FERGI Trial: New Questions About PI3K Inhibition in Breast Cancer

Kate Johnson

December 10, 2014

SAN ANTONIO — Results of the first phase 2 trial to evaluate a phosphatidylinositide 3-kinase (PI3K) inhibitor in estrogen receptor (ER)– positive breast cancer prompted a range of reactions at San Antonio Breast Cancer Symposium (SABCS) 2014, as experts focused on different aspects of the somewhat unexpected findings.

The PI3K pathway is thought to play a key role in the development of resistance to endocrine therapies in ER-positive breast cancer, leading to the hope that combining a PI3K inhibitor with endocrine therapy may partially overcome this resistance.

The FERGI trial was the first to test this hypothesis. It was conducted in postmenopausal patients with advanced ER-positive, HER2-negative disease who had become resistant to treatment with aromatase inhibitors.

The investigators found that adding the investigational PI3K inhibitor pictilisib (Genentech, Inc) to the endocrine therapy fulvestrant (Faslodex, AstraZeneca Pharmaceuticals LP) restored sensitivity to fulvestrant and improved progression-free survival ― but only modestly.

One surprise to the investigators was that PI3K mutation status appeared irrelevant to the outcome.

"We did not see a statistically significant improvement in outcomes in either PI3K mutant or wild-type tumors, only a strong trend, which was independent of mutation status," lead author Ian Krop, MD, told Medscape Medical News in an email.

But an unplanned evaluation of a subset of patients with both ER-positive and progesterone receptor (PR)–positive disease suggested more promising potential.

"Within this subgroup, which accounted for about 70% of patients ― albeit an exploratory analysis ― there was a significant improvement in progression-free survival," said coauthor Eric Winer, MD, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston, Massachusets, who presented the results here.

FERGI included 168 patients who were randomly assigned to receive fulvestrant 500 mg (D1 and D15) with either pictilisib 340 mg QD (n = 89, combination arm) or matching placebo (n = 79, control arm).

Median progression-free survival (PFS) was 6.6 months in the combination arm, compared with 5.1 months in the placebo arm ― a difference that was not statistically significant.

But the ER- and PR-positive patients were 56% less likely to have disease progression when treated with the combination therapy compared with those treated with placebo (median PFS, 7.4 vs 3.7 months; P = 0.002).

"The bottom line is there was enough activity here that there is certainly interest in pursuing additional research related to this pathway in breast cancer," noted Dr Winer during a press conference.

The study provides more evidence that targeting the PI3K pathway "continues to be important in hormone receptor–positive breast cancer," agreed Jennifer Litton, MD, from the University of Texas MD Andersen Cancer Center, in Houston, who moderated the press conference.

But she said the fact that outcomes were not connected to mutations in the PI3K gene "also shows us that PI3K has not yet been proven to be a reliable biomarker."

"The data further confirm the uncertainty of the clinical and functional relevance of PIK3CA genotype in ER-positive breast cancers," commented another expert not involved in the study, Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia.

"Many researchers posited that it is precisely those with PI3K mutations who would derive benefit...but it seems at least that this study makes us question that assumption," added Lidia Schapira, MD, who is also from Dana-Farber but who was not connected with the study.

There are a number of mechanisms by which the PI3K pathway can be activated in cancers besides mutation of the PI3K gene, which may explain why patients with mutant and wild-type genes faired equally in the study, explained Dr Krop. "If the pathway is activated through one of these other mechanisms (eg, loss of PTEN, the suppressor of the pathway, or activation of a growth factor receptor pathway), the pathway can still be blocked by pictilisib, thus restoring sensitivity to the hormonal therapy."

Although the FERGI results underscore the importance of the PI3K pathway, they will likely spell the end of interest in pan-PI3K inhibition with agents such as pictilisib, said Dr Winer.

"There are now ongoing phase 3 trials of agents that are thought to be more potent inhibitors of the PI3K pathway in combination with hormonal therapy, and I think many of us are quite optimistic about those studies in particular," he said.

"PI3 kinase is quite complex, and there are a number of different subunits. The alpha subunit is thought to be responsible for most of the important signaling in breast cancer, and...so by using an alpha-selective agent as opposed to a pan-PI3 kinase inhibitor, there's the ability to hit the target harder."

The study was supported by funds from Genentech. Dr Krop receives research funding from Genentech.

San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S2-02. Presented December 10, 2014.

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