NTRK inhibitors

The genes NTRK1, NTRK2 and NTRK3 encode tropomyosin receptor kinases TRKA, TRKB and TRKC respectively. NTRK fusion genes are formed when NTRK genes undergo chromosomal translocation with other genes (including ETV6, LMNA and TPM3), resulting in the formation of TRKA, TRKB or TRKC fusion proteins that constitutively activate downstream signalling pathways and promote tumour development.

Cancers with NTRK gene fusions can be divided into two broad categories. The first consists of rare cancer types highly enriched for NTRK gene fusions, and the second includes common cancers in which NTRK gene fusions are found with low to intermediate frequency. Rare cancers enriched for NTRK gene fusions include secretory breast carcinoma, mammary analogue secretory carcinoma of the salivary gland, congenital infantile fibrosarcoma and congenital mesoblastic nephroma.

NTRK inhibitors are tyrosine kinase inhibitors that work against TRKA, TRKB and/or TRKC fusion proteins. They can be broadly classified as multi-kinase inhibitors with a range of targets, including TRK, or more selective TRK inhibitors. Multi-kinase inhibitors that target TRK include entrectinib, crizotinib, cabozantinib and nintedanib, while larotrectinib is a more selective TRK inhibitor. Only entrectinib and larotrectinib are approved for use in NTRK fusion-positive solid tumours. To be eligible to receive these drugs within the NHS via the Cancer Drugs Fund, a patient must have no other satisfactory treatment options available.

Larotrectinib was recommended by NICE for use within the NHS on the basis of a pooled analysis of 102 patients from three phase one and two clinical trials involving patients with a locally advanced or metastatic, non-central nervous system primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. In the two larger trials, the overall response rate was 79% across multiple tumour types. However, rare tumour types with frequent NTRK fusions were over-represented, while some tumour types were not represented at all. The long-term survival benefit cannot be reliably estimated because the data are immature. These results must therefore be interpreted with caution and are not generalisable to NHS clinical practice.

The key evidence that led to entrectinib being recommended by NICE comes from a pooled analysis of 54 adult patients from three single-arm phase one and two clinical trials (ALKA-372-001, STARTRK-1 and STARTRK-2), which recruited adults with advanced or metastatic NTRK fusion-positive solid tumours. The overall objective response rate was 57% across all tumour types.

In a later analysis with an expanded cohort of 121 patients, the overall objective response rate was 61%. Median duration of response was 10 months. This data must also be interpreted with caution, for the same reasons outlined above for larotrectinib.

For entrectinib, the most common grade-three or -four treatment-related adverse events were increased weight and anaemia, while the most common treatment-related serious adverse events were nervous system conditions. For larotrectinib, the most common grade-three or -four treatment-related adverse events were increased alanine aminotransferase, anaemia, neutropenia and nausea. The most common treatment-related serious adverse events were increased alanine aminotransferase and increased aspartate aminotransferase.

• NTRK fusion genes are formed when NTRK genes undergo chromosomal translocation with other genes, resulting in the formation of TRKA, TRKB or TRKC fusion proteins.
• These proteins constitutively activate downstream signalling pathways and promote tumour development.
• Cancers with NTRK gene fusions consist of rare cancer types highly enriched for NTRK gene fusions (such as congenital infantile fibrosarcoma) and common cancers with low or intermediate rates of NTRK gene fusions (such as non-small cell lung cancer).
• NTRK inhibitors are tyrosine kinase inhibitors that work against TRKA, TRKB and/or TRKC fusion proteins. They include entrectinib and larotrectinib.
• To be eligible for treatment with these drugs within the NHS, a patient must have no other satisfactory treatment options available.

For clinicians

• NICE: Entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Larotrectinib for treating NTRK fusion-positive solid tumours

References:

• Cocco E, Scaltriti M and Drilon A. ‘NTRK fusion-positive cancers and TRK inhibitor therapy‘. Nature Reviews Clinical Oncology 2018: volume 15, issue 12, pages 731–747. DOI: 10.1038/s41571-018-0113-0
• Demetri GD, De Braud F, Drilon A and others, ‘Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors‘. Clinical Cancer Research 2022: volume 28, issue 7, pages 1,302–1,312. DOI: 10.1158/1078-0432.CCR-21-3597
• Doebele RC, Drilon A, Paz-Ares L and others. ‘Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials‘. The Lancet Oncology 2020: volume 21, issue 2, pages 271–282. DOI: 10.1016/S1470-2045(19)30691-6
• Hong DS, DuBois SG, Kummar S and others. ‘Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials‘. The Lancet Oncology 2020: volume 21, issue 4, pages 531–540. DOI: 10.1016/S1470-2045(19)30856-3

For patients

• Macmillan Cancer Support: Entrectinib (Rozlytrek®)
• Macmillan Cancer Support: Larotrectinib (Vitrakvi®)