Can contemporary trials of chemotherapy for HER2-negative metastatic breast cancer detect overall survival benefit?

Abstract

Sherko Kümmel,1 Christian Jackisch,2 Volkmar Müller,3 Andreas Schneeweiss,4 Sandra Klawitter,5 Michael P Lux6 1Breast Unit Essen, Kliniken Essen-Mitte, Essen, Germany; 2Department of Obstetrics and Gynecology, Sana Klinikum Offenbach, Offenbach, Germany; 3Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Division of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital, Heidelberg, Germany; 5Medical Affairs – Biostatistics and Epidemiology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 6Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany Purpose: Although several trials have demonstrated improved progression-free survival (PFS) with first-line regimens for HER2-negative metastatic breast cancer (mBC), overall survival (OS) benefit is elusive. We calculated required sample sizes to power for OS using published data from recent mBC trials.Patients and methods: Randomized superiority trials of first-line chemotherapy/targeted therapy for HER2-negative mBC including >150 patients, meeting the primary efficacy objective, and published in 2000–2018 were identified. The sample sizes required to power for PFS and OS were calculated retrospectively for each trial using observed results and study/recruitment follow-up durations (α=0.05, two-sided log-rank test, 80% power), and summarized as a factor (x) relative to actual sample size.Results: Nine of 13 identified trials reported all information required for retrospective sample size calculation. Six had sample sizes larger than required to demonstrate a significant PFS benefit but all would have required larger sample sizes to demonstrate significant OS benefit with the observed results. In ten trials, the required sample size was ≥5-fold larger to power for OS than PFS.Conclusion: Designing trials to test potential new treatments for HER2-negative mBC is challenging, requiring a balance of regulatory acceptability, feasibility, and realistic medical assumptions to calculate sample sizes. Powering for OS is particularly difficult in heterogeneous populations with long postprogression survival, potential crossover, heterogeneous poststudy therapy, and evolving treatment standards. Validated surrogate endpoints are critical. Ongoing trials of cancer immunotherapy (new mode of action) in triple-negative mBC (more homogeneous, shorter OS and postprogression survival, fewer treatment options) may show a new pattern. Keywords: progression-free survival, overall survival, endpoint, metastatic breast cancer, clinical trial, regulatory authorities

Keywords

• progression-free survival
• overall survival
• endpoint
• metastatic breast cancer
• clinical trial
• regulatory authorities