Adding the PI3K Inhibitor BYL719 to Letrozole Was Safe, With Early Signs of Activity Against Metastatic ER-positive Breast Cancer


​PHILADELPHIA — Postmenopausal women with metastatic breast cancer positive for the estrogen receptor (ER) found that combination therapy with the phosphatidylinositol-3-kinase (PI3K) inhibitor BYL719 (alpelisib) and the antiestrogen letrozole was safe and tolerable, and a subset of the women gained clinical benefit from the combination, according to data from a phase Ib clinical trial presented at the AACR Annual Meeting 2015, held here April 18-22.

“Antiestrogen therapies like tamoxifen and letrozole are the standard of care for patients with ER-positive breast cancer,” said Ingrid A. Mayer, MD, associate professor of medicine and clinical director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “Unfortunately, in some cases, a patient’s cancer eventually becomes resistant to these treatments and their disease progresses. Ingrid A. Mayer, MD

“Preclinical studies have shown that ER-positive breast cancer cells frequently use the PI3K signaling pathway to circumvent the anticancer effects of an antiestrogen therapy and that adding a PI3K inhibitor to an antiestrogen therapy seems to restore the sensitivity of ER-positive breast cancer cells to antiestrogen therapies,” continued Mayer.

Mayer went on to explain that these preclinical data were the basis for proposing this dose-escalation phase Ib clinical trial, in which 26 patients with metastatic ER-positive breast cancer that was not responding to antiestrogen therapy received letrozole at 2.5 milligrams per day in combination with BYL719.

The researchers found that the maximum-tolerated dose of BYL719 in combination with letrozole was 300 milligrams per day. The most frequent adverse events were diarrhea, nausea, hyperglycemia, fatigue, and rash.

“Our latest analysis of the data showed that some patients with ER-positive breast cancer that is no longer responding to antiestrogen therapies had relatively long-lasting clinical benefit (i.e., lack of disease progression): 19 percent of patients on the study had a partial response and 43 percent of patients had stable disease; 35 percent of patients had clinical benefit for over six months and 30 percent of patients had clinical benefit for over 12 months,” said Mayer. “We are looking forward to investigating whether this is typical for this drug combination in a phase III clinical trial that will soon start global accrual.”

According to Mayer, five patients experienced a partial response, two of whom are still on treatment, having started more than 15 months ago. “Importantly, several patients had long-lasting clinical benefit,” she said. “The longest duration on treatment was 20 months, but several other patients remained on study for over 14 months without disease progression.”

Analysis of tumor samples from the patients showed that 61 percent had mutations in the PIK3CA gene. Mayer noted that the BYL719 and letrozole combination had clinical activity in both patients with and without these mutations, but a higher proportion of the clinical benefit was seen in patients with PIK3CA mutations.

This study was funded by Stand Up To Cancer, Vanderbilt-Ingram Cancer Center Breast Cancer Specialized Program of Research Excellence (SPORE) from the National Cancer Institute, and Novartis. Mayer receives research support from Novartis.

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