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# TRK and RET inhibitors (tumour-agnostic kinase inhibitors)

Oral kinase inhibitors chosen by the tumour's gene, not its organ: larotrectinib for NTRK fusions, selpercatinib for RET fusions and mutations.

Updated Nov 1, 2026

## What they are

Some rare cancers in any organ, in adults and children, are driven by a fused or mutated receptor tyrosine kinase: TRK (from NTRK gene fusions) or RET (fusions in lung and thyroid cancers, point mutations in medullary thyroid carcinoma). Highly selective inhibitors produce deep responses when a molecular test shows the alteration; some approvals are «tumour-agnostic».

## Mechanism of action

They occupy the ATP site of the constitutively active fusion kinase (TRKA, TRKB, TRKC or RET), stopping its autophosphorylation and the downstream MAPK and PI3K signals that drive growth. Resistance appears through new mutations in the kinase domain.

Target: TRK (NTRK1-3) and RET receptor tyrosine kinases

## Key points

- Treatment depends on a molecular test showing an NTRK fusion or a RET alteration.
- Larotrectinib: dizziness, confusion and other neurological effects (TRK works in the nervous system), liver enzyme rises, fractures.
- Selpercatinib: hepatotoxicity, hypertension, QT prolongation, bleeding, hypothyroidism and impaired wound healing.
- Selpercatinib is metabolised by CYP3A4; grapefruit and St John's wort can change the levels of both drugs.

## Drugs in this class

- [**Larotrectinib** Oral TRK inhibitor for solid tumours with an NTRK gene fusion, in adults and children, whatever the organ. Watch for… TRKA, TRKB and TRKC receptor tyrosine kinases (genes NTRK1, NTRK2, NTRK3)](https://durgical.com/en/pharmacology/larotrectinib/)
- [**Selpercatinib** Oral selective RET inhibitor for RET-fusion lung and thyroid cancers and RET-mutant medullary thyroid cancer. Watch… RET receptor tyrosine kinase (fusions and activating mutations)](https://durgical.com/en/pharmacology/selpercatinib/)

## Others in the class

- entrectinib
- repotrectinib
- pralsetinib

## Test yourself

Think of the answer, then tap the question to see it.

## What does «tumour-agnostic» mean for larotrectinib?

It is chosen by the gene alteration (an NTRK fusion), whatever the organ the cancer started in.

## Which thyroid cancer carries RET point mutations and responds to selpercatinib?

Medullary thyroid carcinoma.

## Why do TRK inhibitors cause dizziness and other neurological effects?

TRK receptors are neurotrophin receptors that work in the normal nervous system.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [Larotrectinib: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a619006.html) (MedlinePlus (U.S. National Library of Medicine), 2026); [Selpercatinib: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a620036.html) (MedlinePlus (U.S. National Library of Medicine), 2026); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=L01EX) (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/pharmacology/classes/trk-and-ret-inhibitors/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/pharmacology/classes/trk-and-ret-inhibitors/