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. 2025 Jan 20;32(1):53.
doi: 10.3390/curroncol32010053.

Systematic Review and Network Meta-Analysis on Treating Hormone Receptor-Positive Metastatic Breast Cancer After CDK4/6 Inhibitors

Neha Pathak  1   2 , Abhenil Mittal  3 , Sudhir Kumar  2   4 , Chitrakshi Nagpal  5 , Eitan Amir  1   2 , Partha Haldar  6 , Bharath B Gangadharaiah  5 , Akash Kumar  5 , Ashutosh Mishra  7 , Atul Batra  5
Affiliations

Systematic Review and Network Meta-Analysis on Treating Hormone Receptor-Positive Metastatic Breast Cancer After CDK4/6 Inhibitors

Neha Pathak et al. Curr Oncol. .

Abstract

Introduction: The optimal treatment of estrogen receptor-positive (ER +) metastatic breast cancer (MBC) after progression on cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) is unknown.

Methods: We conducted a systematic review and network meta-analysis (NMA) of phase-II/-III randomized trials of ER + MBC post CDK4/6i + ET progression. We calculated the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) using generic inverse variance and odds ratios (ORs) using the Mantel-Haenszel method for adverse events (AEs) with Review-Manager version-5.4. NMA was executed using WINBUGS (Microsoft Excel). Three molecular subgroups were analyzed: HER2-low, PI3K/AKT/mTOR, and the ESR1 mutation subgroup for selective estrogen receptor degrader (SERD).

Results: A total of 14 studies were included. In the HER2-low group, Sacituzumab govitecan and trastuzumab deruxtecan had a similar efficacy (HR, 95% CI): PFS (0.98; 0.63-1.43) and OS (1.08; 0.76-1.55). In PI3K/AKT/mTOR-altered cases, capivasertib was superior to alpelisib PFS (0.77; 0.53-1.12), and OS (0.80; 0.48-1.35). SERDs had worse PFS and OS versus ongoing CDK 4/6i (ribociclib).

Conclusion: No therapy emerged as the unequivocal choice in the post-CDK 4/6i domain in unselected subgroups. In the HER2-low population, a similar efficacy and different toxicity spectrum was seen. In AKT-altered tumors, capivasertib was less toxic than alpelisib.

Prospero id: CRD4202236412.

Keywords: AKT inhibitor; CDK4/6 inhibitor; HER2-low breast cancer; SERD; hormone receptor-positive cancer; metastatic breast cancer.

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Conflict of interest statement

Dr. Eitan Amir reports personal fees from Seagen (Honorarium), Gilead (Honorarium) AstraZeneca (consulting), and Novartis (consulting), all outside the submitted work. Other authors have nothing to disclose. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
PRISMA flow diagram for the inclusion of studies.
Figure 2
Figure 2
Forest plot of network meta-analysis of grade ≥ 3 adverse events of trastuzumab deruxtecan vs. Sacituzumab govitecan. Red boxes represent the results of each study and the horizontal lines the 95% confidence interval.
Figure 3
Figure 3
(a) Forest plot showing the network meta-analysis of progression-free survival for PI3K/AKT/mTOR pathway-affecting drugs vs. alpelisib. (b) Forest plot showing the network meta-analysis of grade ≥ 3 adverse events for PI3K/AKT/mTOR pathway-affecting drugs vs. alpelisib. Red boxes represent the results of each study and the horizontal lines the 95% confidence interval.
See this image and copyright information in PMC

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