# NTRK fusion-positive non-small-cell lung cancer

Source: https://onco.cc/cancers/ntrk-fusion-nsclc/  
OnCo record `ntrk-fusion-nsclc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

NTRK fusion lung cancer is very rare and is treated with the same TRK-blocking pills approved for any cancer with the fusion: larotrectinib, entrectinib or repotrectinib shrink most tumours, including in the brain, so the point is to test broadly enough to find it.

## Summary

NTRK1, NTRK2 and NTRK3 fusions drive a small share of many cancers, common in a few rare tumours (infantile fibrosarcoma, secretory carcinoma) and rare in common ones such as lung cancer. Larotrectinib was approved in November 2018 for any solid tumour with an NTRK fusion, the second tumour-agnostic approval after pembrolizumab for mismatch-repair deficiency, on a pooled response rate of 75 percent across tumour types in its phase 1 and 2 studies (NAVIGATE among them); entrectinib followed in August 2019 with a 57 percent pooled response rate and intracranial activity, and repotrectinib received a tumour-agnostic accelerated approval in June 2024, with activity against the solvent-front mutations that arise on the first two drugs.

In lung cancer specifically the numbers are small: lung cohorts within the larotrectinib and entrectinib programmes reported response rates of about 70 percent with responses in brain metastases, and the drugs are recommended first line or after chemotherapy. Dizziness, weight gain and paraesthesia from on-target TRK inhibition in the nervous system are the characteristic side effects. Checkpoint inhibitors and chemotherapy are used as for driver-negative disease when TRK inhibitors are exhausted.

Because the fusions are so rare, the practical question is testing: DNA panels miss some NTRK fusions, especially those involving NTRK2 and NTRK3 with large introns, so RNA sequencing or a combined panel is needed when no other driver is found. Open questions are the sequence of TRK inhibitors after resistance and whether next-generation inhibitors can avoid the neurological side effects.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: NTRK-rearranged lung cancer; TRK fusion lung cancer; NTRK1, NTRK2 or NTRK3 fusion NSCLC
- Tags: subtype-page; lung
- Group: lung
- Burden: NTRK fusions occur in well under 1 percent of non-small-cell lung cancers, in adenocarcinoma regardless of smoking history; they are found mainly when broad RNA-based panels are used.
- Subtypes: NTRK1 fusion adenocarcinoma; NTRK2 or NTRK3 fusion adenocarcinoma (often missed by DNA-only panels); TRK inhibitor-resistant disease with solvent-front mutations (repotrectinib)
- Biomarkers: NTRK1, NTRK2 and NTRK3 fusions by RNA sequencing (preferred) or DNA panel; Pan-TRK immunohistochemistry as a screen; NTRK resistance mutations (solvent front, gatekeeper) at progression; Brain MRI

## Standard of care

- Advanced, first line or after chemotherapy: Larotrectinib or entrectinib under their tumour-agnostic approvals; repotrectinib after resistance to either; chemoimmunotherapy as for driver-negative disease before or after. ([Larotrectinib](https://onco.cc/drugs/larotrectinib/), [NAVIGATE](https://onco.cc/trials/navigate/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/))

## State of the art

- Three TRK inhibitors approved for any tumour with an NTRK fusion, with response rates of 57 to 75 percent across cancers and brain activity.
- RNA-based testing recommended when no driver is found on a DNA panel.

## Open problems

- Fusions are missed when only DNA panels are run.
- Neurological side effects from TRK inhibition are class-wide.
- Data specific to lung cancer come from small cohorts within basket trials.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Trk_receptor
- Wikipedia: https://en.wikipedia.org/wiki/Trk_receptor
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [NTRK](https://onco.cc/targets/ntrk/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/)
- companies: [Bayer](https://onco.cc/companies/bayer/), [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- trials: [A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements](https://onco.cc/trials/nct03093116/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [NAVIGATE](https://onco.cc/trials/navigate/)
- people: [Alexander Drilon](https://onco.cc/people/alexander-drilon/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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