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Pictilisib–fulvestrant combination doubled PFS in advanced ER-, PR-positive breast cancer
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SAN ANTONIO — The addition of the investigational PI3 kinase inhibitor pictilisib to fulvestrant did not significantly extend PFS among postmenopausal patients with ER-positive advanced or metastatic breast cancer who were resistant to aromatase inhibitors, according to results of a randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.
However, results of an exploratory analysis showed the combination doubled PFS among the subset of patients who were both ER-positive and PR-positive, results showed.
“The PI3 kinase pathway has been the focus of a great deal of attention over the past 10 years,” researcher Eric P. Winer, MD, chief of the division of women’s cancers, director of the Breast Oncology Program and chair in breast cancer research at Dana-Farber Cancer Institute, said during a press conference. “In ER-positive breast cancer, PIK3CA mutations — which are activating mutations and lead to signaling through the pathway — are present in 40% to 45% of cases.”
Preclinical and early clinical data show activation of the PI3K signaling pathway may promote resistance to endocrine treatment among patients with ER-positive breast cancer. Also, the combination of pictilisib and fulvestrant is more active than either agent alone in ER-positive animal models, Winer said.
In the FERGI study, researchers assessed whether the addition of pictilisib to fulvestrant would extend PFS among patients with ER-positive metastatic breast cancer who were resistant to endocrine therapy with aromatase inhibitors.
The analysis included 168 postmenopausal patients with ER-positive, HER-2–negative advanced or metastatic disease. All patients had progressed or relapsed during or after treatment with an aromatase inhibitor.
Researchers randomly assigned 89 patients to 500 mg fulvestrant on day 1 of each 28-day cycle plus 340 mg daily pictilisib (GDC-0941, Genentech). The other 79 patients received fulvestrant plus placebo. Patients who progressed on fulvestrant alone had the opportunity to cross over to treatment with the combination.
Median follow-up was 17 months.
In the intention-to-treat population, researchers reported a modest improvement in median PFS among patients assigned the combination (6.6 months vs. 5.1 months; HR=0.73; 95% CI, 0.51-1.05), but the difference was not statistically significant.
Researchers then analyzed outcomes among the 116 patients with ER-positive and PR-positive disease. Among that subgroup, 58 patients received fulvestrant plus pictilisib, and 58 received fulvestrant plus placebo.
“This is the group of patients who are thought to have the most hormonally sensitive disease because PR helps to facilitate signaling through the estrogen receptor pathway,” Winer said.
Results of this analysis showed patients who received the combination demonstrated significantly longer median PFS (7.4 months vs. 3.7 months; HR=0.44; 95% CI, 0.28-0.68).
Ian E. Krop
“One surprise from our data was that having breast cancer with a mutation in the PIK3CA gene, a central component of the PI3K signaling pathway, was not predictive of benefit from pictilisib,” said researcher Ian E. Krop, MD, PhD, director of clinical research for the Breast Oncology Program at Dana-Farber Cancer Institute. “It may be that PIK3CA mutation is not the only way to activate PI3K signaling.”
Researchers reported a higher rate of serious adverse events in the combination arm (31% vs. 20%), although the safety of the combination was consistent with that observed during phase 1 evaluation of single-agent pictilisib.
Adverse events that occurred more frequently in the combination arm included diarrhea (63% vs. 9%), nausea (48% vs. 19%), rash (43% vs. 6%), dysgeusia (35% vs. 0%) and fatigue (27% vs. 20%). The most commonly reported grade ≥3 adverse events in the combination arm were rash (17%), diarrhea (7%), fatigue (6%), hyperglycemia (5%) and nausea (3.4%).
No treatment-related deaths occurred.
“There was certainly the hope that this [combination] would be more active,” Winer said. “On the other hand, there was a small improvement in PFS seen in the overall patient population. The exploratory subgroup of patients who had ER- and PR-positive breast cancer is worth looking into further, and there are studies ongoing to do just that.”
The FERGI study is one of several studies designed to evaluate inhibitors of the PI3 kinase pathway, and the results justify the interest in pursuing additional research related to this pathway in breast cancer, Winer said.
“Whether [pictilisib] is the right drug remains to be seen,” Winer said. “There are now ongoing phase 3 trials of agents that are thought to be more potent inhibitors of the PI3 kinase pathway in combination with hormonal therapy. Many of us are quite optimistic about those studies.”
For more information:
Krop IE. Abstract #S2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Disclosure: The researchers report research funding from Genentech; employment relationships with, speaker relationships with and stock ownership in Roche; and contracts and consultant roles with Genentech/Roche, Novartis and Pfizer.
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Jennifer K. Litton, MD
This study shows more evidence that targeting this pathway continues to be important in hormone receptor-positive breast cancer. It also shows us again that the PI3 kinase has not yet been proven to be a reliable biomarker.Click Here to Manage Email Alerts