Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). METHODS: The included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3-5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed. RESULTS: A total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs. CONCLUSIONS: Considering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients.

Is it time for China to prioritize pan-genotypic regimens for treating patients with hepatitis C?

INTRODUCTION: The treatment of hepatitis C has entered the pan-genotypic era, but the effectiveness is not good for the genotype 3b patients who have a large proportion in China. The guidelines for hepatitis C recommend the use of gene-specific regimens when the regional 3b prevalence rate greater than 5%. This study is to explore rationality of this proportion and the cost-effectiveness to implement pan-genotypic regimens in China. METHODS: A decision Markov model was developed from the health system perspective to evaluate the effectiveness and cost-effectiveness between pan-genotypic and gene-specific treatment regimens for hepatitis C patients. Additionally, we set a regional genotype 3b patient proportion of 0-100% to explore at which proportion it is necessary to perform genotype identification and typing therapy on patients. Model parameters were derived from published literature and public databases. Effectiveness was measured by cured patient numbers, newly diagnosed cases of decompensated cirrhosis, hepatocellular carcinoma, need for liver transplantation, and quality-adjusted life years (QALYs). Cost-effectiveness outcomes included costs and the incremental cost-effectiveness ratio (ICER). The 1-3 times 2022 Chinese per capita gross domestic product was used as the willingness-to-pay threshold. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters. RESULTS: Compared with gene-specific regimens, pan-genotypic regimens resulted in an additional 0.13 QALYs and an incremental cost of $165, the ICER was $1,268/QALY. From the view of efficacy, the pan-genotypic regimens cured 5,868 more people per 100,000 patients than gene-specific regimens, avoiding 86.5% of DC cases, 64.6% of HCC cases, and 78.2% of liver transplant needs. Identifying 3b patients before treatment was definitely cost-effectiveness when their prevalence was 12% or higher. The results remained robust in sensitivity analyses. CONCLUSIONS: In China, the prioritized recommendation of pan-genotypic therapeutics proves to be both cost-effective and efficacious. But, in regions where the prevalence of genotype 3b exceeds 12%, it is necessary to identify them to provision of more suitable therapies.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer.

BACKGROUND: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis. METHODS: RCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3-5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics. RESULTS: A total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings. CONCLUSIONS: CDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results' uncertainty, further trials comparing these novel treatments are warranted. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42022377431).

QALY-type preference and willingness-to-pay among end-of-life patients with cancer treatments: a pilot study using discrete choice experiment.

PURPOSE: Quality-adjusted life-year (QALY) is a dominant measurement of health gain in economic evaluations for pricing drugs. However, end-of-life (EoL) patients' preference for QALY gains in life expectancy (LE) and quality of life (QoL) during different disease stages remains unknown and is seldom involved in decision-making. This study aims to measure preferences and willingness-to-pay (WTP) towards different types of QALY gain among EoL cancer patients. METHODS: We attributed QALY gain to four types, gain in LE and QoL, respectively, and during both progression-free survival (PFS) and post-progression survival (PPS). A discrete choice experiment including five attributes (the four QALY attributes and one cost attribute) with three levels each was developed and conducted with 85 Chinese advanced non-small cell lung cancer patients in 2022. All levels were set with QALY gain/cost synthesised from research on anti-lung cancer drugs recently listed by Chinese National Healthcare Security Administration. Each respondent answered six choice tasks in a face-to-face interview. The data were analysed using mixed logit models. RESULTS: Patients valued LE-related QALY gain in PFS most, with a relative importance of 81.8% and a WTP of $43,160 [95% CI 26,751 ~ 59,569] per QALY gain. Respondents consistently preferred LE-related to QoL-related QALY gain regardless of disease stage. Patients with higher income or lower education levels tended to pay more for QoL-related QALY gain. CONCLUSION: Our findings suggest a prioritised resource allocation to EoL-prolonging health technologies. Given the small sample size and large individual heterogeneity, a full-scale study is needed to provide more robust results.