Progression-Free Survival Doubled With New Breast Cancer Combination

A significant improvement in progression-free survival (PFS) was seen when Afinitor (everolimus) was added to Faslodex (fulvestrant) for premenopausal patients with metastatic hormone receptor (HR)—positive, HER2-negative breast cancer who are resistant to aromatase inhibitor (AI) therapy, according to findings from the phase 2 PrECOG 0102 trial presented during a press conference at the 2016 San Antonio Breast Cancer Symposium.

In the study, the Afinitor/Faslodex combination doubled median PFS rates compared with Faslodex alone, from 5.1 months on Faslodex to 10.4 months with the combination.

“We feel that the study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” said Noah S. Kornblum, M.D., assistant professor of medicine, Albert Einstein College of Medicine, and attending physician of medicine, Montefiore-Einstein Center for Cancer Care.

The authors had hypothesized that the combination of Afinitor and Faslodex could be used to treat AI-resistant disease, which usually develops in most patients with HR-positive breast cancer treated with AI therapy. Researchers have shown that AI resistance can be overcome by targeting the PI3K-AKT-mTOR pathway, as seen in the phase 3 BOLERO-2 trial of Afinitor and Aromasin (exemestane) in patients with HR-positive advanced breast cancer and resistance to AI therapy.

In the BOLERO-2 trial, the addition of the mTOR inhibitor to Aromasin improved PFS rates from 3.2 months on Aromasin alone to 7.8 months with the combination. The combination was approved in 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer, largely based on results from the BOLERO-2 trial.

The patient population in the PrECOG trial were similar to those in the BOLERO-2 study, yet Kornblum believes that patients in the PrECOG placebo arm may have had longer PFS rates than those in the BOLERO-2 placebo arm due to the superiority of high-dose Faslodex over Aromasin.

“There are some potential advantages of fulvestrant in some people’s minds over steroidal AIs, such as exemestane,” Kornblum said. We don’t really have a direct comparison of these two combinations, but I think [fulvestrant and everolimus] does offer some [additional] options and it’s nice to have great options.”

Patients in the PrECOG trial were eligible if they had relapsed while on adjuvant AI therapy or had progressed after an AI therapy for metastatic disease, had an ECOG performance status score of 0 or 1, and had previously received no more than one chemotherapy regimen.

The 130 patients were randomized one-to-one in the induction phase to receive either high-dose Faslodex in addition to 10 mg of Afinitor or Faslodex with matching placebo. Patients continued treatment until progression or unacceptable toxicity for a maximum of 48 weeks. After 48 weeks, patients moved on to the continuation phase and could continue treatment of Faslodex with or without Afinitor.

The combination was associated with additional toxicity compared with the Faslodex-alone arm with grade 3 adverse events (AEs) occurring in 48 percent of patients in the combination arm versus 14 percent in the Faslodex group. The most common grade 3 AEs in the combination arm included stomatitis in 9 percent of patients, pneumonitis in 6 percent, fatigue in 5 percent and hyperglycemia in 6 percent.

The safety profile of the Afinitor/Faslodex combination was consistent with that of the Afinitor/ Aromasin combination in the BOLERO-2 trial. Yet Kornblum said that clinicians are all “learning on the fly, somewhat, how to manage the safety and toxicity profiles for these combinations.”

For instance, Kornblum noted that in the trial supportive care with prophylactic corticosteroid mouthwash was not used, which could have possibly prevented the frequency of cases of stomatitis as recent data has shown that the use of corticosteroid mouthwash reduces the risk of low-grade stomatitis. “That information was not known at the inception and conduction of this study,” he said.