Cost-effectiveness of sequential treatment strategies involving first-line pembrolizumab with trastuzumab and chemotherapy for unresectable metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.

Background: Gastric cancer is a leading cause of cancer-related mortality worldwide, and HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma constitutes an aggressive molecular subtype. The KEYNOTE-811 phase III trial demonstrated improved clinical outcomes with combination therapy of pembrolizumab, trastuzumab, and chemotherapy (PTC) compared to trastuzumab and chemotherapy alone (TC), but the economic value of this regimen remains uncertain. Objective: To assess the cost-effectiveness of the PTC regimen versus TC for unresectable metastatic HER2-positive G/GEJ adenocarcinoma in the United States, stratified by PD-L1 combined positive score (CPS), and to evaluate the economic impact of real-world sequential treatment strategies. Design: A model-based pharmacoeconomic evaluation. Method: A 10-year semi-Markov model was developed using data from the KEYNOTE-811 trial to estimate disease progression, costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Additionally, a 21-day cycle micro-simulation model was constructed to evaluate sequential treatment pathways involving first-line PTC or TC, followed by trastuzumab deruxtecan or ramucirumab plus paclitaxel, and third-line paclitaxel monotherapy or best supportive care. One-way and probabilistic sensitivity analyses were conducted to test model robustness. Results: For patients with PD-L1 CPS ⩾1, the PTC regimen provided an additional 0.33 QALY at an incremental cost of $247,474.27 compared to TC, resulting in an ICER of $750,750.50 per QALY-well above the U.S. willingness-to-pay threshold of $150,000/QALY. In CPS < 1 and overall populations, ICERs were -$377,258.54 and $957,550.19 per QALY, respectively. In sequential treatment analyses, the TC-based sequences were more cost-effective than PTC-based sequences, with the ICERs of PTC-based regimens exceeding $745063.32 per QALY. Sensitivity analyses confirmed the robustness of these findings. Conclusion: From a U.S. payer perspective, PTC is not cost-effective for HER2-positive metastatic G/GEJ adenocarcinoma at current prices, regardless of PD-L1 CPS status or treatment sequence. Price reduction strategies and biomarker-driven therapy selection are warranted to improve economic value.