Everolimus Not for Frontline, But HR-Negative Subpopulation Data Offer Hope


Frontline treatment with everolimus (Afinitor) combined with trastuzumab (Herceptin) and paclitaxel failed to delay disease progression versus trastuzumab and paclitaxel alone in patients with HER2-positive advanced breast cancer.

Sara Hurvitz, MD

Frontline treatment with everolimus (Afinitor) combined with trastuzumab (Herceptin) and paclitaxel failed to delay disease progression versus trastuzumab and paclitaxel alone in patients with HER2-positive advanced breast cancer. These results, from the phase III BOLERO-1/TRIO 019 trial, were presented at the 2014 San Antonio Breast Cancer Symposium (SABCS). However, there was a progression-free survival (PFS) benefit observed with everolimus in patients with HR-negative disease.

“The PFS was not improved by everolimus in the full population. In the hormone receptor—negative subpopulation, there was an interesting 7-month improvement in PFS that did not meet statistical significance,” said Sara Hurvitz, MD, lead author of BOLERO-1, at an SABCS press briefing.

The mTOR inhibitor everolimus has shown activity in patients with HER2-positive advanced breast cancer following progression on trastuzumab and/or a taxane. The most recent data came from the BOLERO-3 trial, in which combining everolimus with trastuzumab and vinorelbine improved PFS in pretreated HER2-positive advanced breast cancer.

“Interestingly, in that study there was an exploratory analysis that showed the subset of patients with hormone-receptor negative disease appeared to have more of a benefit from the use of everolimus,” said Hurvitz, who is director of the Hematology/Oncology Breast Cancer Program and an associate professor in the Department of Medicine at UCLA.

The BOLERO-1 trial randomized 719 patients with locally advanced or metastatic HER2-positive breast cancer in a 2:1 ratio to either 10 mg of oral everolimus daily with 80 mg/m2of weekly paclitaxel and trastuzumab at a 4 mg/kg loading dose followed by 2 mg/kg weekly (n = 480), or placebo plus paclitaxel and trastuzumab at the same doses (n = 239 ). The 10-mg/daily trastuzumab dose was higher than the BOLERO-3 dose, which was 5 mg/daily. Treatment was administered until disease progression or unacceptable toxicity.

Patients were enrolled between 2009 and 2011. At baseline, 43.3% of patients (n = 311) were HR-negative, 70.5% had visceral metastases, 24.9% had received a taxane, and 10.8% had prior trastuzumab. The median patient age was 53 years.

The primary endpoints were PFS by investigator assessment in the overall study population and the HR-negative subpopulation. Safety was a secondary endpoint.  

In the full study population, PFS was 14.95 months in the everolimus arm versus 14.49 months in the placebo arm (HR = 0.89; 95% CI, 0.73-1.08;P= .1166). The results were based on 425 PFS events in the overall study population.

“There was no statistically significant difference between the two arms,” Hurvitz said.

Among HR-negative patients, PFS was 20.27 months with everolimus compared with 13.08 months with placebo (HR = 0.66; 95% CI, 0.48-0.91;P= .0049).

“There was a 7-month improvement in favor of the everolimus arm; however, this did not meet our prespecified level of significance,” said Hurvitz.

Hurvitz explained that the researchers had set a prespecified level of significance ofP= .0044, so the HR-negative data were just short of crossing that level.

The adverse-event (AE) profile was consistent with previously reported toxicity data with everolimus, and was similar to what was reported in BOLERO-3. The incidence of several grade 3/4 toxicities was higher in the everolimus arm versus the control arm, including neutropenia (25% vs 15%), stomatitis (13% vs 1%), anemia (10% vs 3%), and diarrhea (9% vs 4%).

Hurvitz also reported that there were more on-treatment deaths related to AEs in the everolimus arm: 3.6% compared with none in the placebo group. The AEs associated with the deaths were primarily pulmonary-related events, including pneumonitis, pneumonia, and cardiopulmonary arrest.

All but one of these deaths occurred in the first 15 months of study enrollment and were mostly reported from study locations without extensive experience in treating patients with everolimus, said Hurvitz.

“When these events occurred, the IDMC sent out a letter to all of the investigators notifying them that very proactive, aggressive management of adverse events was necessary when combining everolimus with chemotherapy, and only one death occurred subsequent to that.”

In summarizing her presentation of the BOLERO-1 results, Hurvitz said, “The data are consistent with the preliminary observation from the BOLERO-3 study that the hormone receptor—negative subpopulation of HER2-positive breast cancer may have a differential response to everolimus, keeping in mind that neither of these studies utilized or allowed endocrine therapy for hormone receptor–positive disease.”

She said that ongoing and planned studies will assess the value of combining mTOR/PI3K inhibitors with endocrine therapy and HER2-targeted therapy in patients with HER2-positive, HR-positive advanced breast cancer.

In an interview withOncLive, Edith Perez, MD, deputy director at large for the Mayo Clinic Cancer Center, suggested that despite the positive frontline data in HR-negative patients, the safety profile of everolimus combined with the emergence of new treatment options might make it difficult to establish the drug in this setting.

“The challenge is that everolimus has some significant toxicities, and now that we have data for trastuzumab with pertuzumab showing pretty impressive improvement in not only progression-free, but also overall survival in the first-line, I think it will be very difficult for everolimus to really develop a role in that particular setting,” said Perez.

Hurvitz SA, Andre F, Jiang Z, et al. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract: S6-01.


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