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Buparlisib prolongs PFS in certain postmenopausal women with advanced breast cancer
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SAN ANTONIO — The addition of buparlisib to fulvestrant extended PFS in postmenopausal women with hormone receptor–positive, HER-2–negative advanced breast cancer who underwent prior treatment with aromatase and mTOR inhibitors, according to results of the BELLE-3 trial presented at San Antonio Breast Cancer Symposium.
However, the benefit appeared confined to patients with PIK3CA–mutant tumors and those with visceral disease.
In addition, patients assigned the combination experienced increased adverse events, including mood disorders and transaminase elevations.
“The higher rate of toxicity ... may represent a clinically relevant challenge,” Ruth M. O’Regan, MD, division head of hematology and oncology in the department of medicine at University of Wisconsin School of Medicine and Public Health, said during a press conference. “However, prospective investigation of this p110-alpha–selective PI3 kinase inhibitor in patients in combination with endocrine therapy in patients whose disease progressed either on or before an mTOR inhibitor is warranted.”
Previous investigations have suggested that activation of the PI3 kinase/mTOR cell signaling pathway contributes to resistance to endocrine therapies, including aromatase inhibitors.
In the phase 3 BELLE-3 trial, O’Regan and colleagues whether adding buparlisib (Novartis) to fulvestrant was safe and effective for treatment of patients with hormone receptor–positive, HER-2–negative locally advanced or metastatic breast cancer.
All 432 patients underwent prior aromatase inhibitor treatment, and they also had progressed within the prior 30 days during treatment with endocrine therapy and the mTOR inhibitor everolimus.
Researchers randomly assigned 289 of them to buparlisib 100 mg/day plus fulvestrant 500 mg. The other 145 patients received placebo plus fulvestrant.
Treatment groups were well balanced with regard to median age (60 years for buparlisib–fulvestrant vs. 62 years for placebo–fulvestrant), percentage of patients with at least three metastatic sites (64% vs. 67%), percentage with visceral metastases (73% vs. 72%), receipt of prior chemotherapy for metastatic disease (36% vs. 34%), receipt of at least two lines of endocrine therapy for metastatic disease (70% vs. 66%), and median duration of mTOR inhibitor treatment (8 months vs. 8.6 months).
PFS served as the primary endpoint. Secondary endpoints included OS, overall response rate, clinical benefit rate, safety and efficacy based on PI3KCA gene status in circulating tumor DNA.
Patients assigned buparlisib achieved longer median PFS (3.9 months vs. 1.8 months; HR = 0.67; 95% CI, 0.53-0.84) and were more likely to remain progression free at 6 months (31% vs. 20%).
Researchers also reported a higher objective response rate (7.6% vs. 2.1%) and clinical benefit rate (24.6% vs. 15.4%) in the buparlisib group.
Investigators further analyzed PFS by PIK3CA status.
Buparlisib extended median PFS among patients with PIK3CA–mutant disease detected by tissue (4.7 months vs. 1.4 months; HR = 0.39; 95% CI, 0.23-0.65) and detected by circulating tumor DNA (4.2 months vs. 1.6 months; HR = 0.46; 95% CI, 0.29-0.73).
Buparlisib conferred smaller PFS benefits among patients with PIK3CA wild-type disease detected by tissue (2.8 months vs. 2.7 months; HR = 0.83; 95% CI, 0.6-1.14) and detected by circulating tumor DNA (3.9 months vs. 2.7 months; HR = 0.73; 95% CI, 0.53-1).
“Testing for PIK3CA mutations seems to be relevant because buparlisib does not seem to have relevant activity in the absence of the mutation,” researcher Angelo Di Leo, MD, oncologist from Ospedale Misericordia e Dolce in Italy, said in a press release.
When researchers evaluated concordance of PIK3CA status in tissue and matched circulating tumor DNA samples (n = 257; 59% of patients), they determined 83% were concordant.
buparlisib also extended a small but statistically significant PFS benefit among patients with visceral disease (median, 3.1 months vs. 1.5 months; HR = 0.56; 95% CI, 0.43-0.74). Researchers observed no significant difference among those with nonvisceral disease (median, 4.2 months vs. 4.1 months; HR = 0.96; 95% CI, 0.61-1.5).
Patients assigned buparlisib experienced higher rates of alanine transaminase increase (all grade, 39% vs. 7%; grade 3/grade 4, 22% vs. 3%), aspartate transaminase increase (all grade, 37% vs. 10%; grade 3/grade 4, 22% vs. 3%), depression (all grade, 21% vs. 8%), anxiety (all grade, 18% vs. 10%), hyperglycemica (all grade, 36% vs. 3%), nausea (all grade, 34% vs. 18%) and diarrhea (26% vs. 9%).
A few patients in the buparlisib group attempted suicide.
“Considering all this, I believe that we need further research in the attempt to identify new PI3K inhibitors with a comparable level of activity and with a better safety profile,” Di Leo said. “The results of this trial are important for the scientific community because the trial shows the promising activity of a new class of anticancer agent but, in my opinion, it is still premature to consider this agent as a new standard of care in the treatment of ER–positive advanced breast cancer.” – by Mark Leiser
Reference:
Di Leo, A, et al. Abstract S4-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio.
Disclosure: Novartis funded this study. Di Leo reports advisory roles with and lecture fees from AstraZeneca, Bayer, Eisai, Eli Lilly, Genomic Health, Novartis, Pfizer, Pierre Fabre and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Carlos L. Arteaga, MD
I probably would not use this combination, but I would not go beyond that and imply that PI3 kinase mutations are not a good target. I learn several things from this. One, inhibiting all isozymes may be a little too tough. Second, I think it gives me an impetus to develop PI3 kinase-alpha–specific inhibitors. That is the isozyme that mutates and becomes the driver of some of these cancers. Third, we desperately need a PI3 kinase-mutant–specific drug, something that will hit the mutant and will not hit the PI3 kinase isozyme that we all have in every other single cell in our body, because the wild-type version performs very important biological functions.
One other implication is that PI3 kinase inhibitors that cross the blood–brain barrier may be something we need to be cautious about because of the psychiatric side effects.
Perspective
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Sara A. Hurvitz, MD
There definitely is a role that needs to be explored for these inhibitors, both in combination with other inhibitors — such as CDK4/6 inhibitors — and combinations in HER-2—positive disease. I think there is real promise as we get smarter about testing for these mutations, and developing or identifying predictive markers of benefit. I don’t think this is a said day for PI3 kinase inhibitors. I think this study actually gives us a very nice view into the biology, which is promising.
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