The results of the first randomized, blinded phase II study of a PI3K inhibitor in estrogen receptor (ER)-positive breast cancer raised, rather than addressed, many questions about the utility of PI3 kinases in breast cancer treatment. The results of the FERGI trial showed that adding the PI3K inhibitor pictilisib to fulvestrant in women with postmenopausal ER-positive, HER2-negative breast cancer improved progression-free survival (PFS) by a median of 1.5 months. The PFS was 6.6 months in the combination arm compared with 5.1 months in the fulvestrant-alone arm (hazard ratio, 0.74; P = .0959).
“What you can see is that there is a modest improvement in PFS but not one that reached a statistical significance,” said study author Eric Winer, MD, director of the breast oncology program at Dana-Farber Cancer Institute in Boston, who presented the results at the 2014 San Antonio Breast Cancer Symposium (SABCS), held December 9–13 in San Antonio, Texas. Winer emphasized that because the trial was relatively small, any statistically significant difference would be a relatively large difference in outcome.
Winer noted that it is possible that the optimal level for PI3K inhibition was not achieved because of the need to dose-adjust a sizable portion of patients on the trial.
Pictilisib is an oral, selective pan-class I PI3K inhibitor. About 40% to 45% of ER-positive breast tumors harbor an activating PI3KCA mutation, which activates PI3K/mTOR signaling. The PI3KCA protein, part of the PI3K/mTOR signaling pathway, is thought to play a role in the resistance of ER-positive disease to anti-estrogen therapies. The hypothesis for the FERGI trial is that the addition of a PI3K inhibitor to endocrine therapy may overcome resistance in these patients.
A total of 168 patients were randomized 1:1 to either 500 mg per day of fulvestrant (79 patients) or fulvestrant and 340 mg of pictilisib once daily (89 patients). All patients had previously been treated with an aromatase inhibitor.
A greater number of patients experienced side effects in the combination arm compared with the control arm. “Most of those side effects tended to be gastrointestinal and dermatologic side effects. They were not overly severe in the vast majority of cases,” said Winer during his presentation. Twenty-eight (31%) patients had serious side effects in the combination arm compared with 16 (20%) in the control arm. The most frequent grade 3 or higher adverse events in the combination arm were rash (17%), diarrhea (7%), fatigue (6%), and hyperglycemia (5%). The only grade 3 or higher adverse events in the fulvestrant-alone arm were two (3%) aspartate aminotransferase (AST) enzyme increases.
An exploratory subpopulation analysis showed that those patients who had both ER- and progesterone receptor (PR)-positive disease derived the most benefit from the combination therapy. Patients in this subgroup treated with the combination were 56% less likely to have disease progression compared with those treated with fulvestrant alone. Among these ER- and PR-positive patients (58 in each treatment arm), the PFS was 7.4 months and 3.7 months in the combination and control arms, respectively (P = .002). The PR helps facilitate signaling through the ER pathway, noted Winer during his presentation. “The exploratory subgroup of patients who had PR- and ER-positive breast cancer is worth looking into further and there are studies ongoing to do just that,” Winer said.
Patients who had PI3KCA mutations did not appear to have improved outcomes with pictilisib, a surprising find, said Winer.
“The bottom line is that there is enough activity here that there is interest in pursuing additional research in this pathway in breast cancer,” concluded Winer. Still, whether this particular drug, a pan-PI3K inhibitor, or more targeted PI3K inhibitors against specific PI3K subunits will prove most efficacious in breast cancer remains to be seen.
“This study shows us that this pathway continues to be impotent in hormone receptor–positive breast cancer and it shows us again another study that PI3KCA has not yet been proven to be a reliable biomarker,” said Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center, who moderated the press conference.
1. Krop I, Johnston S, Mayer IA, et al. FERGI phase II study of PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor-(AI)-resistant advanced or metastatic breast cancer–part 1 results. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S2-02.