Key Points
- Molecular alterations of neurotrophic tyrosine receptor kinase (NTRK) genes, in particular fusion with other genes, appear to play a role in carcinogenesis.
- NTRK gene fusions have been identified in many types of cancer, such as lung, colorectal and breast cancer, and sarcomas, but their prevalence is generally low (in 0.5% to 3% of patients). These anomalies are common, however, in a number of very rare cancers, such as infantile fibrosarcoma and some secretory carcinomas of the salivary glands (found in over 90% of patients).
- Larotrectinib (Vitrakvi°) is the first drug to have been authorised in the European Union for adults and children with a tumour that harbours an NTRK gene fusion, but it can only be used when all other treatment options have been exhausted or are not feasible.
- It is also the first drug to have been authorised in the European Union to treat cancer regardless of the location of the primary tumour.
- JUDGEMENT RESERVED Larotrectinib inhibits the tyrosine kinase activity of tropomyosin receptors. Evaluation of larotrectinib in cancers in which the tumour cells harbour an NTRK gene fusion is based on data obtained in 164 patients included in three non-comparative trials. These limited data suggest that larotrectinib has an antineoplastic effect, especially in children with infantile fibrosarcoma, but do not show improvement in survival or other clinical outcomes. Larotrectinib has mainly neurological and hepatic adverse effects. As of early 2021, further evaluation in comparative clinical trials is required.
EDITORS' OPINION Dissuasion
"Targeted" therapies have been marketed for years now for certain types of cancer. The use of these antineoplastic drugs is generally limited to patients with a well-identified cancer, with a specific genetic feature.
The concept of “targeted” therapy has been taken one step further with larotrectinib (Vitrakvi°). It is the first cancer drug authorised in Europe in which the indication is a genetic feature (an NTRK gene fusion), regardless of the tumour site. Is it acceptable in 2021 to have a genetic feature as the sole inclusion criterion when evaluating a treatment, without taking other tumour characteristics into account?
In the case of NTRK gene fusions, it’s a perplexing prospect, given the widely diverse natural histories of the cancers concerned: sarcomas, and breast, colon and lung cancers, and so on. In order to evaluate larotrectinib properly in the situations covered by its marketing authorisation, trials should have been conducted in homogeneous groups of patients, with matching prognostic factors and sufficient numbers in each group to enable analyses based on clinical endpoints.
However, its marketing authorisation was granted on the basis of an evaluation that came nowhere near to meeting these standards: no control group, few patients, diverse clinical situations, and a nonclinical primary endpoint... And the results were not spectacular. The European Medicines Agency (EMA) has shown that drug companies simply need to present a new concept, without appropriate clinical evaluation, in order to obtain marketing authorisation.
It’s enough to dissuade anyone from carrying out a meaningful clinical evaluation before applying for authorisation. Too bad for patients... |
©Prescrire 1 April 2021
Source: "Larotrectinib (Vitrakvi°) and cancers with an NTRK gene fusion. Grossly inadequate evaluation as of early 2021" Prescrire International 2021; 30 (225): 89-91. Subscribers only.
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