Comparative efficacy and safety of different combinations of three CDK4/6 inhibitors with endocrine therapies in HR+/HER-2 − metastatic or advanced breast cancer patients: a network meta-analysis

BMC Cancer Liu et al. BMC Cancer (2023) 23:816 https://doi.org/10.1186/s12885-023-11322-2 Open Access RESEARCH Comparative efficacy and safety of different combinations of three CDK4/6 inhibitors with endocrine therapies in HR+/HER2 − metastatic or advanced breast cancer patients: a network meta-analysis Yiyuan Liu1†, Jinyao Wu1†, Zeqi Ji1†, Lingzhi Chen1, Juan Zou1, Jiehua Zheng1, Weixun Lin1, Jiehui Cai1, Yaokun Chen1, Daitian Zheng1, Yexi Chen1* and Zhiyang Li1* Abstract Background This network meta-analysis aimed to assess the comparative efficacy and safety of combinations involving three cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapies (ETs) in patients with metastatic or advanced breast cancer (BC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-). Methods We initially identified relevant studies from previous meta-analyses and then conducted a comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases to locate additional studies published between February 2020 and September 2021. Essential data were extracted, and a network meta-analysis was performed using R 4.1.1 software with a random-effects model. Furthermore, we assigned rankings to all available treatment combinations by calculating their cumulative probability. Results Data analysis included ten reports from nine studies. Pooled results demonstrated that each treatment combination significantly reduced the hazard risk of progression-free survival (PFS) compared to treatment with an aromatase inhibitor (AI) or fulvestrant alone. However, there were no differences observed in PFS or overall survival (OS) among the different treatment combinations. Additionally, patients receiving palbociclib plus AI and abemaciclib plus AI or fulvestrant experienced more severe adverse events (AEs), with hazard ratios (HRs) of 10.83 (95% confidence interval [CI] = 2.3 to 52.51) and 4.8 (95%CI = 1.41 to 16.21), respectively. The HR for ribociclib plus AI was 9.45 (95%CI = 2.02 to 43.61), and the HR for palbociclib plus fulvestrant was 6.33 (95%CI = 1.03 to 39.86). Based on † Yiyuan Liu, Jinyao Wu and Zeqi Ji share first authorship *Correspondence: Yexi Chen Zhiyang Li Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. BMC Cancer (2023) 23:816 Page 2 of 12 the ranking probabilities, palbociclib plus fulvestrant had the highest probability of achieving superior PFS (37.65%), followed by abemaciclib plus fulvestrant (28.76%). For OS, ribociclib plus fulvestrant ranked first (34.11%), with abemaciclib plus fulvestrant in second place (25.75%). In terms of safety, palbociclib plus AI (53.98%) or fulvestrant (51.37%) had the highest probabilities of being associated with adverse events. Conclusions Abemaciclib plus fulvestrant or ribociclib plus AI appear to be effective and relatively safe for the treatment of HR+/HER2- metastatic or advanced BC patients. However, given the reliance on limited evidence, our findings require further validation through additional studies. Keywords Breast cancer, Abemaciclib, Ribociclib, Palbociclib, Network meta-analysis Background According to the Global Cancer Statistics 2020 report, breast cancer (BC) has the highest incidence worldwide among all cancer types and is the leading cause of cancerrelated death in women [1]. Studies have indicated that approximately 30–40% of early-stage BC patients eventually progress to advanced BC [2], with a small proportion of patients already diagnosed with distant metastases [3]. A recent study by Shi et al. highlighted COL11A1 as a potential novel biomarker for BC, as it was found to be highly expressed in BC samples and associated with poor prognosis. This suggests that COL11A1 could be a potential therapeutic target in BC. However, it is important to note that BC exhibits significant heterogeneity [4], leading to the identification of four distinct molecular subtypes based on the presence of different biomarkers [5]. Among these subtypes, hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC are the most common, accounting for 60–65% of patients with metastatic or advanced BC [3, 6, 7]. Traditionally, endocrine therapy, including aromatase inhibitors (AI) or fulvestrant, is recommended as first-line treatment for HR+/HER2- BC patients, unless there is a visceral crisis or life-threatening situation [8, 9]. However, some patients either fail to respond to initial therapy due to primary resistance [10] or experience disease progression during treatment due to acquired resistance [11]. Cyclin-dependent kinase 4/6 (CDK4/6) plays a crucial role in cell cycle regulation [12] and has been closely associated with endocrine therapy resistance [13]. Notably, the US Food and Drug Administration (FDA) has approved three CDK4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, for the treatment of HR+/HER2- BC patients [14]. Currently, there is increasing interest among researchers and practitioners in exploring the efficacy and safety of combining different CDK4/6 inhibitors with endocrine therapies [15]. Several pairwise [16–21] and network meta-analyses [22– 24] have confirmed the efficacy and safety of CDK4/6 inhibitors in combination with endocrine therapy for the treatment of metastatic or advanced BC patients with HR+/HER2-. However, definitive investigations of the comparative efficacy and safety of different treatment combinations involving CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) and endocrine therapies (AI and fulvestrant) in clinical trials and previously published meta-analyses are lacking. It is worth noting that network meta-analysis allows for the summary and comparison of the efficacy and safety of different treatment combinations, facilit (...truncated)