PI3K Inhibitor Penetrates Endocrine-Resistant Breast Cancer

Kate Johnson

December 14, 2015

SAN ANTONIO ― Although the news from the phase 3 BELLE-2 study is that the results are good, albeit "modest" overall, a more exciting story is emerging for a subgroup of patients with mutations in the phosphatidylinositol 3-kinase (PI3KCA) gene, researchers reported here at San Antonio Breast Cancer Symposium (SABCS) 2015.

The study investigated the addition of buparlisib (BKM120), a PI3K inhibitor, to fulvestrant (Faslodex, AstraZeneca Pharmaceuticals LP) in postmenopausal women with HR+/HER2 advanced endocrine-resistant breast cancer.

"There was a modest ― and I think we have to emphasize a modest ― improvement in PFS [progression-free survival]," reported lead investigator José Baselga, from Memorial Sloan Kettering Cancer Center, in New York City.

Using liquid biopsy to detect circulating tumor DNA, the researchers isolated a subgroup of PI3KCA mutation carriers for whom the addition of bupalisib had a much more meaningful impact.

"The benefit is of marginal clinical significance when one looks at the overall study population," agreed Eric Winer, MD, director of the Breast Oncology Center at the Dana-Farber Cancer Institute, in Boston, Massachusetts, in an email to Medscape Medical News. "But in the group of patients with circulating PI3KCA mutations, there appeared to be greater clinical benefit. This finding will need to be explored further, and other data sets will need to be examined."

PI3KCA mutations are a hallmark of endocrine-resistant hormone receptor–positive breast cancer, present in approximately 35% of patients, noted Dr Baselga. "It makes a lot of sense to try to provide dual blockade of the PI3-kinase/mTOR and ER pathways that may potentially synergistically help overcome resistance to endocrine therapies."

In BELLE-2, 1147 women were randomly assigned to receive either a combination of fulvestrant (500 mg) plus buparlisib (100 mg/day) (n = 576) or fulvestrant plus placebo (n = 571). The primary endpoint was PFS both in the full population and in a subpopulation of "PI3KCA-activated" patients.

PI3KCA activation was determined at baseline using tumor tissue to identify either a PI3KCA mutation or PTEN loss.

For the full population, the study showed a statistically significant 22% reduction in risk for progression with the addition of buparlisib, yielding a PFS of 6.9 months in the combination arm vs 5 months in the placebo arm (hazard ratio [HR]. 0.78; P < .001).

In the PI3KCA-activated patients, there was a nonsignificant difference in median PFS between the groups (6.8 with combination treatment and 4.0 months with placebo; HR, 0.76; NS).

However, a preplanned prospective evaluation of 587 patients using liquid biopsy rather than tumor tissue to detect circulating tumor DNA (ctDNA) for the PI3KCA mutation showed a clearer picture.

Among 200 patients in whom the PI3KCA mutation was detected by liquid biopsy, there was a 44% reduction in the risk for progression for those treated with buparlisib in comparison with those who were not (median PFS, 7 vs 3.2 months; HR, 0.56; P < .001).

 
Assessment of PI3KCA mutations in circulating tumor DNA may help select patients. Dr José Baselga
 

"Assessment of PI3KCA mutations in circulating tumor DNA may help select patients who benefit from adding a PI3K inhibitor to endocrine therapy," noted Dr Baselga (echoing other speakers at the meeting who emphasized the superiority of this minimally invasive method over tissue biopsy). "These patients performed poorly on fulvestrant monotherapy but achieved a clinically meaningful improvement in PFS with buparlisib and fulvestrant.

"This is the first time we show that inhibiting the PI3K pathway may be a viable option for patients with hormone therapy–resistant breast cancer," senior investigator Mario Campone, MD, from the Institut de Cancérologie de l'Ouest–René Gauducheau, in Nantes, France, said during a press conference at the meeting.

"This is the first time that PI3KCA mutation status in advanced ER+ breast cancer has predicted higher benefit to agents targeting the PI3K pathway," Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, told Medscape Medical News.

"This may suggest that the liquid biopsy is more reflective of the most biologically dominant disease at the time of sampling as compared to biopsy from a single metastatic lesion or archival tissue.... Indeed, it seems that the frequency of PI3KCA-mutated ctDNA was higher than seen in archival tissue samples," she said.

However, a significant drawback to the buparlisib/fulvestrant combination is adverse events.

A significant number of patients in the buparlisip group discontinued treatment because of adverse events (13.2% vs 1.8%), said Dr Baselga.

The most common adverse events associated with combination treatment in comparison with monotherapy were increased liver enzyme levels (for ALT, 40.1% vs 6.8%; for AST, 37.3% vs 9.3%), hyperglycemia (43.1% vs 7.7%), nausea (38.7% vs 23.2%), and diarrhea (34.2% vs 14.6%).

Mood disorders, including depression (26.2% vs 8.9%) and anxiety (22.3% vs 8.2%), were also a significant concern.

"Four patients experienced grade 4 depression that was suspected to be relative to study treatment, and all these patients recovered in full once the therapy was interrupted," said Dr Baselga.

As a result of these adverse events, dose reductions occurred in 46.4% of the combination arm vs 7% of the monotherapy arm, and therapy interruptions occurred in 55.8% of the combination arm vs of the monotherapy arm.

"One could hypothesize that a more potent and mutant-specific PI3K pathway inhibitor may result in higher benefit in patients with PI3KCA-mutated circulating DNA," suggested Dr Loi.

Analysis of the data for overall survival, a secondary endpoint of the trial, has not yet been completed, "but there's a trend in favor of the buparlisib arm," concluded Dr Baselga.

"It'll take time to see whether we see an overall survival benefit ― I wouldn't be surprised if we didn't," commented Kent Osborne, MD, codirector of the San Antonio Breast Cancer Symposium and director of the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, Texas.

"Buparlisib provides significant benefit compared to fluvestrant, but still, it's not a home run in terms of patient benefit," he added.

Yet, Dr Osborne acknowledged, "while this is modest, it's still the first time that a PI3K inhibitor has shown this. I would say it's still an advance and gives us more information about this pathway in endocrine-resistant disease."

The study was funded by Novartis. Dr Campone has received consulting fees from Novartis, Servier, and Menarini and service fees from Novartis and Sanofi non-CME.

San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S6-01. Presented December 11, 2015.

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