Key messages
- Tumour-agnostic (TA) therapies disrupt conventional oncology paradigms by targeting molecular alterations rather than tumour histology. The path from regulatory approval to patient access remains highly variable and complex across jurisdictions.
- Regulatory, HTA and reimbursement approaches vary widely across key national health systems. Diagnostic access also remains uneven, further limiting patient identification and uptake.
- To unlock the full potential of TA therapies, stakeholders must evolve evidence standards, HTA methodologies and payment models. National coverage for molecular testing and international collaboration are also critical enablers.
This Contract Research Report was commissioned and funded by AstraZeneca and Daiichi Sankyo and was developed by the Office of Health Economics (OHE).
To realise the full potential of TA therapies, stakeholders must confront the inherent tension between innovation and traditional assessment requirements.
Tumour-agnostic (TA) therapies represent a paradigm shift in oncology by targeting molecular alterations regardless of tumour histology. Since the landmark approval of pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumours by the US FDA in 2017, the number of TA therapies has grown substantially. Despite this scientific progress, TA therapies face a combination of challenges, including the reliance on evidence from basket trials, small and heterogeneous patient populations, scarcity or lack of tumour-specific comparator evidence, the use of surrogate endpoints like objective response rate and availability of molecular testing, making it difficult to assess, reimburse, pay and adopt them in clinical practice. Consequently, the path from regulatory approval to patient access remains highly variable and complex across jurisdictions.
This report provides a landscape analysis of access to TA therapies across 11 countries – Australia, Brazil, Canada, China, France, Germany, Italy, Japan, Spain, the UK, and the US. It focuses on three TA therapies – pembrolizumab, larotrectinib, and entrectinib – to assess regulatory, health technology assessment (HTA), and reimbursement outcomes and identify barriers and possible solutions along the access pathway.
The key findings are:
- Regulatory Variability: While all countries have approved at least one TA therapy, regulatory approaches vary. Neurotrophic tyrosine receptor kinase (NTRK) inhibitors have been widely accepted due to their consistent clinical response, whereas MSI-H/dMMR therapies have faced more scrutiny. The FDA has led with early approvals of TA therapies, while others like the EMA have adopted a more cautious approach, requiring additional evidence to support TA-based indications and restricting indications when considerable treatment heterogeneity was observed.
- HTA Challenges: TA therapies challenge traditional HTA frameworks, which are designed for organ-specific treatments. Key challenges include their reliance on single-arm trials, surrogate endpoints like objective response rate (ORR), and limited comparative effectiveness data. Some HTA bodies, like Canada’s CDA-AMC, have begun to issue TA-specific guidance and considered Bayesian statistical approaches, but are under review by most other agencies.
- Reimbursement Gaps: Reimbursement remains inconsistent across and within countries. While TA therapies targeting ultra-rare biomarkers (e.g., NTRK fusions) often gain conditional coverage, other therapies (e.g., MSI-H/dMMR) face greater hurdles. Differences in payment models, HTA frameworks, and regional-level decision-making further complicate access.
- Diagnostic Access Is Critical: Adoption of advanced diagnostic infrastructure is essential to identifying eligible patients. Testing access is uneven and often depends on the targeted therapies available in the clinical setting, with significant disparities in funding, infrastructure, and clinical integration, especially in lower-resourced settings.
- Emerging Policy Trends: Key developments include FDA and CDA-AMC guidance on TA-specific evidence generation and assessment, ESMO’s screening framework for TA potential, and early signs of HTA reform in jurisdictions like Australia. International efforts, such as Project Orbis, may support greater alignment and efficiency.
Our analysis identified evidence gaps in some countries – particularly Brazil, China, and Japan – where published information on evidence assessment and decision-making approaches remains limited.
Implications
To realise the full potential of TA therapies, stakeholders must confront the inherent tension between innovation and traditional assessment requirements. Novel trial designs, improved biomarker validation, adaptive reimbursement models, and molecular testing that align with clinical recommendations will all be critical. The findings underscore a need for systemic alignment between developers and decision-makers to support timely and equitable access to these paradigm-shifting therapies.
For systems where limited evidence was found, further research is needed to better understand decision-makers’ positions on TA therapies, clarify evidence requirements, and identify ways to improve current systems – particularly by making them more structured and transparent to external stakeholders.
The key recommendations are:
- Tailor evidence-generation strategies and analytical approaches to accommodate tumour heterogeneity and small populations, leveraging real-world data and Bayesian methods in supporting trial data.
- Evolve HTA methodologies to increase acceptance of surrogate endpoints and methods for indirect comparisons, including situations where only observational data are available.
- Increase the implementation of innovative payment models that can facilitate conditional reimbursement and continue evidence development to address uncertainties.
- Ensure national coverage for molecular testing, co-evaluating diagnostics and therapies, and integrating testing into cancer pathways.
- Promote cross-stakeholder and cross-border collaboration, including joint guidance on basket trials and coordinated post-marketing data collection.
Study limitations and recommendations for next steps
This analysis was scoped to draw on publicly available sources to examine regulatory, HTA, and reimbursement pathways for tumour-agnostic therapies across 11 countries across the globe. This approach ensures transparency and consistency. It also comes with inherent limitations.
Not all the reasoning behind regulatory and payer decisions is made public, and informal practices or behind-the-scenes factors are often not documented. As such, while findings reflect the state of play based on accessible evidence, they may not capture the full complexity of each system.
Future work should consider qualitative methods – such as interviews with decision-makers and stakeholders – to uncover the context behind the decision and better understand evolving thinking around TA therapies. Additionally, a more detailed analysis of individual HTA reports could reveal patterns in how uncertainties are managed, and which methodological flexibilities are (likely) being accepted.