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

 

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

 

by Hope S Rugo, Florence Lerebours, Eva Ciruelos, Pamela Drullinsky, Manuel Ruiz-Borrego, Patrick Neven, Yeon Hee Park, Aleix Prat, Thomas Bachelot, Dejan Juric, Nicholas Turner, Nickolas Sophos, Juan Pablo Zarate, Christina Arce, Yu-Ming Shen, Stuart Turner, Hemanth Kanakamedala, Wei-Chun Hsu, Stephen Chia 

 

The Lancet Oncology: VOLUME 22, ISSUE 4, P489-498, APRIL 01, 2021

 

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.

Efficacy of extended aromatase inhibitors for hormone-receptor–positive breast cancer: A literature-based meta-analysis of randomized trials

Efficacy of extended aromatase inhibitors for hormone-receptor–positive breast cancer: A literature-based meta-analysis of randomized trials

The Breast: August 2019 Volume 46, Pages 19–24

by S.P. Corona, G. Roviello, C. Strina, M. Milani, S. Madaro, D. Zanoni, G. Allevi, S. Aguggini, M.R. Cappelletti, M. Francaviglia, C. Azzini, A. Cocconi, M. Sirico, M. Bortul, F. Zanconati, F. Giudici, P. Rosellini, F. Meani, O. Pagani, D. Generali

Endocrine treatment with Tamoxifen and aromatase inhibitors (AIs) is a staple in the management of hormone receptor positive breast cancer (HR + BC). It has become clear that HR + BC carries a consistent risk of relapse up to 15 years post-diagnosis. While increasing evidence supports the use of extended adjuvant Tamoxifen over 5 years, controversial data are available on the optimal duration of extended AIs adjuvant treatment.We performed a meta-analysis to assess the real impact of extended adjuvant therapy with AIs on disease-free survival (DFS).

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value

 by Saroj Niraula  

The Breast: February 2019, Volume 43, Pages 81-84

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment.

Prognostic assessment and systemic treatments of invasive local relapses of hormone receptor-positive breast cancer

Prognostic assessment and systemic treatments of invasive local relapses of hormone receptor-positive breast cancer
Zingarello A et al
The Breast October 2017 Volume 35, Pages 162–168

The rate of local recurrences, after breast-conserving surgery or mastectomy for hormone receptor-positive (HR+) breast cancer, has dramatically changed in last decades, due to advances in surgical and radiation techniques and a more extensive use of adjuvant systemic treatments. However, the occurrence of local recurrences remains a major predictor for distant metastasis and is responsible for increased cancer-specific death. It has been estimated that 1 in 4 HR+ and HR-ipsilateral breast recurrences leads to widespread metastatic disease, with an annual mortality rate of 10% in the first 5 years.