Presentation (CTI)

OBJECTIVES: Despite advances in immunotherapy, treatment resistance remains a major source of real-world outcome variability and uncertainty in value assessment. Tumor immune escape, T-cell exhaustion, and microenvironmental suppression shorten response duration, accelerate progression to combination regimens, and reduce cost-effectiveness. These biological factors are rarely incorporated into current health economic models. This study aimed to integrate mechanistic evidence on immunotherapy resistance with HEOR data to quantify its impact on effectiveness, treatment sequencing, and uncertainty in value‑based decisions. As multiple resistance mechanisms can influence HEOR outcomes, we illustrate this broader phenomenon using one example focused on resistance‑associated declines in real‑world effectiveness.
METHODS: A targeted literature review (2015-2025) of PubMed and HTA sources was conducted using terms for “immunotherapy resistance,” “real-world outcomes,” and “value assessment.” Extracted data were synthesized across four domains: (1) effectiveness decay, (2) cost and sequencing, (3) model uncertainty, and (4) implications for adaptive value frameworks.
RESULTS: Of 212 records screened, 37 provided data linking resistance mechanisms with HEOR outcomes. Across tumor types (renal cell carcinoma, non-small cell lung cancer, and tumor-agnostic indications), resistance was associated with 30-60% shorter real-world progression-free survival than in trials. This gap increased incremental cost-effectiveness ratios by up to 70% and accelerated uptake of combination regimens, raising cumulative treatment costs by 38-72%. Sensitivity analyses identified assumptions around durability and post-resistance transitions as key drivers of value misestimation, particularly for pembrolizumab and nivolumab.
CONCLUSIONS: Immunotherapy resistance represents both a biological and economic inflection point shaping real-world value. Economic models that exclude resistance dynamics overestimate long-term benefit and misalign reimbursement with clinical effectiveness. Embedding resistance mechanisms into value frameworks and integrating with real-world evidence can improve accuracy and adaptability in value-based pricing. Future research should link molecular correlates of resistance with economic outcomes to guide evidence generation and reimbursement for evolving combination strategies.