SABCS 2014: PI3K Inhibition With Pictilisib in Hormone Receptor–Positive Breast Cancer Not Ready for Prime Time
Interest is high in studying the PI3K pathway in hormone receptor–positive breast cancer, but it is not clear which of the PI3K inhibitors under development—if any—will be a “home run.”
Adding the pan-class I selective PI3K inhibitor pictilisib to fulvestrant (Faslodex) did not significantly improve progression-free survival in women with estrogen receptor–positive breast cancer, but in an exploratory analysis of the trial, progression-free survival was significantly extended in women with both estrogen receptor–positive and progesterone receptor–positive breast cancer. The findings were presented at the 2014 San Antonio Breast Cancer Symposium (Abstract S2-02).
Targeting the PI3K Pathway
“When we considered only women with breast cancer positive for both estrogen receptor and progesterone receptor, adding pictilisib resulted in a significant doubling of progression-free survival in an exploratory analysis. We plan to investigate whether the benefit of pictilisib for women with estrogen receptor-/progesterone receptor–positive breast cancer holds true in an additional cohort of patients within this study,” stated lead author Ian Krop, MD, Director of Clinical Research for the Breast Oncology Program at the Dana-Farber Cancer Institute, Boston.
“We saw enough activity in the combination arm that makes it worthwhile to look at this pathway in breast cancer. Whether pictilisib is the right drug remains to be seen. There are ongoing studies of other more potent PI3K inhibitors that may have better results,” said study coauthor Eric Winer, MD, of Dana-Farber Cancer Institute.
PIK3CA mutations are present in 40% to 45% of cases of estrogen receptor–positive breast cancers, and PI3K/mTOR signaling is a suspected resistance mechanism to antiestrogen therapy. Pictilisib is an oral potent, pan-class I selective PI3K inhibitor, and there was interest in determining the effect of adding this agent to fulvestrant in patients resistant to aromatase inhibitor therapy.
FERGI Trial
The phase II FERGI trial included 168 postmenopausal women with estrogen receptor–positive, HER2-negative, advanced or metastatic breast cancer who had relapsed or progressed following or during treatment with an aromatase inhibitor. The women were randomly assigned 1:1 to receive treatment with fulvestrant plus pictilisib vs fulvestrant plus placebo and treated until disease progression, at which point placebo patients could cross over to the pictilisib arm.
The safety of the combination was consistent with single-agent phase I experience. No treatment-related deaths were reported. Adverse events of grade 3 or higher in the combination arm included diarrhea (7%), rash (17%), and fatigue (6%).
“These effects were not overly severe in the vast majority of patients. On the other hand, there were more dose adjustments and discontinuations due to adverse events with combination therapy,” Dr. Winer said.
Improvement Shown in Subset Analysis
A modest improvement in progression-free survival was observed in an intent-to-treat analysis of the entire study population,with a median of 6.6 months for the combination vs 5.1 months for the placebo arm. However, in the subgroup of patients with both estrogen receptor–positive and progesterone receptor–positive disease, an unplanned subset analysis showed median progression-free survival of 7.4 months vs 3.7 months.
“We had hoped the combination would be somewhat more active. The subgroup data are worth exploring further and ongoing studies will look at this,” Dr. Winer said.
One surprise was that patients with PIK3CA mutations did not seem to have a preferential benefit from combination therapy, Dr. Winer said.
“It is likely that the field is going toward more selective PI3K inhibitors, such as alpha selective agents,” he noted.
The study was supported by funds from Genentech. Dr. Krop receives research funding from Genentech.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
