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Buparlisib plus fulvestrant extends PFS in PIK3CA-mutated, hormone receptor-positive breast cancer
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SAN ANTONIO — The addition of buparlisib to fulvestrant conferred a statistically significant PFS benefit among postmenopausal women with advanced hormone receptor-positive, hormone therapy-resistant breast cancer who harbored PIK3CA mutations, according to initial results of a randomized phase 3 study presented at San Antonio Breast Cancer Symposium.
“This is the first time we show that inhibiting the PI3 kinase pathway may be a viable option for patients with hormone therapy-resistant breast cancer,” Mario Campone, MD, PhD, of Institut de Cancérologie de l’Ouest in Nantes, France, said during a press conference.
Considerable preclinical data showed activation of the PI3K cell-signaling pathway contributes to resistance to endocrine therapies, such as aromatase inhibitors.
In the BELLE-2 trial, Campone and colleagues assessed whether blocking the PI3K pathway would increase response among patients whose breast cancer was resistant to endocrine therapy.
The analysis included 1,147 postmenopausal women with hormone receptor-positive, HER-2–negative inoperable locally advanced or metastatic breast cancer that progressed on or after aromatase inhibitor therapy. Women who underwent prior therapy with a PI3 kinase, AKT or mTOR inhibitor, those previously treated with fulvestrant, women who underwent more than 1 prior chemotherapy regimen for metastatic disease, and those with a history of anxiety, depression or major psychiatric disorders were excluded.
All patients received 500 mg fulvestrant (Faslodex, AstraZeneca) for 14 days. Researchers then randomly assigned patients 576 patients to 100-mg daily doses of the investigational PI3 kinase inhibitor buparlisib (Novartis). The other 571 patients received placebo.
PFS in the entire study population and in PI3 kinase-activated patients — defined as those with PIK3CA mutations and/or PTEN loss in archival tissue — served as primary endpoints.
Secondary endpoints included OS, overall response rate, clinical benefit rate, safety, pharmacokinetics and quality of life. PFS as determined by circulating tumor DNA and PIK3CA mutation status served as an exploratory endpoint.
Initial results showed the addition of buparlisib to fulvestrant extended median PFS in the full study population (6.9 months vs. 5 months; HR = 0.78; 95% CI, 0.67-0.89) and in the PI3 kinase-activated population (6.8 months vs. 4 months; HR = 0.76; 95% CI, 0.6-0.97).
Researchers then used circulating tumor DNA obtained from blood samples to measure PIK3CA mutation status in 587 patients.
Among the 200 patients with PIK3CA-mutant disease, the addition of buparlisib to fulvestrant conferred a statistically significant improvement in median PFS (7 months vs. 3.2 months; HR = 0.56; 95% CI, 0.39-0.8). Among the 387 patients without PIK3CA mutations, researchers reported comparable median survival between the buparlisib and placebo arms (6.8 months vs. 6.8 months; HR = 1.05; 95% CI, 0.82-1.34).
Up to one-quarter of buparlisib-treated patients experienced serious adverse events. These included hyperglycemia and increases in markers for liver damage.
Patients assigned buparlisib demonstrated higher rates of grade 3 (63.2% vs. 27.4%) and grade 4 (14.1% vs. 4.6%) adverse events. Buparlisib-treated patients experienced higher rates of increased alanine transaminase (all grades, 40.1% vs. 6.8%; grade 3, 18.7% vs. 1.1%; grade 4, 6.8% vs. 0%), increased aspartate aminotransferase (all grades, 37.3% vs. 9.3%; grade 3, 15% vs. 2.8%; grade 4, 3% vs. 0%), hyperglycemia (all grades, 43.1% vs. 7.7%; grade 3, 15.2% vs. 0.2%; grade 4, 0.2% vs. 0%), rash (all grades, 32.1% vs. 6.3%), diarrhea (all grades, 34.2% vs. 14.6%), anxiety (all grades, 22.3% vs. 8.2%), fatigue (all grades, 31.9% vs. 23.9%) and depression (all grades, 26.2% vs. 8.9%).
José Baselga
Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy, Campone said.
“PI3K is an important pathway for normal cellular functions; therefore, as one would expect, side effects from buparlisib were substantial,” researcher José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, said in a press release. “We are hopeful that future, newer-generation PI3K inhibitors would be less toxic.”
Still, the results suggest patients with tumors that harbor PIK3CA mutations achieved a clinically meaningful improvement with the addition of buparlisib to fulvestrant,” Campone said. “Assessment of PIK3CA mutations … may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” Campone said during the press conference. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations.” – by Mark Leiser
Reference:
Baselga J, et al. Abstract S6-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
Disclosure: Campone reports consultant fees from Menarini, Novartis and Servier, as well as non-CME service fees from Sanofi. Please see the full abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Lisa A. Carey, MD
My reaction to this study is twofold.
First, the overall trial results showed a statistically significant improvement in PFS with the addition of buparlisib to fulvestrant in pretreated, postmenopausal, hormone receptor-positive metastatic breast cancer. However, there was a fair amount of toxicity for pretty modest effect — about a 2-month difference in PFS. Some of those toxicities, like psychiatric changes, are pretty hard on patients. I always tell my patients the goals of therapy in the metastatic setting are to control the cancer and to not make you sick. In the parent trial, the drug is having a little bit of a positive effect on the first goal but it’s failing on the second.
However, there is an inkling that we can be a little more selective. The subset analysis that tested blood for circulating tumor DNA looking for PI3 kinase mutations found pretty compelling evidence that buparlisib has very little impact in those who were wild type, and all of the impact — essentially a doubling of PFS — among those whose circulating DNA had mutations. In that sense, the risk–benefit ratio starts to move a little more in favor of the drug.
It’s important to remember this is early, it’s a subset and it’s a proof-of-principle concept. The idea of liquid biopsies helping to guide therapy is very hot right now, and these are really intriguing data in support of that idea.
Also, there are many drugs in this sphere, and there are others that may have fewer of these particularly onerous side effects. And in truth, this is not all about PI3 kinase mutations. There are several ways of disrupting that pathway. We are going to have to find ways of interrogating PTEN loss and other things that are associated with that pathway that are not going to be quite as easy as looking for a mutation.
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