A paradigm shift is occurring in cancer care with the introduction of tumour-agnostic therapies, for which the indication is defined by the molecular signature of the tumour rather than by its location. While promising for patients, healthcare systems are facing major challenges with the clinical and economic assessment of such therapies and subsequent reimbursement decisions.
As several agents have already gained regulatory approval, and many other emerging molecules are set to enter the market over the next decade, there is a window of opportunity to learn from the various approaches undertaken to date and prepare for more consistent assessments in the future. Recent approvals include pembrolizumab for solid tumours with high microsatellite instability (MSI-H) or high tumour mutational burden (TMB-H), and larotrectinib and entrectinib for neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours.
For healthcare systems, one of the biggest challenges lies in the clinical and economic assessment of these therapies, and subsequent decisions regarding reimbursement. As head-to-head data and comparative analyses remain a challenge for tumour-agnostic therapies, clinical evidence provided at the time of regulatory or reimbursement dossier submissions may include indirect comparisons to real-world data (RWD), or intrapatient analyses. In addition, testing costs and value need to be considered, given the need for broad genomic profiling platforms to facilitate patient identification and matching to novel treatments. The evaluation framework of each country’s health technology assessment (HTA) agency determines how these challenges are currently addressed.
This report provides an analysis of HTA agency assessments and reimbursement decisions for entrectinib and larotrectinib across England, Germany, France, Canada, Denmark, Sweden and Scotland. Overall, 13 reimbursement decisions (six for entrectinib, seven for larotrectinib) with publicly accessible documents were analysed to understand the assessment outcomes and what evidence may have influenced them.
We found that across HTA agencies different evidence requirements and criteria were used to assess tumour-agnostic therapies, and that these influence the assessment and reimbursement decisions for tumour-agnostic therapies. Unsurprisingly, uncertainty about the clinical data was among the biggest concerns by payers, especially when non-traditional data sets were used, and this contributed to negative or partial funding recommendations in some countries. The option of conditional reimbursement to manage uncertainty, which exists in some but not all countries, may allow acceptance of currently available evidence with the caveat that additional data should be provided at an agreed later date.
Considering the different approaches to the clinical and health economic assessments, there is a need for more guidance on how HTA assessments and economic models should be structured for future tumour-agnostic molecules. Currently, countries that reject therapies solely because of uncertainty in the clinical data, but neither allow RWD in submissions or do not provide clear directions on how to generate acceptable RWD, nor have post-launch arrangements where RWD could be generated, do not seem to help themselves or patients very much. Some HTA systems however have developed, or are in the process of developing, internal guidelines for the assessment of tumour-agnostic therapies. This is a necessary and useful approach to ensure that future tumour-agnostic therapies are assessed consistently.
Funding: This consulting report was commissioned and funded by F. Hoffmann-La Roche Ltd. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Lietta Nicolaides, PhD, of Ashfield MedComms, an Ashfield Health company, and funded by F. Hoffmann-La Roche Ltd.