SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

msullivan@frontlinemedcom.com

Pictilisib plus fulvestrant boosts PFS in ER/PR+ patients