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.” The phase II FERGI study, reported at the 2014 San Antonio Breast Cancer Symposium, failed to meet its primary endpoint with the PI3K inhibitor pictilisib but did provide hints of activity and areas for further investigation of this drug.1
In the FERGI trial, the addition of pictilisib to fulvestrant (Faslodex) did not significantly improve progression-free survival in women with estrogen receptor–positive metastatic breast cancer resistant to previous aromatase inhibitor therapy. However, in an exploratory analysis of the trial, pictilisib extended progression-free survival in women with both estrogen receptor–positive and progesterone receptor–positive metastatic breast cancer.
“When we considered only women with metastatic breast cancer positive for both the estrogen receptor and progesterone receptor, adding pictilisib resulted in a doubling of progression-free survival in an exploratory analysis. We plan to investigate whether the benefit of pictilisib for women with estrogen receptor–positive and progesterone receptor–positive breast cancer holds true in an additional cohort of patients within this study,” stated lead author Ian Krop, MD, PhD, Director of Clinical Research for the Breast Oncology Program at the Dana-Farber Cancer Institute in Boston.
“We saw enough activity in the combination arm to investigate this class of drugs further in the setting of metastatic breast cancer. Whether pictilisib is the right drug remains to be seen. There are ongoing studies of other more potent PI3K inhibitors that may ultimately have better results,” said study coauthor Eric Winer, MD, of Dana-Farber Cancer Institute.
PI3K 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.
Study Details and Findings
The phase II FERGI trial included 168 postmenopausal women with advanced or metastatic breast cancer previously treated with an aromatase inhibitor as adjuvant or metastatic therapy. 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 time patients receiving placebo could cross over to pictilisib.
The median age of patients was about 62 years, and more than one-third of patients were older than age 65. About 40% of patients in both arms had PIK3CA mutations. In the pictilisib arm, 65% were progesterone receptor–positive, and 24% were progesterone receptor–negative; in the placebo arm, 73% were progesterone receptor–positive, and 18% were progesterone receptor–negative. The progesterone receptor status was unknown for the remaining patients in both arms. All patients were estrogen receptor–positive.
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.
A modest improvement in progression-free survival was observed in an intent-to-treat analysis of the entire study population: a median of 6.6 months for the combination vs 5.1 months for the placebo. However, in the subgroup of patients with both estrogen receptor–positive and progesterone receptor–positive disease, an unplanned subset analysis showed a median progression-free survival of 7.4 months vs 3.7 months.
“Although 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 an increased benefit from combination therapy. However, testing for PIK3CA mutations should be done only in the context of a clinical trial, Dr. Winer stated.
“It is likely that the field is going toward more selective PI3K inhibitors, such as alpha-selective agents,” he noted.
Dr. Krop said that an additional 60 patients would be entered in this study.
Glass Half Empty?
At the press conference, moderator Jennifer Litton, MD, of MD Anderson Cancer Center in Houston, said evidence shows that targeting the PI3K pathway continues to be important in hormone receptor–positive breast cancer.
“The pathway is clearly activated in breast cancer. The modest 1- to 2-month advantage with pictilisib was not impressive,” she said. “Also, this therapy has toxicity.” In addition, in this study, PI3K mutations were not a reliable biomarker.
Both she and Dr. Winer agreed that pictilisib would not turn out to be the PI3K inhibitor “most likely to succeed,” and both said that perhaps investigational alpha-selective PI3K inhibitors may turn out to be more effective than pictilisib in breast cancer. ■
Disclosure: Drs. Krop and Winer have received research funding from Genentech/Roche. Dr. Litton has received uncompensated research funding from BioMarin Pharmaceutical, Novartis, and BMS.
Reference
1. Krop I, Johnston S, Mayer IA, et al: The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER-positive, aromatase inhibitor-resistant advanced or metastatic breast cancer: Part I results. 2014 San Antonio Breast Cancer Symposium. Abstract S2-02. Presented December 10, 2014.
