Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2- Metastatic Breast Cancer

Joseph J Zhao; Khi Yung Fong; Yiong Huak Chan; Jeremy Tey; Shaheenah Dawood; Soo Chin Lee; Richard S Finn; Raghav Sundar; Joline S J Lim

doi:10.3390/cancers15184558

Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2- Metastatic Breast Cancer

Cancers (Basel). 2023 Sep 14;15(18):4558. doi: 10.3390/cancers15184558.

Authors

Joseph J Zhao^{1

2}, Khi Yung Fong¹, Yiong Huak Chan³, Jeremy Tey⁴, Shaheenah Dawood⁵, Soo Chin Lee^{1

2

6}, Richard S Finn⁷, Raghav Sundar^{1

2

8

9

10}, Joline S J Lim^{1

2

6}

Affiliations

¹ Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore.
² Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119074, Singapore.
³ Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
⁴ Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore 119074, Singapore.
⁵ Department of Medical Oncology, Mediclinic City Hospital, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates.
⁶ Cancer Science Institute, National University of Singapore, Singapore 119074, Singapore.
⁷ Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90024, USA.
⁸ Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169547, Singapore.
⁹ The N.1 Institute for Health, National University of Singapore, Singapore 117456, Singapore.
¹⁰ Singapore Gastric Cancer Consortium, Singapore 119074, Singapore.

Abstract

Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.

Keywords: CDK4/6-inhibitor; metastatic breast cancer.

Grants and funding

R.S. is supported by the National Medical Research Council (NMRC) (NMRC/Fellowship/0059/2018 and NMRC/MOH/000627). J.S.J.L. is supported by the NMRC (NMRC/MOH/00414). All other authors have no funding to declare.