Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

doi:10.1016/S1470-2045(17)30376-5

The Lancet Oncology

Volume 18, Issue 7, July 2017, Pages 904-916

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/S1470-2045(17)30376-5 Get rights and content

Summary

Background

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.

Methods

The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 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. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.

Findings

Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred.

Interpretation

The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Hormone receptor-positive tumours are the most common subtype of breast cancer,¹ for which endocrine therapy-based regimens form the backbone of treatment.2, 3, 4 Recent studies have indicated that hormone receptor-positive breast cancer is not homogeneous, but rather is characterised by various genomic alterations that might affect treatment outcomes, providing opportunities for targeted therapies.1, 5 Activating PIK3CA mutations (encoding the p110α isoform of phosphatidylinositol 3-kinase [PI3K]) are often observed in hormone receptor-positive breast cancer and have been associated with disease progression and endocrine therapy resistance;1, 6, 7, 8, 9 targeting PI3K is therefore a potential therapeutic strategy. Identification of patients with PIK3CA mutations who derive benefit from PI3K-targeted therapy could help guide treatment decisions. One of the non-invasive techniques that can be used for detection of PIK3CA mutations is circulating tumour DNA (ctDNA) analysis. ctDNA analysis provides a more accurate measure of mutational status and heterogeneity over time and treatment, compared with archival tumour tissue.10, 11

In early clinical studies, PI3K inhibitors have shown low single-agent activity.¹² Further preclinical and early clinical investigations showed that resistance can arise through enhanced oestrogen receptor pathway signalling, such as through ESR1 mutations.7, 11, 13 Combining PI3K inhibition with the oestrogen receptor antagonist fulvestrant can prevent oestrogen receptor activation, resulting in synergistic antitumour activity.7, 14 Thus, dual blockade of PI3K and oestrogen receptor pathways could restore treatment sensitivity and inhibit growth of endocrine therapy-resistant tumours. The phase 3 BOLERO-2 study showed that the mammalian target of rapamycin (mTOR) inhibitor everolimus plus the aromatase inhibitor exemestane is an effective treatment for hormone receptor-positive and human epidermal growth factor receptor (HER2)-negative advanced breast cancer;³ however, mTOR's mechanism of activation is complex and only partially dependent on PI3K.15, 16

Research in context

Evidence before this study

We searched PubMed for articles published between Nov 21, 2006, to Nov 21, 2016, using the terms “PI3K inhibitor” OR “PI3 kinase inhibitor” AND “metastatic breast cancer”, and identified 140 full-text original articles in English. Of these articles, 11 publications reported data from phase 1 or phase 2 clinical trials involving phosphatidylinositol 3-kindase (PI3K) inhibitors in breast cancer. No publication related to any phase 3 trial of a PI3K inhibitor in metastatic breast cancer was identified.

Added value of this study

To our knowledge, BELLE-2 is the first global phase 3 clinical trial assessing the safety and efficacy of a pan-PI3K inhibitor, buparlisib, in postmenopausal women with aromatase inhibitor-resistant, hormone receptor-positive and HER2-negative advanced breast cancer, which showed significantly longer progression-free survival with buparlisib and fulvestrant compared with placebo and fulvestrant. In this disease setting and in light of the emerging treatment landscape, a progression-free survival benefit of about 2 months observed in the overall population can be considered a clinically moderate improvement. However, many patients discontinued the study treatment early, mainly for tolerability reasons, resulting in short treatment exposure, particularly with buparlisib (median 1·9 months), which might have limited the potential benefit. Additionally, to our knowledge, this was the first randomised, phase 3 clinical trial to include a prospective analysis of progression-free survival in a subset of patients with ctDNA PIK3CA mutations. This subset of patients showed a clinically meaningful improvement in progression-free survival with buparlisib plus fulvestrant compared with fulvestrant alone.

