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
Medical Oncology
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.
79 in 100
Responses to larotrectinib across 159 patients, Lancet Oncol 2020
0.30%
Share of more than 295,000 tumors carrying an NTRK fusion, NPJ Precis Oncol 2021
14 of 15
Children with a fusion who responded in the first pediatric trial, Lancet Oncol 2018
Free
Oncologist review of your gene report
Free consultation
Send the pathology report and, if you have one, the gene test report naming the fusion and its partner gene, the latest scans including a brain MRI, and a list of treatments so far. If no gene test covering NTRK has been done, tell us which tissue is available, and we say whether it can be tested and how. A medical oncologist, with a pediatric oncologist for children, replies with what the result means. The review is free and carries no obligation.
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
1
Screen with a stain
An immunohistochemistry stain for pan-TRK protein can be run on the biopsy block in a day or two. A negative stain in most tumor types makes a fusion unlikely. A positive one needs confirmation.
2
Confirm with sequencing
Next-generation sequencing of the tumor, preferably of its RNA, which catches fusions that DNA panels miss. The report should name the NTRK gene and the partner gene.
3
Test blood if tissue has run out
Liquid biopsy looks for tumor DNA in the blood. It finds fusions less reliably than tissue, so a negative blood result does not rule one out.
Who should be tested
Every patient with advanced cancer for whom a broad gene panel is done anyway, which includes most lung, thyroid and bowel cancers. Every child with infantile fibrosarcoma or an unexplained sarcoma. Every patient with secretory carcinoma. Patients with rare cancers that have run out of standard treatment deserve a test, since a fusion changes everything for the few who carry one.
The drugs
Two approved drugs, and a third for later
All three come as capsules, and two have liquid forms for children.
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NTRK inhibitors
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 tumor
Fifty-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
In 54 adults with fusion-positive tumors of ten types, entrectinib produced a response in 57 percent, complete in 7 percent, with a median duration of response of 10 months at the time of analysis. The commonest severe related side effects were weight gain in 10 percent and anemia in 12 percent. Doebele and colleagues, Lancet Oncology, 2020. The lower response rate than larotrectinib's reflects different patients and trials, since the two drugs have never been compared directly.
Larotrectinib in children
The first pediatric trial
Twenty-four children and young people with a median age of 4.5 years were treated, 17 of them with fusion-positive tumors, including eight with infantile fibrosarcoma. Fourteen of the 15 evaluable children with a fusion responded, and the fifteenth had shrinkage short of a formal response. None of the seven without a fusion responded. For some children the drug shrank a tumor enough to avoid a disfiguring or limb-losing operation. Laetsch and colleagues, Lancet Oncology, 2018.
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.
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Side effects of NTRK inhibitors
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
1
Confirm the fusion
The oncologist checks that the report names an NTRK gene fused to a partner and that the fusion is in frame, meaning it produces a working hybrid protein.
2
Baseline tests
Blood counts, liver tests, weight, a brain MRI, and for children growth and development measures.
3
First dose
Capsules or liquid at home, with or without food. Children have their dose recalculated as they grow.
4
First scan
Eight weeks in. Responses are often visible by then.
After surgery, or instead of it
When a fusion-positive tumor can be removed easily, surgery comes first. When removal would be mutilating, as with some infantile fibrosarcomas of the limbs, the drug is often given first to shrink the tumor, and surgery follows, sometimes much smaller than planned.
Length of stay, flying, cost and the trip
1
Before you travel
Send the reports. If tissue needs testing, the block can often be couriered ahead so the sequencing result is ready when you arrive.
2
In Istanbul, five to seven days
Consultation, baseline tests and brain MRI, the first doses and a check two or three days later. Children see the pediatric oncologist and the family receives a dosing chart for the liquid.
3
Home
You can fly as soon as the first check is done. Blood tests continue every two weeks for two months at home, and scans every two to three months.
What decides the cost
The drug, taken daily for as long as it works, dominates the cost, and access varies between countries, from full reimbursement to named-patient import, so we check the position for your country with you. Sequencing, if not already done, and the MRI and scans come next. Published packages in Istanbul cover the consultation, tests, the first review, an interpreter and transfers, and leave out the hotel, flights and the drug supply. The coordinator writes in English, Arabic, French, Russian, Serbian, Romanian or Spanish, or arranges an interpreter, sends an appointment confirmation and an invitation letter naming the hospital and the treating doctor ten days before travel, and books the hotel and transfers. Two family members may join consultations, meals come in halal, vegetarian and diabetic versions, a prayer room is on site, and a female doctor can be requested at first contact. Our review of your reports costs nothing.
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?
A break in the DNA that joins part of an NTRK gene to an unrelated gene, producing a protein that tells the cell to grow constantly. It is found in about 0.3 percent of solid tumors, and in far more of a few rare cancers such as infantile fibrosarcoma and secretory carcinoma.
How well do NTRK inhibitors work?
Very well in patients with a true fusion. Larotrectinib produced responses in 79 percent of 159 patients, including 16 percent whose tumors disappeared, and entrectinib in 57 percent of 54 adults.
How do I know if my tumor has an NTRK fusion?
Only a test shows it. A pan-TRK stain can screen the biopsy, and sequencing of the tumor, ideally of RNA, confirms the fusion and names the partner gene.
Can children take NTRK inhibitors?
Yes. Larotrectinib is approved from birth in many countries and comes as a liquid. In the first pediatric trial, 14 of 15 children with a fusion responded, some avoiding major surgery.
What are the side effects?
Dizziness, weight gain, raised liver tests, tiredness and constipation, mostly mild. Falls and fractures have been reported, and some patients have muscle and joint pain for a few weeks after stopping.
How long do I need to stay in Istanbul?
Five to seven days for the consultation, tests and the start of treatment. The capsules or liquid are taken at home afterward, with blood tests and scans that a doctor at home can arrange following the written plan.
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. Metin GÜDEN, Radiation Oncology.
