FDA Approval: Larotrectinib (Vitrakvi) for Cancer

An approval that never names an organ

Almost every cancer drug label starts with a body part. Lung. Breast. Colon.

The larotrectinib label does not. On November 26, 2018, the FDA granted accelerated approval to larotrectinib, sold as Vitrakvi, for adults and children with solid tumors carrying an NTRK gene fusion. The FDA called it the second tissue-agnostic approval for cancer treatment.

Tissue-agnostic means the eligibility test is molecular. What matters is a specific change inside the tumor, not where the tumor grew.

What an NTRK fusion is

Genes sit on chromosomes in a set order. Sometimes a piece of a chromosome breaks and rejoins in the wrong place. When that break joins two genes end to end, the result is a fusion gene.

The NTRK family has three members: NTRK1, NTRK2 and NTRK3. They carry instructions for TRK proteins, which normally help nerve cells develop. When an NTRK gene fuses with an unrelated partner, the TRK protein it makes gets stuck in the on position. The cell is told to keep growing and never told to stop.

Larotrectinib blocks TRK proteins. If the fusion is the engine driving the tumor, cutting that engine has an unusually direct effect.

NCI makes one warning explicit: not every NTRK change is a fusion. Other kinds of NTRK variants exist, and drugs in this class have not shown benefit against them. The report has to say fusion.

Who the label actually covers

The FDA's wording is specific. It covers solid tumors with an NTRK gene fusion and no known acquired resistance mutation, that are either metastatic or where surgery would cause severe harm, in people who have no satisfactory alternative treatment or whose cancer has grown after treatment.

So it is not a first-line drug for most people. It is for a situation where the usual options have run out or would cost too much.

What the evidence showed

Approval rested on three open-label, single-arm trials: LOXO-TRK-14001, SCOUT and NAVIGATE. Single-arm means nobody received a comparison treatment.

Efficacy came from the first 55 patients with unresectable or metastatic NTRK fusion-positive tumors across those studies. Twelve were under 18. Twelve different cancer types appeared, most often salivary gland tumors, soft tissue sarcoma, infantile fibrosarcoma and thyroid cancer.

The overall response rate was 75%, with a 95% confidence interval of 61% to 85%. Complete responses made up 22% and partial responses 53%. Median duration of response had not been reached when the data were locked. Responses lasted 6 months or more in 73% of patients, and 12 months or more in 39%.

Safety came from 176 patients, including 44 children. The most common side effects were fatigue, nausea, dizziness, vomiting, raised liver enzymes, cough, constipation and diarrhea.

Adults take 100 mg twice daily. Children are dosed by body surface area. A liquid form exists specifically so young children can take it. The adult figure is the label's; children's amounts are worked out by the team. Either way, follow the prescription you hold.

That is what the label sets out. The prescription written for you is the one to follow, and children are dosed differently again.

Why finding these tumors is the hard part

NTRK fusions are rare in common cancers and common in a few rare ones. That combination creates a practical problem: the people who could benefit are scattered across almost every tumor type.

In the trials, fusions were found by next generation sequencing or by fluorescence in situ hybridization at local laboratories. Neither test is automatic. Someone has to order it.

This is the case for broad genomic testing in advanced cancer generally. Our page on biomarker testing explains what a sequencing report contains and how to ask whether one was done. The wider idea behind it is covered in targeted therapy.

When to raise this with a team

This is not a symptom you can watch for. There is no NTRK screening. What follows is about testing, not self-checks.

Ask about NTRK and broader gene fusion testing if any of these apply:

• You or your child has an advanced solid tumor and standard options are running out.
• The diagnosis is one of the rarer types that showed up repeatedly in these trials: infantile fibrosarcoma, a salivary gland tumor, a soft tissue sarcoma, or thyroid cancer.
• Your pathology report mentions immunohistochemistry for pan-TRK but no confirmatory fusion test.
• A tumor panel was run years ago and did not include fusion detection.

Ask two questions plainly. Was the tumor tested for gene fusions, and does the report distinguish a fusion from another NTRK variant?

What this approval cannot tell you

• Accelerated approval was based on response rate and duration, not on how long people lived. Confirmatory evidence was still required.
• Fifty-five patients across twelve cancer types is a small base. Some tumor types were represented by only a handful of people.
• A response means the tumor shrank. It does not mean the cancer was cured, and resistance mutations do develop.
• The label excludes tumors with a known acquired resistance mutation.
• Larotrectinib is one of several drugs in this space. NCI's PDQ summary lists entrectinib and repotrectinib for the same target, with their own evidence and their own labels.

Sources

• FDA approves larotrectinib for solid tumors with NTRK gene fusions
• NCI PDQ: Agnostic Cancer Therapies (Health Professional Version)
• NCI: Targeted Therapy Larotrectinib Shows Promise in Early Trials, Regardless of Cancer Type
• Drugs@FDA overview: VITRAKVI (larotrectinib), NDA 210861

How this page was made

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

Cancer Explained is published by the National Cancer Information Foundation. It is not medical advice and does not suggest a test or treatment.

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