VITRAKVI

First assessment.

Favourable opinion for reimbursement only in the treatment of paediatric patients with refractory or relapsed, locally advanced or metastatic infantile fibrosarcoma or another soft tissue sarcoma, with NTRK (Neurotrophic Tyrosine Receptor Kinase) gene fusion.

Maintenance of this opinion is subject to submission of comparative data for VITRAKVI (larotrectinib) versus the standard of care in these patients within a maximum period of 12 months, as well as the implementation of an exhaustive registry identifying all children treated with VITRAKVI in France.

Unfavourable opinion for reimbursement in the other paediatric indications included in the MA and in adults with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion:

• who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and
• who have no satisfactory treatment options.

What therapeutic improvement?

No clinical added value, on the basis of currently available data, in the treatment of paediatric patients with refractory or relapsed, locally advanced or metastatic infantile fibrosarcoma or another soft tissue sarcoma, with NTRK gene fusion.

Role in the care pathway?

Solid tumours with NTRK gene fusion represent a heterogeneous group of tumours, in both adults and children. At present, the frequency of fusion is not precisely known. Overall, this frequency is low (0.5% to 1%) in common cancers (e.g. lung, prostate, colon and breast cancers) and in CNS tumours, whereas it is high (> 80%) for certain rare cancers, for example in adults with salivary gland cancer of subtype MASC - Mammary Analogue Secretory Carcinoma, secretory breast cancer, and, in children, infantile fibrosarcoma.

Currently, the prognostic value of NTRK 1, 2 or 3 fusion in solid cancers is not known and the French national health insurance system funds only IHC-based detection tests, not NGS or RT-PCR tests. The molecular biology platforms of university hospitals and cancer centres perform the test on demand. In some rare tumours, the detection of this abnormality is an integral part of the diagnosis, particularly for infantile fibrosarcoma.

Role of the medicinal product in the care pathway

In paediatrics, despite the low level of evidence of the data supplied and pending new efficacy and safety data, the Committee considers that VITRAKVI (larotrectinib), as monotherapy, is a treatment option for patients with refractory or relapsed, locally advanced or metastatic infantile fibrosarcoma or other paediatric soft tissue sarcomas, with NTRK gene fusion.

In view of the number of patients having received an objective response in a non-comparative phase I/II study and according to the experts, VITRAKVI (larotrectinib) could have a limited role in the paediatric management of:

• infantile fibrosarcoma with NTRK gene fusion in the event of failure of vincristine-actinomycin chemotherapy (the reference treatment for several decades) and the impossibility of non-mutilating surgery, to avoid exposure to intense chemotherapy, and for exceptional refractory or relapsed metastatic forms;
• other paediatric soft tissue sarcomas with NTRK gene fusion following failure of standard therapies, for refractory or relapsed tumours.

It is necessary to indicate that in a context in which no comparative data are available to guarantee the solidity of the conclusion with respect to the effect of treatment with VITRAKVI (larotrectinib), the introduction of this medicinal product into the treatment strategy is accompanied by a higher risk than for medicinal products for which the efficacy is based on a comparison conducted with control of the risk of wrongly concluding that the treatment is effective (two-tailed alpha risk conventionally accepted to be 5%).

The Committee recommends that the choice of treatment should be made in the context of the proposal made following a multidisciplinary review meeting, in order to supervise the limited role of VITRAKVI (larotrectinib) in the therapeutic strategy.

In the other situations included within the broad scope of the MA and in view of available data based on three phase I, I/II and II non-comparative proof of concept studies, which are insufficient to support the clinical benefit of VITRAKVI (larotrectinib), in a context in which the prognostic value of the presence of NTRK gene fusion is not known, the Committee considers that VITRAKVI (larotrectinib) has no role in the therapeutic strategy, despite the medical need that may be unmet, particularly in last-resort situations.