PI3K Inhibitor Improves PFS in BELLE-2 Trial

Inhibiting the PI3K pathway may be a viable treatment option for women with advanced hormone receptor (HR)–positive breast cancer that becomes resistant to endocrine therapy, according to data presented at the 2015 San Antonio Breast Cancer Symposium in Texas, held December 8–12.

In the phase III BELLE-2 trial, 1,147 patients with advanced or metastatic HR-positive breast cancer that had become resistant to aromatase inhibitor therapy received the estrogen-receptor antagonist fulvestrant (Faslodex; AstraZeneca) for 14 days, after which they received fulvestrant either alone or in combination with the PI3K inhibitor buparlisib (BKM120; Novartis). Researchers also analyzed blood samples in a subset of 587 patients for PIK3CA mutation status.

In the overall study population, progression-free survival (PFS) was 6.9 months in the combination therapy group versus 5.0 months in the control group, meeting the study's primary endpoint. In patients who had PIK3CA mutations detected in their circulating tumor DNA, PFS was longer (7.0 months) if they received the combination therapy versus fulvestrant alone (3.2 months).

“This study suggests that assessment of PIK3CA mutations in circulating tumor DNA may help select patients who benefit from adding a PI3K inhibitor to endocrine therapy,” said senior investigator Mario Campone, MD, PhD, a medical oncologist at the Institute of Oncology West-Rene Gauducheau in Nantes, France, who presented the findings during a press briefing. However, he noted that further studies are needed to confirm whether PIK3CA mutation status can predict response to treatment.

The combination of fulvestrant and buparlisib was associated with serious side effects that caused some patients to discontinue therapy, Campone said. The most common grade 3 and 4 adverse events were liver dysfunction, rash, hyperglycemia, and mood disorders.

Preclinical studies have shown that activation of the PI3K cell-signaling pathway, which can be triggered by PIK3CA mutations, plays a key role in promoting resistance to endocrine therapies, such as aromatase inhibitors. However, many signaling pathways appear to be involved in this type of resistance, possibly explaining why inhibiting PI3K alone produces a statistically significant but modest benefit over standard therapy, said Kent Osborne, MD, director of Baylor College of Medicine's Cancer Center in Houston, TX, and moderator of the press briefing.

Using circulating tumor DNA to assess PIK3CA mutations may help oncologists determine which patients might benefit most from endocrine therapy, reported Mario Campone at the San Antonio Breast Cancer Symposium.

“We know that if you block pathways further downstream with [the mTOR inhibitor] everolimus [Afinitor; Novartis], as seen in BOLERO-2, or with [the CDK4/6 inhibitor] palbociclib [Ibrance; Pfizer] in the PALOMA-3 trial, you also get significant benefit,” he said. “We have to identify the many other pathways involved to discover which treatments we can combine for optimal effect.”

In addition, “it will take time before we can tell whether adding a PI3K inhibitor improves overall survival,” said Osborne. “However, this new data gives us more information about the importance of the PI3K pathway in endocrine-resistant disease.” –Janet Colwell