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Buparlisib Phase III Findings: Glass Half Empty or Half Full?


The pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib combined with fulvestrant (Faslodex) prolonged progression-free survival compared with placebo and fulvestrant in postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer previously treated with an aromatase inhibitor and the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor).1 However, the combination of buparlisib plus fulvestrant was associated with toxicities, including psychiatric disturbances and transaminase elevations.

Ruth O’Regan, MD

Ruth O’Regan, MD

These results of the phase III BELLE-3 trial were presented at a press conference during the 2016 San Antonio Breast Cancer Symposium by study coauthor Ruth O’Regan, MD, of the University of Wisconsin-Madison. Angelo Di Leo, MD, an oncologist at the Istituto Toscano Tumori, Prato, Italy, presented at one of the plenary sessions of the meeting.

“The results of this trial are important for the scientific community, because the trial shows the promising activity of a new class of anticancer agents. But in my opinion, it is still premature to consider a drug in this class as a new standard of care in the treatment of estrogen receptor–positive advanced breast cancer patients,” Dr. Di Leo stated.


The trial shows the promising activity of a new class of anticancer agents. But in my opinion, it is still premature to consider a drug in this class as a new standard of care in the treatment of estrogen receptor–positive advanced breast cancer patients.
— Angelo Di Leo, MD

Study Details

The BELLE-3 trial enrolled 432 heavily pretreated patients with metastatic breast cancer and randomized them 2:1 to treatment with buparlisib at 100 mg/d plus fulvestrant at 500 mg/d every 4 weeks vs placebo and the same dose of fulvestrant.1 The majority of patients progressed on or within 30 days after mTOR inhibitor treatment.

Baseline characteristics were similar between the two arms. The median age was 61 years, two-thirds had three or more metastatic sites, almost three-quarters had visceral metastases, about one-third had prior chemotherapy for metastatic disease, and 69% had two or more prior lines of endocrine therapy for metastatic breast cancer.

Adverse events in the buparlisib arm led to more dose interruptions, dose reductions, and treatment discontinuations compared with the control arm. Deaths thought to be related to treatment occurred in two patients in each arm.

Primary Endpoint Met

The study met the primary endpoint of progression-free survival. At 6 months, the rate of progression-free survival was 31% for the buparlisib arm vs 20% for the placebo arm— representing a 33% improvement favoring buparlisib (P < .001). Objective response rate was higher for the combination arm (7.6% vs 2.1%, respectively).

Subgroup analysis showed that every subgroup had a progression-free survival benefit from buparlisib.

Update on New Class of Agent in Breast Cancer

  • Buparlisib, a pan-PI3K inhibitor, combined with fulvestrant extended survival in postmenopausal women with breast cancer that progressed on previous treatment with an aromatase inhibitor and an mTOR inhibitor.
  • The combination appeared to have the best results in PI3K-mutated breast cancer and in patients with visceral metastases.
  • Elevated transaminase levels and psychiatric symptoms such as depression and anxiety were reported with the use of buparlisib. Newer PI3K-targeted therapies selective for the PI3K-alpha isoenzyme may be as effective yet less toxic.

Analysis of progression-free survival according to PIK3CA status showed that patients with mutant PI3KCA in primary tumor tissue had a progression-free survival benefit from buparlisib (median progression-free survival of 4.7 months vs 1.4 months, P < .001), whereas those with wild-type PIK3CA had almost identical progression-free survival in both arms. Additionally, buparlisib achieved superior progression-free survival in patients with visceral metastasis, whereas there was no difference in progression-free survival between the two arms for patients with nonvisceral metastasis.

Dr. O’Regan noted that patients who did not benefit from prior mTOR treatment did achieve a benefit from buparlisib. “This supports the idea that PI3K inhibitors can be used in patients whose cancers don’t respond to mTOR inhibition,” she stated.

More Adverse Events

These positive results were counterbalanced by more adverse events reported in the buparlisib arm. Adverse events in more than 10% of patients of particular concern included elevated transaminase levels and psychiatric symptoms such as depression and anxiety.

“A few patients on buparlisib attempted suicide,” revealed Dr. O’Regan. “Transaminase elevations and mood disorders in patients on this drug may represent a clinically relevant challenge.” ■

Disclosure: The BELLE-3 study was funded by Novartis. Dr. O’Regan has received grant/research support from Novartis, Eisai, and Pfizer and has consulted for Lilly, Pfizer, and Eisai. Dr. Di Leo has received honoraria from AstraZeneca, Novartis, and Pfizer for participation in advisory boards and as a speaker at sponsored symposia.

Reference

1. Di Leo A, Keun SL, Ciruelos E, et al: BELLE-3: A phase III study of buparlisib and fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. 2016 San Antonio Breast Cancer Symposium. Abstract S4-07. Presented December 8, 2016.


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Expert Point of View: Carlos L. Arteaga, MD


We learned from this study that inhibiting all the PI3K isoenzymes with drugs like buparlisib is associated with undue toxicity. However, this study gives us further impetus to develop PI3K-alpha inhibitors.
— Carlos L. Arteaga, MD

Press conference moderator ­Carlos L....


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