Implications of all the available evidence

Results from this study as well as others with PI3K inhibitors add to the growing evidence that targeting the PI3K pathway via dual-blocking strategies plays an important part in the treatment of hormone receptor-positive breast cancer and overcoming resistance to endocrine therapy. Furthermore, these results also support the hypothesis that endocrine resistance might be linked to PI3K pathway activation. ctDNA analysis seemed to be a more accurate and reliable method to assess the actual PI3K status compared with archival tissue because of possible changes in tumour biology over time. Assessment of PIK3CA mutations in ctDNA might help to select patients who could benefit from such treatment. Further efforts should focus on assessment of PI3K α-isoform-specific inhibition, which might be more effective than pan-PI3K inhibition, with a more tolerable toxicity profile, permitting prolonged administration at higher doses.

Buparlisib (BKM120), an oral pan-PI3K inhibitor, targets all four isoforms of class 1 PI3K (α, β, γ, and δ).¹⁷ Combined treatment with buparlisib and fulvestrant induced tumour regression in mice bearing oestrogen receptor-positive breast cancer xenografts.¹⁴ In a phase 1 study, the combination was generally well tolerated and showed preliminary clinical activity in patients with oestrogen receptor-positive advanced breast cancer.¹⁸

The BELLE-2 study reported here assessed the efficacy and safety of buparlisib plus fulvestrant in postmenopausal women with aromatase inhibitor-resistant, hormone receptor-positive and HER2-negative advanced breast cancer, and investigated tumour PI3K pathway activation status as a biomarker for treatment response.

Section snippets

Study design and participants

The BELLE-2 trial was a randomised, double-blind, placebo-controlled, phase 3 trial. Eligible participants were postmenopausal women aged 18 years or older with a histologically or cytologically confirmed diagnosis of hormone receptor-positive and HER2-negative breast cancer, and availability of adequate tumour tissue. Patients must have progressed within 12 months of receiving aromatase inhibitor therapy in the adjuvant setting, or within 1 month for metastatic or advanced disease, and have

Results

Between Sept 7, 2012, and Sept 10, 2014, 2025 patients were screened for eligibility, from 267 centres in 29 countries (appendix pp 5–9), of whom 847 were excluded for various reasons (figure 1). The most common reasons for screen failure in around half of these screen failures was inadequate tumour tissue (poor quality or quantity, or both) required for PI3K pathway activation status testing, followed by inadequate bone marrow and organ function reserve. Among 1178 patients enrolled in the

Discussion

The results of this study show that the addition of buparlisib to fulvestrant significantly increased progression-free survival in postmenopausal women with aromatase inhibitor-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. These findings are consistent with the recently presented BELLE-3 results²⁶ wherein the addition of buparlisib to fulvestrant prolonged progression-free survival compared with the placebo plus fulvestrant group in postmenopausal women with

References (36)

F Cardoso et al.
ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)
Ann Oncol
(2014)
M Elkabets et al.
AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas
Cancer Cell
(2015)
L De Mattos-Arruda et al.
Capturing intra-tumour genetic heterogeneity by de novo mutation profiling of circulating cell-free tumour DNA: a proof-of-principle
Ann Oncol
(2014)
SR Johnston et al.
Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial
Lancet Oncol
(2013)
RS Finn et al.
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study
Lancet Oncol
(2015)
Comprehensive molecular portraits of human breast tumours
Nature
(2012)
J Baselga et al.
Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer
N Engl J Med
(2012)
NC Turner et al.
Palbociclib in hormone-receptor-positive advanced breast cancer
N Engl J Med
(2015)
CM Perou et al.
Molecular portraits of human breast tumours
Nature
(2000)
TW Miller et al.
Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer
J Clin Invest
(2010)

A Bosch et al.

PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer

Sci Transl Med

(2015)

CG Sanchez et al.

Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer

Breast Cancer Res

(2011)

DS Micalizzi et al.

Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer

Cancer Res

(2015)

MJ Higgins et al.

Detection of tumour PIK3CA status in metastatic breast cancer using peripheral blood

Clin Cancer Res

(2012)

JM Spoerke et al.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Nat Commun

(2016)

J Rodon et al.

Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumours

Invest New Drugs

(2014)

E Toska et al.

Epigenetic regulation of estrogen receptor transcription by the PI3K pathway in breast cancer

AACR

(2016)

TW Miller et al.

