FDA Grants Accelerated Approval to Repotrectinib for Cancers with NTRK Fusions 

Dr. Alexander Drilon

Dr. Alexander Drilon has led the development of many novel targeted therapies for cancer.

On June 13, 2024, a targeted drug called repotrectinib (AugtyroTM) received accelerated approval from the US Food and Drug Administration (FDA) for treating cancers caused by gene changes called NTRK fusions. The clinical trial that resulted in the approval was led globally by early drug development specialist Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK). 

NTRK fusions are implicated in many kinds of cancer, and this drug appears to be effective regardless of where the cancer originates,” Dr. Drilon says. “MSK has been a leader in studies that test drugs based on a tumor’s genetic profile rather than where in the body that cancer starts from.” 

The NTRK gene changes are linked to many types of tumors, including brain cancer, soft tissue sarcoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, and certain head and neck cancers. The FDA approved repotrectinib for adults and children ages 12 and older who have advanced or metastatic cancers with NTRK fusions that can’t be treated with surgery and who have not responded to other treatments. 

NTRK fusions occur when a piece of one gene breaks off and attaches itself to another gene, a change that triggers out-of-control cell growth. Repotrectinib, which is in a class of targeted therapies called tyrosine kinase inhibitors, works by blocking signals that cause tumor cells to multiply. Blocking the signals helps to stop the spread of cancer. 

There are three known NTRK fusion types that are involved — NTRK1NTRK2, and NTRK3. They can be detected with tumor-sequencing tests like MSK-IMPACT® or liquid-biopsy tests like MSK-ACCESS®.

Results from Repotrectinib Clinical Trial

The approval was based on a clinical trial in which more than half of patients with NTRK fusions in their tumors responded to repotrectinib. Based on data presented at the most recent Congress of the European Society of Medical Oncology, a response was seen both in patients who had and who had not previously received an older drug called larotrectinib (Vitrakvi®). 

  • 50% of those who had received the older drug responded to the new drug, which means their tumors shrank by at least 30%. 
  • 58% of those who had not previously received targeted therapies responded. 

Importantly, tumors disappeared in all patients whose cancer that had spread to the brain. The number of patients was small — only 5 — but the investigators say it’s significant that repotrectinib is able to cross the blood-brain barrier, allowing the medicine to reach the tumors in the brain. 

Like other tyrosine kinase inhibitors, repotrectinib is taken at home as a pill. The most common side effects are: 

  • dizziness 
  • a metallic taste in the mouth 
  • numbness or tingling in the hands and feet 

For most patients in the trial, the side effects were mild enough that they didn’t need to stop taking the drug. 

Previous Landmark Approval of Another Treatment for NTRK Cancers 

Repotrectinib is not the first NTRK fusion–targeting drug that MSK investigators helped bring into the clinic. In November 2018, the FDA approved larotrectinib for patients of any age with tumors caused by NTRK mutations. That approval was a landmark — the first drug ever to be developed and approved based solely on its molecular activity, regardless of where in the body the tumor originated. The trials that resulted in that drug’s approval were also led by Dr. Drilon and other members of MSK’s Early Drug Development Service. 

“We have been pioneers in ‘basket studies’ where the focus is on a cancer’s genes, rather than what it looks like under the microscope,” Dr. Drilon says. 

Repotrectinib Is Effective Against Tumors Resistant to Other NTRK Drugs 

Although larotrectinib is an important drug and can work for a very long time, unfortunately most patients taking it eventually develop resistance. The tumor cells evolve in a way that stops the drug from working, allowing the cancer to start growing again. Repotrectinib works in a different way, according to research from Dr. Drilon and his colleagues. It’s a new option for many patients whose tumors have stopped responding to the older drug. 

 “Until now, there was nothing approved for patients after failing earlier-generation drugs like larotrectinib,” Dr. Drilon says. “For many years, MSK has been a leader in studying how resistance to targeted therapies develops and how to design drugs to get around it.” 

In 2018, Dr. Drilon was first author of a paper published in Cancer Discovery reporting that repotrectinib was able to overcome acquired resistance to other drugs that target NTRK and ROS1 fusions.   

A Second Approval for Repotrectinib, Already Approved for ROS1 Lung Cancers 

Repotrectinib was first approved by the FDA in November 2023 for treating lung cancers linked to fusions in another gene, ROS1, based on results of a clinical trial called TRIDENT-1. 

The same phase 1/2 clinical trial has now resulted in repotrectinib’s approval for NTRK fusion–linked cancers. Dr. Drilon is one of the principal investigators of the trial, which included patients treated at hospitals around in the United States and in several other countries. 

“This FDA approval means that we now have a new generation of drugs to treat patients who historically have not had other good options,” Dr. Drilon says. “This approval illustrates MSK’s leadership in the development of cutting-edge targeted therapies.” 

Dr. Drilon discloses relationships with and/or financial interests in the following companies and organizations including: Bristol Myers Squibb/TP Therapeutics, A.C. Camargo Cancer Center; AbbVie; Answers in CME (AiCME); Associazione Italiana Oncologia Toracica (AIOT); Bayer; Boundless Bio, Inc.; Clinical Care Options; Clinical Education Alliance, LLC; Didactika S.r.l.; EcoR1 Capital LLC; Elevation Oncology, Inc.; InnoCare Pharma Inc.; Korean Society of Medical Oncology (KSMO); Lung Cancer Research Foundation; MBrace Therapeutics, Inc.; MI&T S.r.l. Organizzazione Congressi; MJH Life Sciences; Medscape; Monte Rosa Therapeutics, Inc.; PeerView Institute for Medical Education (PVI); Physicians’ Education Resource; Projects In Knowledge; Springer Nature Group; Total CME; Treeline Biosciences, Inc.; Universidad Autónoma de Madrid; Vindico Medical Education; and i3 Health.