Elsevier

The Lancet Oncology

Volume 22, Issue 4, April 2021, Pages 489-498
The Lancet Oncology

Articles
Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study

https://doi.org/10.1016/S1470-2045(21)00034-6Get rights and content

Summary

Background

Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.

Methods

This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.

Findings

Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5–15·9). 61 (50·4%; 95% CI 41·2–59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.

Interpretation

BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

Funding

Novartis Pharmaceuticals.

Introduction

Hormone receptor-positive, HER2-negative disease accounts for more than 70% of incident breast cancer cases.1, 2 For patients with hormone receptor-positive, HER2-negative advanced breast cancer, first-line treatments recommended by expert guidelines include endocrine therapy plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.3, 4 Resistance to endocrine-based therapies is common and can result from hyperactivated PI3K pathway signalling, which can arise from mutations in PIK3CA.5 PIK3CA encodes the alpha isoform of PI3K (p110α), and mutations in this gene have been observed in about 40% of hormone receptor-positive, HER2-negative advanced breast cancer.1, 6, 7 Patients with PIK3CA-mutated hormone receptor-positive, HER2-negative advanced breast cancer have a worse prognosis than those with wild-type disease.8 Thus, there is a need for therapies that address the effects of the PIK3CA mutation and provide optimal treatment after progression on endocrine therapy plus a CDK4/6 inhibitor.

Alpelisib is an orally bioavailable, α-selective PI3K inhibitor and degrader that showed efficacy and a manageable safety profile in combination with fulvestrant in the phase 3 SOLAR-1 study of patients with PIK3CA-mutated disease that progressed on or after previous aromatase inhibitor therapy.1, 9, 10 SOLAR-1 focused on an endocrine-resistant patient population, including patients whose disease relapsed on or within 12 months of completing adjuvant endocrine therapy. The study completed enrolment before implementation of CDK4/6 inhibitor-based treatment as the standard of care in the first-line setting, although in a small proportion of patients with PIK3CA-mutated disease in SOLAR-1 who received previous CDK4/6 inhibitors (n=20, 5·9%), progression-free survival was longer in the alpelisib plus fulvestrant group (n=9) than in the placebo plus fulvestrant group (n=11; hazard ratio [HR] 0·48, 95% CI 0·17–1·36).1, 11

Research in context

Evidence before this study

We searched PubMed between date of inception and June 15, 2020 for clinical trials or studies published in public medical databases assessing targeted therapies used for the treatment of advanced breast cancer after progression on treatments including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Terms used in this search included “CDK4/6 inhibitor” and “targeted therapies for advanced breast cancer”. We did not identify any trials evaluating a PI3K inhibitor in advanced breast cancer in the post-CDK4/6 inhibitor setting. International guidelines recommend endocrine therapy plus CDK4/6 inhibitors as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer; however, resistance develops in the majority of patients. Alpelisib (PI3Kα-selective inhibitor and degrader) plus fulvestrant demonstrated efficacy versus placebo plus fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer in the SOLAR-1 trial, but at the time that this trial was enrolling, CDK4/6 inhibitors were not available in many areas around the world, and only a small proportion of patients who had progressed on CDK4/6 inhibitors were enrolled.

Added value of this study

To our knowledge, BYLieve is the first, prospective clinical study to examine the use of alpelisib plus fulvestrant for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer solely in the post-CDK4/6 inhibitor setting. The primary endpoint of the study, evaluating the proportion of patients who were alive and without disease progression at 6 months, was met. Side-effects were manageable, with diarrhoea and hyperglycaemia the most common any-grade adverse events observed.

Implications of all the available evidence

Our results support the use of alpelisib plus fulvestrant for treatment of hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in the post-CDK4/6 inhibitor setting.

The BYLieve phase 2 trial is assessing the safety and activity of alpelisib plus letrozole or fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer who progressed on or after previous therapy, including a CDK4/6 inhibitor. Here, we present results from cohort A, namely, patients who previously received a CDK4/6 inhibitor plus an aromatase inhibitor.

Section snippets

Study design and participants

In this phase 2, multicentre, open-label, non-comparative, three-cohort trial, patients were enrolled from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide (appendix pp 5–6). Eligible patients were women and men aged 18 years or older, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less and hormone receptor-positive, HER2-negative advanced breast cancer not amenable to curative therapy, with a

Results

Between Aug 14, 2017, and data cutoff at Dec 17, 2019, 127 patients (full analysis set) with at least 6 months' follow-up (on treatment or post treatment) were enrolled into cohort A (figure 1). Median follow-up (from enrolment to data cutoff) was 11·7 months (IQR 8·5–15·9). 121 patients with centrally confirmed PIK3CA mutations were included in the modified full analysis set. At data cutoff, treatment was ongoing in 33 (26%) of 127 patients and 94 (74%) had discontinued treatment. Primary

Discussion

In BYLieve, the primary endpoint was met showing activity of alpelisib plus fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer whose immediate previous treatment was a CDK4/6 inhibitor plus an aromatase inhibitor. To our knowledge, BYLieve establishes a benchmark in the post-CDK4/6 inhibitor setting, as the first prospective study explicitly designed to investigate the activity of a PI3Kα-selective inhibitor in these patients.

Thus far,

Data sharing

All data supporting the findings of this analysis, including the redacted study protocol, are available within the Article and its appendix. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymised to respect the privacy of patients who have participated in the

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