Conference Coverage

PIK3 inhibitor gives slight PFS edge at high cost for HR+/HER2– advanced breast cancer

 

Key clinical point: The PI3K inhibitor buparlisib plus fulvestrant slightly prolonged progression-free survival of HR+/HER2– breast cancer pretreated with an aromatase inhibitor and mTOR inhibitor.

Major finding: The combination met its primary endpoint of better PFS than fulvestrant/placebo, but with high liver toxicity and mood disorders.

Data source: Randomized phase III trial of 432 women with hormone receptor–positive, HER2-negative, AI-pretreated breast cancer that progressed on or after mTOR inhibitor therapy.

Disclosures: Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.


 

AT SABCS 2016

– A combination of a PI3K inhibitor and selective estrogen receptor down-regulator (SERD) met its primary endpoint of 2.1 months better progression-free survival (PFS) in postmenopausal women with locally advanced or metastatic breast cancer who were quickly running out of other treatment options.

Yet the small gain in PFS came at a very high price in terms of toxicities, including mood disorders that may have led to patient suicide attempts, according to investigators.

The BELLE-3 trial looked at the combination of the SERD fulvestrant (Faslodex) and an experimental inhibitor of the PI3 kinase, buparlisib, in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor–2 (HER2)-negative breast cancer treated with an aromatase inhibitor (AI) who experienced disease progression either on or after receiving therapy with an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1).

The combination of fulvestrant and buparlisib was associated with a median PFS of 3.9 months, compared with 1.8 months for fulvestrant and placebo (P less than .001), Angelo Di Leo, MD, of Ospedale Misericordia e Dolce in Prato, Italy, reported at the San Antonio Breast Cancer Symposium,

Objective response rates (ORR) were low, at 7.8% in the combination arm, and 2.1% in the fulvestrant-plus-placebo arm.

Although the PFS difference was statistically significant, “the higher rate of toxicity in patients receiving buparlisib and fulvestrant, including transaminase elevations and mood disorders, may represent a clinically relevant challenge for future development of this compound in this particular group of patients,” Dr. Di Leo said.

Blocks AKT pathway

The preclinical rationale for the use of a P13K inhibitor after disease progression on mTORC1 inhibitor is that current mTOR inhibitors such as everolimus have a feedback mechanism that activates the AKT pathway, and that the use of P13K inhibitors can “abrogate or attenuate this activation, potentially blocking that pathway,” explained coinvestigator Ruth O’Regan, MD, head of the division of hematology and oncology at the University of Wisconsin–Madison School of Medicine and Public Health. Dr. O’Regan discussed the BELLE-3 findings in a briefing prior to Dr. Di Leo’s presentation of the data in general session.

Dr. Ruth O'Regan
Dr. Ruth O'Regan

In BELLE-3, 432 postmenopausal women with HR+/HER2-, AI-pretreated, locally advanced or metastatic breast cancer that had progressed on or after treatment with an mTOR inhibitor as the last line of therapy were enrolled. The patients were stratified by the presence or absence of visceral disease and then randomized on a 2:1 basis to fulvestrant 500 mg daily plus either buparlisib 100 mg/day (289 patients), or placebo (143).

As noted, the primary endpoint of investigator-assessed PFS favored the addition of buparlisib, with a hazard ratio for progression of 0.67 (P less than .001). PFS results by independent central review were similar (HR 0.57, P less than .001).

The ORR for the buparlisib/fulvestrant combination, 7.6%, consisted of 0.3% complete responses, and 7.3% partial responses. The ORR for placebo/fulvestrant, 2.1%, was composed entirely of partial responses. The respective clinical benefit rates, defined as a combination of complete and partial responses and stable disease, were 24.6% and 15.4.

The benefit of buparlisib was evidently entirely among patients with visceral disease, with a PFS of 3.1 vs. 1.5 months. In contrast, PFS among patients with no visceral disease was 4.2 vs. 4.1 months, respectively, and was not significant.

In addition, the P13K inhibitor seemed to benefit patients with PIK3CA mutations detected in either the primary tumor or in circulating DNA samples, but not patients with wild-type PIK3CA.

Depression, anxiety with combination

Patients assigned to buparlisib/fulvestrant had substantially higher proportions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations compared with patients on placebo fulvestrant, as well as more reported depression and anxiety. Three patients in the buparlisib arm attempted suicide. There were no reported suicide attempts in the placebo arm.

Dr. O’Regan said at the briefing that mood disorders are known adverse events associated with buparlisib, and that patients with psychiatric disorders were excluded from the trial.

Carlos Arteaga, MD, co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., who moderated the briefing, said in an interview that PI kinase mutations do not appear to be a good target, and that a pan-PIK3 inhibitor such as buparlisib may be hitting too many targets at once.

Inhibiting all of the PIK3 isoforms – alpha, beta, gamma, and delta – “may be a little too tough,” he said.

The trial should serve as impetus for developing agents that inhibit only the alpha isoform of PIK3 which mutates and appears to be the driver of some types of breast cancer, he said.

Following Dr. Di Leo’s presentation, perennial SABCS gadfly Steven Vogl, MD, New York, told the speaker that “you presented this very nicely, it’s very interesting biology. I don’t think you’d want to do this again to a human, right? Three month prolongation in PFS, miserable, with diarrhea, depression – you don’t want to do this again, is that correct?”

“I think buparlisib is probably not the best compound to be used in this particular setting of patients,” Dr. Di Leo said, but added that a better-tolerated PI3K inhibitor might be more effective.

“Actually, the study is raising an important question: Should we use the PI3K inhibitor in place of the mTOR inhibitor, or perhaps, as the study suggests, should we use the P13K inhibitors sequentially, after the mTOR inhibitor. This is an open question,” he replied.

Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.

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