NTRK Inhibitor Therapy
NTRK inhibitors are capsules for cancers carrying an NTRK gene fusion, found in about 0.3 percent of solid tumors and in most infantile fibrosarcomas and secretory carcinomas. Larotrectinib shrank tumors in 79 percent of 159 patients from newborns to 84 years, and entrectinib in 57 percent of adults. A gene test decides who can benefit.
About This Department
Fewer than one solid tumor in three hundred carries an NTRK fusion. Find it, and a capsule shrinks the cancer in three patients out of four.
NTRK inhibitors belong to the targeted drugs. They block cancers driven by a rare gene fusion, whatever organ the cancer started in, from the soft tissue of a newborn's arm to the thyroid, lungs, bowel or salivary glands of an adult. Regulators approved them for the change they block, whatever the site of the tumor, one of the first times that happened. In the first 55 patients treated with larotrectinib, aged four months to 76 years with 17 different tumor types, 75 percent responded, and in a later pooled group of 159 patients 79 percent did. Finding these patients takes effort, because the fusion hides in about 0.3 percent of all solid tumors and only a gene test shows it.
Most cancer drugs are approved for one organ. The drugs on this page, NTRK Inhibitor Therapy, are approved for a genetic change, and a child with a rare soft tissue sarcoma and an adult with thyroid or lung cancer may take the same capsule. That makes the gene test, and the laboratory that runs it, as important as the drug.
What an NTRK fusion is
The receptor and the fusion
What TRK does normally
Three genes, NTRK1, NTRK2 and NTRK3, carry the instructions for the TRK receptors. These proteins sit on nerve cells, respond to growth signals while the nervous system develops, and help nerves survive. Outside the nervous system they stay mostly silent in adults.
What a fusion does
In a fusion, a break in the DNA joins part of an NTRK gene to part of an unrelated partner gene, and the two pieces are read together as if they were one. The resulting hybrid protein keeps the TRK engine and loses the switch that should turn it off, so it tells the cell to grow and divide all the time, with no signal needed from outside. A tumor built this way comes to depend on that single message more completely than most cancers depend on anything. Block the message and the tumor often shrinks within weeks. That dependence explains why responses to NTRK inhibitors are so frequent and so deep, why they occur in babies and in the elderly alike, and why the same drug works in a sarcoma of the arm, a cancer of the thyroid and a cancer of the lung. The organ matters far less than the fusion. That is new.
Where the fusion turns up
Common in a few rare cancers
Infantile fibrosarcoma and other childhood tumors
Babies and young children develop this soft tissue tumor, and most cases carry an NTRK3 fusion. Other pediatric sarcomas and some childhood brain tumors carry the fusion too. Across a database of more than 295,000 tumors, fusions were present in 1.34 percent of patients under 18 and in 2.28 percent of those under five, several times the adult rate.
Secretory carcinomas of the breast and salivary glands
The ETV6-NTRK3 fusion defines these two rare cancers and appears in nearly all cases. Salivary gland tumors had the highest fusion rate of any group in the large database, 2.62 percent, and pathologists who see a secretory carcinoma now order the fusion test almost as a reflex.
Rare in common cancers
Thyroid, lung and bowel
In papillary thyroid cancer, lung adenocarcinoma and bowel cancer, fusions turn up in well under one case in a hundred. In bowel cancer they cluster in tumors with microsatellite instability, a clue that guides which tumors to test.
Everywhere else
Doctors have described fusions in some 45 cancer types. The overall prevalence came to 0.30 percent. Of the 88 partner-gene pairs found, 66 percent had never been reported. Westphalen and colleagues, NPJ Precision Oncology, 2021.
Finding the fusion
Who should be tested
The drugs
Two approved drugs, and a third for later
All three come as capsules, and two have liquid forms for children.
This table scrolls sideways on a narrow screen. Swipe or drag to see every column.
| Drug | How it is taken | Notes |
|---|---|---|
| Larotrectinib | 100 milligrams twice a day as a capsule, or a liquid dosed by body surface in children | Highly selective for TRK. Approved for adults and children from birth in many countries |
| Entrectinib | 600 milligrams once a day as a capsule, with lower doses for children | Also blocks ROS1 and ALK, and reaches the brain well |
| Repotrectinib | Capsule, twice daily after an initial once-daily period | Newer, designed to work after resistance to the first two |
Larotrectinib
Designed to hit only the three TRK receptors. Its side effects stay narrow as a result, and the liquid form matters in infants, who cannot swallow capsules and whose dose changes as they grow week by week.
