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FINDING CURES TOGETHER<sup>SM</sup>

Phase III BELLE-2 Trial Meets Primary Endpoint of Progression-free Survival

12/11/2015

SAN ANTONIO — Among women with locally advanced or metastatic hormone receptor-positive breast cancer that was resistant to hormone therapy, those who had mutated PIK3CA detected in their blood benefited from a combination of the investigational PI3K inhibitor buparlisib and fulvestrant, according to data from the phase III BELLE-2 trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8–12.José Baselga, MD, PhD

“BELLE-2 is a randomized, phase III clinical trial designed to assess the efficacy of the investigational PI3K inhibitor buparlisib in combination with fulvestrant in breast cancer patients whose tumors no longer respond to aromatase inhibitors,” said José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center in New York.

Vast preclinical data have shown that activation of a cell-signaling pathway called the PI3K pathway, driven in some cases by a mutation in the gene PIK3CA, plays a major role in promoting resistance to endocrine therapies such as aromatase inhibitors, explained Baselga, who is also president of the American Association for Cancer Research (AACR). “We wanted to block the PI3K pathway to see if that would yield improved responses in patients with endocrine therapy-resistant breast cancer,” he said.

“We are happy to announce that the trial met its primary endpoint. While we found that the entire study population benefited from the buparlisib–fulvestrant combination, the primary outcome was quite dramatic in patients whose tumors had mutant PIK3CA—a median progression-free survival [PFS] of seven months in those who received buparlisib plus fulvestrant versus 3.2 months in those who received placebo plus fulvestrant,” Baselga added.

In this trial, 1,147 patients with advanced or metastatic hormone receptor-positive breast cancer who had received no more than one prior chemotherapy received 500 mg fulvestrant for 14 days, after which they were randomly assigned (1:1) either 100 mg/day oral buparlisib or placebo. All patients continued to receive 500 mg fulvestrant. Randomization was stratified by PI3K pathway status, and in 587 patients, PIK3CA mutation status was assessed in circulating tumor DNA (ctDNA) at trial entry.

For the full study population, the patients who received fulvestrant alone had a progression-free survival of five months; those who received buparlisib plus fulvestrant had a progression-free survival of 6.9 months (HR 0.78; P value <0.001). Patients who had mutant PIK3CA detected in their ctDNA had much better outcomes if they received buparlisib plus fulvestrant when compared with those who received fulvestrant: progression-free survival of seven months in the buparlisib plus fulvestrant group versus 3.2 months in the fulvestrant group (HR 0.56; P value <0.001).

“We showed for the first time that inhibiting the PI3K pathway may be a viable option for patients with endocrine therapy-resistant breast cancer,” Baselga said.

Up to 25 percent of the patients who received buparlisib experienced serious adverse events, including hyperglycemia and an increase in markers of liver damage, according to Baselga. “PI3K is an important pathway for normal cellular functions; therefore, as one would expect, side effects from buparlisib were substantial,” he noted. “We are hopeful that future, newer-generation PI3K inhibitors would be less toxic.”

This study was funded by Novartis. Baselga declares no conflicts of interest.

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