Σάββατο, 10 Δεκεμβρίου 2016

PI3K INHIBITORS IN BREAST CANCER- A FAILURE STORY

SAN ANTONIO — The potential expansion of treatment options in metastatic breast cancer sometimes comes in a mixed bag. Take the case of investigational PI3K inhibitor buparlisib (BKM120).
Adding this agent to fulvestrant in postmenopausal women with hormone-positive, human epidermal growth factor receptor–negative locally advanced or metastatic breast cancer resulted in significant improvements in progression-free survival (PFS) compared with placebo, according to results of the phase III BELLE-3 study reported here at the San Antonio Breast Cancer Symposium (SABCS) 2016.
The study "confirms the importance of continued inhibition of the mTOR [mammalian target of rapamycin]/PI3K axis in hormone-refractory breast cancer, and supports PIK3CA mutations as predictors of benefit from agents targeting this pathway," trial investigator Ruth O'Regan, MD, from University of Wisconsin in Madison, told Medscape Medical News.
However, a high toxicity rate in patients receiving buparlisib "may represent a clinically relevant challenge," she acknowledged during a press briefing here.
"As has previously been reported, there were increased transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)], and also psychiatric issues like depression and anxiety — there were a number of patients that attempted suicide in the buparlisib arm," she said. 
High toxicity from buparlisib stems from its nonspecific effect on the PIK3CA gene, targeting nonmutant along with mutant types, as well as all isozymes, explained press conference moderator Carlos Arteaga, MD, codirector of the SABCS and director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
"I would not say that PI3 kinase mutations are not a good target," he said, but "inhibiting all isozymes, which is what these inhibitors do, may be a little too tough."
The goal would be to develop PI3 kinase inhibitors that specifically target the α isozyme — "because that is the isozyme that mutates and becomes the driver in some of these cancers. We also desperately need a PI3 kinase mutant-specific drug that would only hit the mutant," he added, explaining that buparlisib's effect on the nonmutant PIK3CA gene causes rashes and hyperglycemia.
Sara Hurvitz, MD, from the University of California Los Angeles, another panel member at the meeting press conference, agreed that "there definitely is a role that needs to be explored with these inhibitors. I don't think this is a sad day for PI3 kinase inhibitors. I think it actually gives us a nice view into the biology, which is promising."
In BELLE-3, much like the previously reported BELLE-2 study, patients, with a median age of 61 years, all of whom received fulvestrant 500 mg, were randomly assigned to the addition of buparlisib 100 mg/day (n = 289) or placebo (n = 143).
"What's different about this trial from other trials we've seen is that all patients had progressed either on or following treatment with an mTOR inhibitor," said Dr O'Regan, adding that 99% of patients had received everolimus (1% ridaforolimus) for a median of 8 to 8.6 months, and 69% had previously received at least two lines of endocrine therapy for metastatic disease.
The study made its primary endpoint, showing significant improvement in PFS in the buparlisib-treated group compared with controls (median, 3.9 vs 1.8 months; P < .001).
However, overall response rate was low in both the buparlisib and placebo groups (7.6% vs 2.1%), as was clinical benefit (24.6% vs 15.4%), she said.
Mutant PIK3CA status was confirmed in 34% of samples taken from the primary tumor tissue, as well as 39% taken from circulating DNA liquid biopsy specimens. Compared with patients with nonmutated (wild-type) status, who showed a modest benefit in PFS when treated with buparlisib over placebo, patients with PIK3CA mutations had significantly (P < .001) improved PFS with buparlisib (hazard ratio [HR], 0.39 and 0.46 in the groups with tissue samples and liquid biopsy specimens, respectively).
In addition, patients with visceral disease (which was not correlated with PIK3CA status) showed significant benefit from treatment with buparlisib (HR, 0.56), whereas those with nonvisceral disease did not (HR, 0.96).
"Investigation of α-selective PI3K inhibitors in patients with PIK3CA-mutant tumors is warranted" in light of the high toxicity rates associated with buparlisib, Dr O'Regan concluded, pointing to the ongoing SOLAR-1 study looking at the α-specific PI3K inhibitor alpelisib (BYL719).

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