Entrectinib
Broader.
Entrectinib also treats ROS1 fusion lung cancer, and its makers designed it from the start to cross into the brain, which counts when brain metastases are present.
Larotrectinib, the evidence
Two analyses from three early trials
The first 55 patients
75 percent responded, whatever their age or tumorFifty-five patients aged four months to 76 years, with 17 different fusion-positive tumor types, received larotrectinib. Independent reviewers found a response in 75 percent. At one year 71 percent of responses were continuing and 55 percent of patients were free of progression, and no patient stopped the drug because of side effects. Drilon and colleagues, New England Journal of Medicine, 2018.
The pooled 159
In a larger analysis of 159 patients, from newborns to 84 years, 79 percent responded and 16 percent saw the tumor disappear completely. Across 260 treated patients, severe drug-related side effects stayed rare, led by raised liver tests in 3 percent, and none proved fatal. Hong and colleagues, Lancet Oncology, 2020. Single-arm trials without a comparison group produced these numbers, the usual design for a change this rare, and they measured response rather than survival.
Entrectinib, and children
Different drug, different population
Entrectinib in adults
Integrated analysis of three trials
Larotrectinib in children
The first pediatric trial
Side effects
Mostly mild, and linked to the nervous system
TRK receptors work in the brain and nerves, so the side effects follow them there.
This table scrolls sideways on a narrow screen. Swipe or drag to see every column.
| Effect | Why it happens | What is done |
|---|---|---|
| Dizziness and unsteadiness | TRK receptors help control balance | Care on stairs, no driving until it settles, dose reduction if it persists |
| Weight gain and appetite | TRK signalling helps regulate appetite | Dietary advice from the start, especially with entrectinib |
| Raised liver tests | Drug effect on the liver | Blood tests every two weeks at first |
| Tiredness, constipation, nausea | General drug effects | Usually mild |
| Taste changes and tingling | Nerve effects | Usually mild and stable |
Falls and fractures
Dizziness raises the risk of a fall. Bone fractures have been reported during treatment too, so elderly patients and parents of toddlers learn to watch for them.
Stopping the drug
Some patients ache after stopping. Muscle and joint pain can last a few weeks, and the team tapers the dose or treats it until it settles.
Starting treatment
After surgery, or instead of it
Length of stay, flying, cost and the trip
What decides the cost
Resistance, and follow-up at home
When the tumor escapes
Resistance mutations
Resistance comes eventually for many patients with advanced disease, although some have now taken the drug for years without it. It arrives in one of two ways. First, the tumor may develop a new mutation in the TRK receptor itself, often at a spot called the solvent front, which changes the shape of the pocket where the drug sits so that it can no longer bind. Second, the tumor may switch to a different growth pathway altogether, such as MET or the MAPK pathway, and stop needing TRK. Both can show up as slow growth of a single spot on a scan or as new spread, and neither is a reason to give up on targeted treatment, because the next step depends on which of the two has happened, and that is something a test can answer within two weeks.
Next-generation drugs
Testing again shows which. A receptor mutation can respond to a next-generation inhibitor such as repotrectinib. A pathway switch needs a different drug. Or chemotherapy.
Follow-up at home
Scans and tests
Once you are back home, your oncologist there follows the written plan, with blood tests before each new supply, a CT every two to three months and a brain MRI at intervals. The coordinator stays reachable on the same WhatsApp number. Clinical questions go to the treating oncologist.
Warning signs
See a doctor the same day for a fall or new bone pain, yellow skin, severe dizziness, or new headaches or weakness, which can signal disease in the brain.
NTRK Inhibitor Therapy FAQ
What is an NTRK fusion?
How well do NTRK inhibitors work?
How do I know if my tumor has an NTRK fusion?
Can children take NTRK inhibitors?
What are the side effects?
How long do I need to stay in Istanbul?
References
- Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-739.
- Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours, a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540.
- Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours, integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282.
- Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions, phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714.
- Westphalen CB, Krebs MG, Le Tourneau C, et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. NPJ Precis Oncol. 2021;5(1):69.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Mustafa Teoman YANMAZ, Medical Oncology.
Medically reviewed by
Prof. Dr. Mustafa Teoman YANMAZ
Medical Oncology
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