Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial

Summary

Background

Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors.

Methods

BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients.

Findings

Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8–4·2] vs 1·8 months [1·5–2·8]; hazard ratio [HR] 0·67, 95% CI 0·53–0·84, one-sided p=0·00030). The most frequent grade 3–4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group).

Interpretation

The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Hormone-receptor-positive breast cancer accounts for approximately 75% of breast cancer diagnoses worldwide.¹ Endocrine therapy is the mainstay of treatment for hormone-receptor-positive advanced breast cancer, but resistance eventually develops and disease progression occurs.² Various different mechanisms of resistance to endocrine therapy have been identified, including oestrogen-independent activation of the oestrogen receptor, increased signalling through the RAS/MAPK, NFκB, or PI3K/AKT/mTOR pathways, and maintenance of cyclin D1 expression.³ PI3K/AKT/mTOR activation is frequently observed in hormone-receptor-positive breast cancer that is resistant to endocrine therapy.⁴ The BOLERO-2 phase 3 study showed that combining endocrine therapy with the mTOR inhibitor everolimus prolongs progression-free survival when compared with endocrine therapy alone in postmenopausal patients with hormone-receptor-positive, HER2-negative, advanced breast cancer.⁵ In the same population, combining everolimus with either tamoxifen or fulvestrant also provided efficacy benefits when compared with endocrine therapy alone.6, 7 Despite an expectation that tumours dependent on a hyperactive PI3K/AKT/mTOR pathway might show a greater benefit from everolimus than from endocrine therapy alone, data from this study suggested that patients with wild-type PIK3CA achieved a longer median progression-free survival than did those with PIK3CA mutations.⁸ Therefore, it might be expected that treatment with a direct PI3K inhibitor could yield greater benefit in patients with PIK3CA mutations than in those with wild-type PIK3CA. Preliminary data from in-vitro and in-vivo studies of the PI3K/AKT/mTOR pathways have shown that mTOR inhibition elicits AKT phosphorylation via several feedback activation pathways that could result in resistance to mTOR inhibitors.9, 10, 11, 12 As shown in preclinical studies, PI3K inhibitors can attenuate or abrogate AKT phosphorylation following mTOR inhibition.9, 10, 11, 12 Accordingly, inhibition of PI3K might be clinically important in patients progressing on mTOR inhibitor treatment. The BELLE-3 study was therefore designed to test this hypothesis, by comparing the efficacy and safety of buparlisib or placebo when combined with fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer who had been treated with an aromatase inhibitor, progressing on or after endocrine therapy plus mTOR inhibitor therapy. Buparlisib is an oral pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, δ, and γ).¹³ In the phase 3, randomised, placebo-controlled BELLE-2 trial,¹⁴ the combination of buparlisib plus fulvestrant was shown to have clinical activity and manageable safety in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on aromatase inhibitor therapy but naive to mTOR inhibitor therapy. Prespecified exploratory analyses in BELLE-2 showed that patients with the PIK3CA mutation in circulating tumour DNA (ctDNA) at study entry had meaningful clinical benefit from the combination regimen.¹⁴ On the basis of these findings, a secondary objective was added to BELLE-3 to assess the efficacy of buparlisib or placebo in combination with fulvestrant in patients with PIK3CA-mutant and wild-type status detected in ctDNA.

Research in context

Evidence before this study

We searched PubMed to identify clinical studies published between March 30, 2012, and March 30, 2017, using the terms “PI3K”, “endocrine therapy”, “mTOR”, “advanced”, and “breast cancer”. Several phase 1 and 2 studies were identified that had investigated PI3K inhibitors combined with endocrine therapy in advanced breast cancer, but none focused on this combination of agents in patients with advanced breast cancer who were previously treated with endocrine therapy plus mTOR inhibitors.

Added value of this study

This is, to our knowledge, the first phase 3 study to evaluate the efficacy and safety of buparlisib, a pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, δ, and γ), combined with fulvestrant, an endocrine therapy, in patients with advanced breast cancer relapsing on or after endocrine therapy and mTOR inhibition. Our results show that buparlisib plus fulvestrant prolonged progression-free survival compared with fulvestrant alone, particularly in patients with tumours harbouring PIK3CA mutations detected in circulating tumour DNA or those with visceral disease. This combination also offered improvements in overall response and clinical benefit when compared with fulvestrant alone. However, the safety profile of buparlisib plus fulvestrant was consistent with that of previous reports; unfavourable adverse events included mood disorders, liver toxicities, and hyperglycaemia.

Implications of all the available evidence

On the basis of the safety profile of buparlisib plus fulvestrant, we recommend discontinuation of further research of this combination therapy within the setting of advanced breast cancer. However, the positive efficacy outcomes associated with buparlisib plus fulvestrant support continued investigation of endocrine therapy combined with more selective PI3K inhibitors. Further studies are warranted to validate the predictive value of PIK3CA mutations as biomarkers for PI3K inhibitor activity.