Uncertainties around tumour-agnostic therapies in Europe: barriers and facilitators of patient access to novel medicines

Abstract

With the approval of two tumour-agnostic therapies by the European Medicines Agency for the treatment of NTRK gene fusion-positive solid tumours, a new era of personalised cancer medicine has begun in Europe. Larotrectinib and entrectinib represent the recent advance in pharmacological tumour treatments, by targeting substrates (NTRK gene fusions) throughout the body. However, their stories have not been without difficulties. Clinical trials were complicated by the overall rarity of NTRK gene fusion tumours and specific tumour types. The single-arm, uncontrolled basket trials were reason for concern. Still, both therapies were granted CMA by the EMA, after withdrawal of their initial orphan designations, on the condition of gathering more data to increase sample size, and on the role of NTRK fusions as oncogenic drivers. The complete EMA procedure took 6 months longer for entrectinib, despite PRIME. HTA organisations struggled to assess the added benefit of these tumour-agnostic therapies. To a more or lesser extent, the sufficiency of decision framework, generalisability of the trial populations with the clinical practice population, the use of basket trials, and the absence of data comparing with a comparator therapy formed causes for concern. Still, all HTA organisations (ZIN, NICE, HAS, GBA) recommended both therapies for inclusion in national reimbursement lists based on the tumour-agnostic indication. However, in Germany, the extent of reimbursement is unclear, and in France, only larotrectinib was reimbursed for certain sarcomas. Meanwhile, the European Society for Medical Oncology recognised NTRK-gene fusion tumours as a separate tumour type, possibly enabling the recommendation of these therapies in a tumour-agnostic guideline in addition to the few tumour-specific guidelines. Still, limited reimbursement and recommendations for use may vitiate achievements made by developing these innovative therapies. More tumour-agnostic therapies may be introduced to the European market. So, the lifecycle experiences of larotrectinib an entrectinib can provide pivotal insights in advancing the drug lifecycle for these types of therapies, regarding development, market approval, reimbursement, and ultimate patient access. Here, we review all these aspects for larotrectinib and entrectinib.