Regulatory Approval and Economic Evaluation of Tumor-Agnostic Therapies: A Comparative Study of Larotrectinib and Entrectinib
Author(s)
JONGHO PARK, Master's student1, YiSook Jung, Ph.D2, Hankil Lee, BS, MS, RPh, PhD3.
1Department of Biohealth Regulatory Science, Ajou University, Suwon, Korea, Republic of, 2College of Pharmacy, Ajou University, Suwon, Korea, Republic of, 3Ewha Womans University, College of Pharmacy, Seoul, Korea, Republic of.
1Department of Biohealth Regulatory Science, Ajou University, Suwon, Korea, Republic of, 2College of Pharmacy, Ajou University, Suwon, Korea, Republic of, 3Ewha Womans University, College of Pharmacy, Seoul, Korea, Republic of.
OBJECTIVES: Cancer-agnostic agents, such as larotrectinib and entrectinib, provide innovative treatment options for patients with NTRK fusion-positive tumors regardless of cancer type. However, their unique clinical profiles challenge existing economic evaluation (EE) frameworks, which typically assess value based on tumor location. This study investigates the approval and reimbursement status, along with specific regulatory and reimbursement details, of these agents in South Korea compared to major international markets.
METHODS: Countries conducting health technology assessments (HTAs) were included in the study: the United Kingdom (UK), Canada, Australia, and South Korea. Data on approval and reimbursement were collected from regulatory publications, HTA reports, reimbursement databases, literature sources, and direct inquiries to manufacturers. A comparative analysis was conducted on the year of approval, approved indications, regulatory pathways, reimbursement assessment processes, and EE outcomes.
RESULTS: Larotrectinib and entrectinib differed in terms of whether they were listed and how they were covered by the drug in each country. The UK recommended reimbursement through conditional pathways, specifically via the Cancer Drugs Fund, based on EE utilizing Bayesian hierarchical models and tumor-specific analyses. In Canada, conditional reimbursement was recommended for larotrectinib, contingent upon a price reduction exceeding 90% to meet the cost-effectiveness threshold. Australia initially declined reimbursement due to cost-effectiveness concerns but later included both agents in the Pharmaceutical Benefits Scheme following price negotiations. South Korea exempted both agents from formal economic evaluation and granted reimbursement.
CONCLUSIONS: Larotrectinib and entrectinib, while targeting relatively small patient populations, have established important precedents for future biomarker-driven, tumor-agnostic therapies such as those targeting RET, BRAF, MSI-H, or TMB-H alterations. However, the EE of such agents poses unique challenges due to the absence of tumor-specific comparators, limited clinical data from single-arm basket trials, and uncertainty in extrapolating long-term outcomes.
METHODS: Countries conducting health technology assessments (HTAs) were included in the study: the United Kingdom (UK), Canada, Australia, and South Korea. Data on approval and reimbursement were collected from regulatory publications, HTA reports, reimbursement databases, literature sources, and direct inquiries to manufacturers. A comparative analysis was conducted on the year of approval, approved indications, regulatory pathways, reimbursement assessment processes, and EE outcomes.
RESULTS: Larotrectinib and entrectinib differed in terms of whether they were listed and how they were covered by the drug in each country. The UK recommended reimbursement through conditional pathways, specifically via the Cancer Drugs Fund, based on EE utilizing Bayesian hierarchical models and tumor-specific analyses. In Canada, conditional reimbursement was recommended for larotrectinib, contingent upon a price reduction exceeding 90% to meet the cost-effectiveness threshold. Australia initially declined reimbursement due to cost-effectiveness concerns but later included both agents in the Pharmaceutical Benefits Scheme following price negotiations. South Korea exempted both agents from formal economic evaluation and granted reimbursement.
CONCLUSIONS: Larotrectinib and entrectinib, while targeting relatively small patient populations, have established important precedents for future biomarker-driven, tumor-agnostic therapies such as those targeting RET, BRAF, MSI-H, or TMB-H alterations. However, the EE of such agents poses unique challenges due to the absence of tumor-specific comparators, limited clinical data from single-arm basket trials, and uncertainty in extrapolating long-term outcomes.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
EE646
Topic
Economic Evaluation, Health Policy & Regulatory, Health Technology Assessment
Topic Subcategory
Cost/Cost of Illness/Resource Use Studies
Disease
Oncology, Rare & Orphan Diseases