Results: Patient with cutaneous melanoma and a somatic (tumour) NTRK rearrangement

A 52-year-old man with a history of cutaneous melanoma is diagnosed with lung and liver metastases. After progression through two lines of therapy, somatic (tumour) testing via a multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel reveals an NTRK rearrangement.

• The NTRK genes NTRK1, NTRK2 and NTRK3 encode neurotrophin receptors TRKA, TRKB and TRKC respectively.
• NTRK fusion genes are formed when rearrangements – such as translocations or inversions – occur between or within chromosomes in such a way that an NTRK gene is brought into contact and fuses with a partner, like ETV6, LMNA or TPM3. This NTRK-partner gene fusion results in a fusion protein product that constitutively activates downstream signalling pathways, such as MAPK, PI3K and PKC.
• NTRK fusion genes are oncogenic drivers of various adult and paediatric tumours.
• NTRK fusion genes are found in about 1% of all solid tumours, but frequency varies significantly between different tumour types.
• NTRK fusions are present in 0.3% of melanomas.
• NTRK inhibitors are targeted therapies (tyrosine kinase inhibitors) associated with high response rates in NTRK-fusion positive cancers regardless of tumour histology.

• Patients with inoperable or metastatic melanoma with an NTRK rearrangement who have no satisfactory treatment options are eligible for treatment with the NTRK inhibitor drugs entrectinib or larotrectinib.
• These drugs are currently made available via the Cancer Drugs Fund.
• Overall, data are limited for the efficacy of NTRK inhibitors in patients with melanoma owing to the low frequency of eligible patients. However, these drugs offer a further choice of therapy in a tumour type in which options are limited.

For clinicians

• European Society for Medical Oncology: Epidemiology of cancers with NTRK gene fusion
• NHS England: National Genomic Test Directory
• NICE: Entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Larotrectinib for treating NTRK fusion-positive solid tumours

For patients

• Macmillan Cancer Support: Entrectinib (Rozlytrek®)
• Macmillan Cancer Support: Histology independent therapies (HITs)
• Macmillan Cancer Support: Larotrectinib (Vitrakvi®)