Role of Systemic Therapy for Advanced/Metastatic Gastric Carcinoma in the First-line Setting

Abstract

Introduction: Globally, gastric cancer is sixth most common cancer and ranks third in mortality, with a 5-year survival rate of 32% for advanced/metastatic gastric cancer (A/MGC). Systemic therapy is often the preferred treatment for A/MGC since it offers survival benefits. Exploration of immunotherapies and/or targeted agents in A/MGC offer more treatment combinations than standard systemic chemotherapies. Nivolumab, an immune checkpoint inhibitor was approved by United States (US) Food and Drug as a first-line systemic therapy for A/MGC. The purpose of this study is to: to summarize the clinical, safety, and humanistic outcomes of first-line systemic chemotherapy for adult patients with locally A/MGC; quantitatively synthesize outcomes data from identified studies using network meta-analysis (NMA) and, to evaluate cost-effectiveness of nivolumab-chemotherapy combination versus chemotherapy alone as first-line therapy from a US payer perspective. Methods: Systematic literature review was performed in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and the American Society of Clinical Oncology meeting library using an English language restriction from inception to March 2022. Specifically, phase II and III randomized control trials (RCTs) conducted among western population diagnosed with metastatic phase III and IV stages of gastric cancer were included if they assessed comparative efficacy, safety, or humanistic outcomes of systemic therapies. Two investigators independently reviewed the studies, conducted data extraction, and assessed risk of bias in accordance with PRISMA guidelines. For the quantitative network meta-analysis, inclusion criteria were trials conducted in western populations and published before March 2022. NMA included regimens recommended in 2022 National Comprehensive Cancer Network guidelines. Overall survival (OS), objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (AEs) were captured. Comparative effectiveness results of both direct and indirect evidence were summarized in the network structures using hazard ratios (HR) and odds ratios (OR). P-scores were used to rank treatments. NMA was conducted using R software netmeta package (version 4.2.0). Economic evaluation was conducted in Microsoft Excel® using a partitioned survival model with the CheckMate-649 trial data. Three discrete mutually exclusive health states were included in model; progression-free, post-progression and death. This reflected the disease course of the CheckMate-649 patients. Outcomes were measured as quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses (D/PSA) assessed the uncertainty of the model parameters. Results: A total of 24 RCTs of 8,705 patients were included in the SR. Across active treatment arms, median overall survival ranged from 5.0 to 13.1 months, median progression-free survival from 2.0 to 7.7 months and objective response from 13.0% to 64.1%. Two studies reported higher quality of life outcomes and grade 3/4 AEs were reported in most included studies. In the NMA, 13 studies were included for the analysis and nivolumab-chemotherapy was associated with significantly better OS (HR=0.71, 95% confidence interval [CI]=0.59-0.86) and PFS (HR=0.68, 95%=CI 0.57-0.82) than 5-fluorouracil-oxaliplatin. Nivolumab-chemotherapy had the highest probability of being best treatment among all included regimens for improvement in overall survival (OS) (P-score=0.948) and progression-free survival (PFS) (P-score=0.969) outcomes. No heterogeneity and inconsistencies were observed. Cost-effectiveness analysis showed that nivolumab-chemotherapy provided an additional 0.25 life years compared to chemotherapy alone. The QALYs were 0.701 and 0.561 for nivolumab-chemotherapy and chemotherapy respectively, producing a gain of 0.140 QALYs and an ICER of $572,254/QALY. The model was robust and was not sensitive to any assumptions made in terms of the discount rate, health utilities, disutilities, or cost of monitoring from both deterministic and probabilistic sensitivity analysis. Conclusions: With the advancing treatment landscape among A/MGC, improvement in clinical outcomes can be seen in recent published RCTs. Nivolumab-chemotherapy showed better estimates of OS and PFS compared to other treatments. Under model assumptions and from the US payer perspective, nivolumab was found to be not cost-effective as a first-line systemic therapy at a willingness to pay threshold of $US150,000/QALY. Future research should re-evaluate this model outputs and ICERs using long-term follow-up data from real-world settings.