Early Phase Study Finds PI3K Inhibitor Pictilisib Helps a Subset of Advanced Breast Cancer Patients

The addition of the investigational PI3K inhibitor pictilisib to Faslodex (fulvestrant), an aromatase inhibitor, in patients with metastatic breast cancer (MBC) yielded some intriguing findings in the phase 2 FERGI study.

Pictilisib helped double progression-free survival (PFS) in women with both estrogen receptor (ER)- and progesterone receptor (PR)-positive disease; however, it did not demonstrate statistically significant results in women with ER-positive tumors. The data also showed, unexpectedly, that having breast cancer with a mutation in the PIK3CA gene did not predict benefit from adding pictilisib.

“The PI3 kinase pathway has been the focus of a great deal of attention over the past 10 years,” said Eric P. Winer, presenting the findings at a press briefing during the 2014 San Antonio Breast Cancer Symposium. He said that this pathway is particularly relevant in ER-positive disease, where the activating mutation PIK3CA has been found to be present in 40 percent to 45 percent of these tumors.

Preclinical and clinical data suggest that activation of the PI3K signaling pathway drives resistance to endocrine treatment for ER-positive breast cancer. The study reported here marks the first randomized phase 2 trial looking at whether this resistance might be at least partially overcome by combining the oral, potent, pan-class I selective PI3K inhibitor pictilisib with Faslodex among patients with MBC patients with and without PIK3CA-mutant tumors.

The trial involved 168 postmenopausal women with ER-positive, HER2-negative MBC who had relapsed during their adjuvant aromatase inhibitor treatment or within six months of completing it. Patients were randomized to receive either Faslodex plus pictilisib once daily (combination arm) or to Faslodex with placebo (control arm).

After 17 months of follow-up, patients in the combination arm with ER-positive disease were found to be 26 percent less likely to have disease progression, but this finding did not achieve statistical significance. For the study population overall, PFS was 6.6 months in the combination arm and 5.1 months in the placebo arm.

“Because this was a relatively small phase 2 trial, the only difference that would be statistically significant would be a relatively large difference in outcome,” said Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston. However, a statistically significant improvement was observed in an exploratory analysis of a subset of patients receiving the combination therapy: patients with the most hormone-sensitive disease who were both ER- and PR-positive and accounting for approximately 70 percent of the patients in the study. This subset of patients was 56 percent less likely to experience disease progression with a PFS of 7.4 months, compared with 3.7 months among controls.

The safety profile of pictilisib in this trial was consistent with the phase 1 data, with gastrointestinal and dermatologic toxicities the most commonly experienced. Adverse events (AEs) of all grades included diarrhea, affecting 63 percent of patients in the combination arm (of which 7 percent were serious), versus 9 percent in the control arm, none of which were serious. Other all-grade AEs included nausea and rash. Overall, 28 serious side effects were reported in the combination arm (31 percent) versus 16 (20 percent) in the control group.

“There were a greater number of side effects with the combination therapy than with Faslodex alone,” said Winer, adding that they were “not overly severe in the vast majority of cases. On the other hand, there were more patients who had to discontinue the therapy because of side effects.”

He said that it is very possible that optimal levels of PI3 kinase inhibition were not achieved due to dose adjustments in a sizeable proportion of patients. “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 lead author Ian E. Krop, director of clinical research for the Breast Oncology Program at Dana-Farber, in a statement. “It may be that PIK3CA mutation is not the only way to activate PI3K signaling.”

“In terms of efficacy, there was the hope that [this agent] would be somewhat more active,” said Winer. “On the other hand, there was a small improvement in progression-free survival in the overall population and in the exploratory subgroup of patients who had ER- and PR-positive breast cancer, which is worth looking into further.”

Researchers are examining whether the benefit of the combination therapy holds true for women with ER/PR—positive breast cancer in an additional cohort of patients within the study, with data anticipated in 2015.

“I think 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,” concluded Winer. “Whether or not this particular drug is the right drug remains to be seen, and there are now ongoing phase 3 trials of the 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.”

Winer said that of these, the newer alpha-selective PI3 kinase inhibitors appear to be more active in patients who have PIK3CA mutations.