whether chemotherapy was included with the prior adjuvant hormonal therapy.

Pending results from the recently launched BOLERO-4 trial, which will directly evaluate the efficacy of everolimus as a first-line therapy in patients with HR+ advanced breast cancer, these results support the combination of everolimus plus exemestane in patients whose cancer recurs after adjuvant therapy or never responds to that therapy, said lead author Hope Rugo, MD, professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco.

“Many people have assumed that everolimus would do nothing for patients who did not initially respond to hormone therapy and then grow resistant to it, that hormone therapy simply wouldn’t work for that patient group,” Rugo said. “But these results strongly suggest that everolimus can help hormones work in patients who never respond to hormones as a monotherapy.”

Rugo was also the lead author of the second trial, which analyzed genetic materials from a representative sample of 227 BOLERO-2 participants (157 in the everolimus-plus-exemestane arm and 70 in the placebo-plus-exemestane arm) to test how different mutations responded during the initial trial.²Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox proportional hazard models.

The treatment benefit of everolimus over placebo was maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg,PIK3CA,FGFR1,CCND1) or when less frequently mutated genes (eg,PTEN,AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alterations inPI3KorFGFRpathways orCCND1had a greater treatment effect from everolimus (HR = 0.27; 95% CI, 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to everolimus in this setting.

“Almost half of the tumors had a mutation inPI3Kand the others had less-common mutations that included cell cycle pathway markers as well as fibroblast growth factor receptor and others,” Rugo said. “All patients, no matter what their individual mutations, benefited from the addition of everolimus, which was quite curious. It didn’t matter whether the patients had an activation in the PI3K pathway or not.”

But the news was not all good. “Patients whose tumors had mutations in multiple pathways, which was a small subset, seemed to have the worst overall outcome,” Rugo said, “and they did not benefit from the addition of everolimus.”

On the whole, Rugo thinks that the BOLERO-2 results and all of the subsequent analyses indicate that everolimus is a major step forward in the treatment of hormone receptor-positive breast cancer.

“We’ll have a better idea of just how major the advance is when we see the overall survival data from BOLERO-2, which should be out next year, but every indication we have so far is excellent,” Rugo said. “The progression-free survival numbers are very impressive, and it is well tolerated, which is why a huge number of companies are pouring money into developing their own mTOR inhibitors.”

Everolimus is a synthetic analogue of rapamycin, a naturally occurring mTOR inhibitor that was discovered in 1975 on Easter Island and found useful first as an antifungal, and then as an immunosuppressant. Researchers in the 1980s discovered anticancer activity but did not understand the mechanism of action until the 1990s.

Everolimus was first approved for use against advanced kidney cancer in 2009, and then for progressive or metastatic pancreatic neuroendocrine tumors and for breast cancer in postmenopausal women with advanced hormone-receptor positive, HER2-negative cancer, in conjunction with exemestane.

Those approvals have spurred interest in mTOR inhibitors. The National Cancer Institute lists more than 200 ongoing tests of mTOR inhibitors, either as monotherapies or as part of combination therapies.

1. Rugo HS, Campone M, Gnant M, et al. BOLERO-2: efficacy and safety of first-line everolimus plus exemestane in advanced breast cancer. Presented at: 2013 Breast Cancer Symposium; September 7-9, 2013; San Francisco, CA. Abstract 152.
2. Rugo HS, Hortobagyi GN, Piccart-Gebhart MJ, et al. Correlation of molecular alterations with efficacy of everolimus in hormone-receptor—positive, HER2-negative advanced breast cancer: results from BOLERO-2. Presented at: 2013 Breast Cancer Symposium; September 7-9, 2013; San Francisco, CA. Abstract 142.