SAN ANTONIO – Adding daily everolimus to weekly trastuzumab and paclitaxel as first-line therapy resulted in a median 7.2-month gain in progression-free survival in women with hormone receptor-negative, HER2+ advanced breast cancer in the Phase III BOLERO-1 trial.
Median progression-free survival was 20.27 months with the addition of everolimus (Afinitor) compared with 13.08 months with placebo in the 309 patients with hormone receptor-negative disease who participated in the randomized, double-blind study conducted at 141 centers in 28 countries, Dr. Sara A. Hurvitz reported at the San Antonio Breast Cancer Symposium. This translated to a 34% relative risk reduction for disease progression in patients randomized to everolimus, an oral mTOR inhibitor (P = .0049). However, this seemingly robust outcome did not actually achieve statistical significance. Since this was a subgroup analysis -- the other 410 participants in BOLERO-1 had hormone receptor-positive, HER2+ advanced breast cancer -- the prespecified threshold for significance set by the study statisticians for the analysis in hormone receptor-negative patients was P = .0044.
An Australian statistician rose from the audience to take issue with the BOLERO-1 statisticians in setting the bar for statistical significance so high.
“This was a statistical decision that was made. We’re all thinking about that,” admitted Dr. Hurvitz, director of the breast oncology program in the division of hematology-oncology at the University of California, Los Angeles.
Dr. Sara A. Hurvitz
Everolimus showed no benefit in the full study population, where median progression-free survival was virtually identical in the two treatment arms: 14.95 months with everolimus at 10 mg daily, 14.49 months with placebo.
Trastuzumab (Herceptin) has dramatically improved outcomes in patients diagnosed with HER2+ breast cancer, both in the early-stage and advanced settings. But not everyone benefits.
“Resistance to treatment remains a major clinical unmet challenge,” she observed.
The rationale for BOLERO-1 was that hyperactivation of the P13 kinase/mTOR pathway is one likely mechanism for HER2 resistance, and therefore an mTOR inhibitor such as everolimus might close off this resistance.
The most common adverse events associated with everolimus in BOLERO-1 were stomatitis, diarrhea, neutropenia, and anemia.
Of greater concern was the 3.6% mortality due to adverse events in the everolimus group compared with none in placebo-treated controls. Most of the deaths were due to pulmonary causes. Study leaders noticed that these deaths were occurring in centers with little experience in using everolimus. A letter was sent to all investigators underscoring the need for proactive aggressive management of adverse events in patients taking everolimus with chemotherapy; after that there was only a single additional death.
Dr. C. Kent Osborne commented that he thought it was a mistake for the BOLERO-1 investigators not to allow endocrine therapy in the patients with hormone receptor-positive disease.
“I think it’s important to add endocrine therapy because the estrogen receptor provides an immediate escape mechanism. If you don’t block it in a HER2+ tumor, the estrogen receptor can start activating and signaling the tumor cell to survive. It’s a very important issue,” said Dr. Osborne, professor of medicine and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston.
Dr. Hurvitz concurred.
“Now, with our retrospectoscope on, I think ongoing and future studies are going to be utilizing endocrine therapy with HER2-targeted therapy and P13 kinase inhibitors in this setting,” the oncologist said.
The BOLERO-1 trial was sponsored by Novartis. Dr. Hurvitz reported receiving research support from Genentech, Roche, and Novartis.