Simple SummaryRecently updated results of clinical studies have confirmed that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as palbociclib (Palbo), ribociclib (Ribo), and abemaciclib (Abem) plus letrozole/anastrozole (NSAI) significantly prolong survival compared to placebo plus NSAI in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2−) advanced or metastatic breast cancer (ABC). However, the high cost of CDK4/6 inhibitors imposes a huge financial burden on patients and healthcare systems. We conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) combined study to compare the effectiveness and cost-effectiveness of CDK4/6 inhibitors in HR+/HER2− ABC from the perspective of payers in China. Our study indicated that Abem + NSAI was cost-effective in China as the first-line treatment for postmenopausal women with HR+/HER2− ABC, owing to its better clinical efficacy and lower price. However, the Palbo + NSAI and Ribo + NSAI groups were not cost-effective unless adjusting drug prices to 50% or 10% of current prices ($320.67 per cycle or $264.60 per cycle).Abstract(1) Background: This study aimed to conduct a NMA and CEA combined study to compare the effectiveness and cost-effectiveness of different CDK4/6 inhibitors (Abem, Palbo, and Ribo) plus NSAI with placebo plus NSAI in the first-line treatment of postmenopausal women with HR+/HER2− ABC from the perspective of payers in China. (2) Methods: Studies which evaluated CDK4/6 inhibitors plus NSAI for HR+/HER2− ABC were searched. A Bayesian NMA was carried out and the main outcomes were the hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The costs and efficacy of first-line therapies for HR+/HER2− ABC were evaluated using the Markov model. The main outcomes in the CEA were incremental cost–utility ratios (ICURs), incremental monetary benefit (INMB), and incremental net-health benefit (INHB). The robustness of the model was assessed by one-way, three-way, and probabilistic sensitivity analyses. Then, we further simulated the impact of different prices of CDK4/6 inhibitors on the results. (3) Results: Seven studies involving 5347 patients were included in the NMA. The three first-line CDK4/6 inhibitors plus NSAI groups provided significant PFS and OS superiority to NSAI alone. Abem + NSAI represented a significant statistical advantage onPFS (HR 0.74, 95% CI 0.61–0.90,p= 0.009) and indicated a trend of being the best OS benefit compared to the placebo + NSAI group (HR 0.89, 95% CI 0.72–1.08). The Abem + NSAI, Palbo + NSAI, and Ribo + NSAI groups resulted in additional costs of $12,602, $20,391, and $81,258, with additional effects of 0.38, 0.31, and 0.30 QALYs, respectively, leading to an ICUR of $33,163/QALY, $65,777/QALY, and $270,860/QALY. Additional pairwise comparisons showed that Abem + NSAI was the only cost-effective option in three CDK4/6 inhibitors plus NSAI groups at a willingness-to-pay (WTP) of $38,029/QALY. The sensitivity analyses showed that the proportion of receiving subsequent CDK4/6 inhibitors and the cost of Abem significantly influenced the results of Abem + NSAI compared with placebo + NSAI. (4) Conclusion: From the perspective of Chinese payers, Abem + NSAI was a cost-effective treatment option compared with placebo + NSAI at the WTP of $38,029/QALY, since only the ICUR of $33,163/QALY of Abem + NSAI was lower than the WTP of $38,029/QALY in China (2022). The Palbo + NSAI and Ribo + NSAI groups were not cost-effective unless drug prices were adjusted to 50% or 10% of current prices ($320.67 per cycle or $264.60 per cycle). (5) Others: We have prospectively registered the study with the PROSPERO, and the PROSPERO registration number is CRD42023399342.