ER-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer

Cancer Discov

(2011)

Cited by (414)

Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer
2024, The Lancet Oncology
The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K–AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.
Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer
2023, American Journal of Pathology
Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3ca^H1047R mouse model expressing one or two R26-Pik3ca^H1047R alleles in a urothelium-specific manner was generated. Pik3ca^H1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3ca^H1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3ca^H1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3ca^H1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.
Tumor cell-derived exosomes regulate macrophage polarization: Emerging directions in the study of tumor genesis and development
2023, Heliyon
As an extracellular vesicle, exosomes play an important role in intercellular information transmission, delivering cargos of the parent cell, such as RNA, DNA, proteins, and lipids, activating different signaling pathways in the target cell and regulating inflammation, angiogenesis, and tumor progression. In particular, exosomes secreted by tumor cells can change the function of surrounding cells, creating a microenvironment conducive to tumor growth and metastasis. For example, after macrophages phagocytose exosomes and accept their cargos, they activate macrophage polarization-related signaling pathways and polarize macrophages into M1 or M2 types to exert antitumor or protumor functions. Currently, the study of exosomes affecting the polarization of macrophages has attracted increasing attention. Therefore, this paper reviews relevant studies in this field to better understand the mechanism of exosome-induced macrophage polarization and provide evidence for exploring novel targets for tumor therapy and new diagnostic markers in the future.
Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer
2023, Heliyon
Endocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing immune evasion.
Patient-derived HR + ABC xenografts were implanted into immune-humanized NSG mice and subsequently treated with YY20394 (PI3Kδ inhibitor) and camrelizumab. The mice were monitored for tumor progression, biochemical blood indicators, and peripheral blood T-cell subsets. The xenografted tumors were collected at the end of the treatment cycle and subjected to HE staining, immunohistochemistry and protein phosphorylation analysis. Besides, the xenografted tumors were also used to isolate primary breast cancer cells (BCCs) and regulatory T-cells (Tregs), which were subsequently used to evaluate drug sensitivity in vitro.
The humanized PDX model showed a favorable initial treatment response to camrelizumab combined with YY20394 and manageable toxicity. YY20394 plus camrelizumab showed a strong inhibitory effect on HR + BC in vivo mediated by suppression of Treg activity and an increased proportion of CD8⁺ T cells. Mice bearing tumors treated with YY20394 and camrelizumab had less invasion, mitotic figures, and ki67 expression, while having higher IL-12 expression compared with other groups. Mechanistically, YY20394 only effectively inhibited the PI3K pathway and proliferation activity in Tregs but not in BCCs.
Our study suggests PI3Kδ inhibitor could the enhance the efficacy of ICIs in HR + BC PDX models by combating immune suppression and provides a feasible approach that may overcome the resistance of ICIs in HR + BC patients.
Bypassing phase 2 in cancer drug development erodes the risk/benefit balance in phase 3 trials
2023, Journal of Clinical Epidemiology
Drug developers sometimes launch phase 3 (P3) trials without supporting evidence from phase 2 (P2) trials. We call this practice “P2 bypass.” The aims of this study were to estimate the prevalence of P2 bypass and to compare the safety and efficacy results for P3 trials that bypassed with those that did not.
We created a sample of P3 solid tumor trials registered on ClinicalTrials.gov with primary completion dates between 2013 and 2019. We then attempted to match each with a supporting P2 trial using strict and broad criteria. P3 outcomes were meta-analyzed using a random effects model with subgroup contrast between trials that bypassed and those that did not.
129 P3 trial arms met eligibility and nearly half involved P2 bypass. P3 trials involving P2 bypass produced significantly and nonsignificantly worse pooled efficacy estimates using broad and strict matching criteria, respectively. We did not observe significant differences in safety outcomes between P3 trials that bypassed P2 and those that did not.
The risk/benefit balance of P3 trials that bypassed P2 is less favourable than for trials supported by P2.
Reporting on invasive lobular breast cancer in clinical trials: a systematic review
2024, npj Breast Cancer

View all citing articles on Scopus

View full text

ArticlesBuparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial