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Phase II Study Shows ER/PR Status, Not PIK3CA Mutations, May ID Responders to PI3K Inhibitor

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SAN ANTONIO – If Genentech's phosphatidylinositide 3-kinase (PI3K) inhibitor pictilisib is advanced in later stage clinical trials, then further research is warranted investigating the response of breast cancer patients whose tumors are estrogen receptor (ER)- and progesterone receptor (PR)-positive, according to investigators involved in the Phase II FERGI study.

Meanwhile, results from the same study, presented at the San Antonio Breast Cancer Symposium, have shed doubt on the potency of pictilisib as a PI3K inhibitor, study investigators said, and raised questions as to whether PIK3CA mutations are predictive of treatment.

In the FERGI Phase II study, researchers led by Ian Krop of Dana-Farber Cancer Institute randomized 168 women with estrogen receptor-positive, HER2-negative metastatic breast cancer to treatment with either pictilisib in combination with the selective estrogen receptor downregulator fulvestrant, or fulvestrant with placebo.

Researcher were looking to see if the addition of pictilisib to fulvestrant improved patients' progression-free survival compared to just fulvestrant. They had also planned to compare progression-free survival in patients with PIK3CA activating mutations, which occur in up to 45 percent of ER-positive breast cancers, as well as in those with loss of the tumor suppressor gene PTEN. Although PIK3CA mutations and PTEN loss don't usually occur simultaneously, both can deregulate the PI3K pathway. Researchers assessed mutations in patients using an RT-PCR assay.

When Krop and colleagues analyzed outcomes in the overall study population, median progression-free survival was 6.6 months in the pictilisib group and 5.1 months in the comparator group, which was not a statistically significant finding. When they looked at the subgroup of patients with PIK3CA mutations, median progression-free survival was 6.2 months in the pictilisib arm and 5.1 in the comparator group. Having a detectable PIK3CA mutation doesn't predict response to pictilisib, Krop said during a presentation at SABCS.

Unable to report a statistically significant benefit in progression-free survival to the drug, Krop and colleagues explored whether there might be another subgroup that could identify a best responder population. They discovered that patients with ER- and PR-positive disease when treated with the pictilisib/fulvestrant combination experienced median progression-free survival of 7.4 months compared to 3.7 months in the fulvestrant/placebo arm. This finding was statistically significant. There weren't enough patients with PTEN loss for researchers to come to any conclusions about drug response.

The ER and PR subset analysis was unplanned, Dana-Farber Cancer Institute's Eric Winer and one of the study investigators said at the meeting. ER- and PR-positivity occurs in 70 percent of invasive breast cancer patients and represents "the group ... who are thought to have the most hormonally sensitive disease," Winer noted. The progesterone receptor facilitates signaling through the estrogen receptor pathway.

In FERGI, researchers combined pictilisib, a class I selective PI3K inhibitor, with an ER downregulator hoping to see efficacy in PI3K mutated patients, since studies have previously shown that the PI3K/mTOR pathway plays a role in driving resistance to anti-estrogen treatments. The Genentech-funded Phase II study "was trying to look for a signal of activity," Winer said. "It was never intended to be a definitive trial."

Gastrointestinal and dermatological reactions in the trial led investigators to reduce the dose of pictilisib significantly. As such, "it is possible that the optimal levels of PI3 kinase inhibition were not achieved due to the need to move forward with dose adjustments in a sizable proportion of patients," Winer said.

In the study, 31 percent experienced serious adverse events compared to 20 percent of those in the comparator arm. The most common pictilisib-related grade 3 or higher events included rash, diarrhea, and fatigue. In the fulvestrant only arm, common grade three or higher adverse reactions included hot flush, fatigue, and rash. More patients discontinued from the pictilisib arm due to toxicities than from the placebo arm.

"In terms of efficacy, the bottom line is … that there was certainly the hope that [pictilisib] would be somewhat more active," Winer said, acknowledging that the finding that PIK3CA mutations were not predictive of treatment response was a surprise. "On the other hand, [the] small improvement in progression-free survival seen in the overall patient population and the exploratory subgroup … is worth looking into further." Researchers are conducting another study to analyze additional biomarkers.

"Whether or not this particular drug is the right drug, remains to be seen," Winer added. "There are now ongoing Phase III 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."

In Winer's view, alpha-selective PI3K inhibitors appear to be more active in those with PIK3CA mutations. "PI3K is quite complex, and there are a number of different subunits," he noted. "The alpha subunit is thought to be responsible for most of the important signaling in breast cancer. And suppressing the alpha portion of PI3K is what is thought to be important." An inhibitor for a specific subunit of the kinase could potentially block the target more potently. With a pan-PI3K inhibitor like pictilisib, there is a chance for greater toxicity – as was seen in FERGI – which could lead to lower dosing that doesn't inhibit the pathway sufficiently.

The field is moving toward these selected agents, Winer said, suggesting that such agents have a greater chance than pictilisib of making it to the market. "With this particular agent … there is a view that this could potentially go forward, but that the others are probably more promising. And this [in breast cancer] may be different than in other malignancies."

Genentech is developing taselisib, a selective inhibitor of PI3K alpha in HER2-negative metastatic breast cancer, solid tumors, and hormone receptor-positive breast cancer. Gilead's Idelalisib, a PI3K delta inhibitor, received FDA approval earlier this year in combination with Rituxan (rituximab) for relapsed chronic lymphocytic leukemia (CLL) and follicular lymphoma and small lymphocytic lymphoma (SLL). The drug is also approved for previously treated relapsed follicular B-cell non-Hodgkin lymphoma and relapsed SLL.

Noting that data from FERGI and other studies possibly indicates that PI3K isn't a "reliable biomarker," Jennifer Litton, director of the Breast Medical Oncology Education Program at the University of Texas MD Anderson Cancer Center, asked Winer if researchers should stop testing for PI3K mutations as an inclusion criteria in trials. Winer responded that researchers should continue to try to better characterize the response of patients with PIK3CA mutations to targeted drugs in trials but testing for this marker shouldn't be done as a matter of standard practice.

While in FERGI researchers investigated pictilisib in patients with advanced breast cancer, another group at SABCS presented data from a trial in which early-stage, ER-positive patients received two weeks of pre-operative treatment with either pictilisib plus anastrozole or just anastrozole. In this study, researchers led by Peter Schmid of Barts Cancer Institute in the UK found that the addition of pictilisib to anastrozole did increase anti-proliferative responses in ER-positive early-stage breast cancer patients, particularly those with Luminal B type tumors, compared to single agent anastrozole. However, similar to FERGI, researchers were unable to show that PIK3CA mutations or PTEN loss were predictive of response to pictilisib.

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