This is the second blog post in a series of posts focused on NTRK and NTRK gene fusions. This blog post provides an overview of the NTRK gene inhibitors, more precisely, Tropomyosin receptor kinase A (Trk) inhibitors. For the first blog post related to the NTRK gene, please check the link below:
📊 What Are the Most Common NTRK Inhibitors?
There are currently two FDA-approved NTRK inhibitors: larotrectinib (Vitrakvi) and entrectinib (Rozlytrek).
These NTRK inhibitors have shown excellent response rates in clinical trials and are effective even in patients with advanced or metastatic disease. So, we will focus on these two NTRK inhibitors in this post.
🤔When and Why Are NTRK Inhibitors Indicated to Be Used?
NTRK inhibitors are used when a patient has an NTRK fusion-positive tumor.
NTRK fusion-positive tumors are a group of rare cancers with an abnormality in their NTRK genes, specifically, gene fusions where the NTRK gene has been fused with one of several partner genes.
These NTRK gene fusions result in the formation of an abnormal NTRK fusion protein that can lead to uncontrolled growth and division of cancer cells. So, the NTRK inhibitors are a class of drugs that specifically target tumors with NTRK gene fusions by blocking the activity of the abnormal NTRK fusion protein, which can drive the growth and division of cancer cells. They counteract NTRK genes and fusion proteins, reducing tumor growth rate and potentially stopping it.
💊 What Type of Drug Is Vitrakvi (Larotrectinib)?
Vitrakvi (Larotrectinib) is a potent and selective inhibitor of all three TRK proteins. It treats NTRK-positive tumors that most commonly arise in the salivary gland, thyroid, lung, and soft tissue. Larotrectinib is a type of targeted therapy.
Larotrectinib is currently the most specific TRK inhibitor being tested in patients with cancer [citation].
Of these agents, larotrectinib and entrectinib are furthest along in clinical development. Larotrectinib is a potent and selective inhibitor of all three TRK proteins. Based on in vitro kinase assays, both compounds inhibit TrkA, TrkB, and TrkC. In addition, entrectinib and larotrectinib are highly effective in inhibiting the growth of cells transduced with different NTRK fusions and primary cancer cell lines harboring NTRK rearrangements in vitro in mice [citation].
🏥 Is Larotrectinib Chemotherapy?
Larotrectinib is not chemotherapy but a monotherapy, a form of targeted therapy.
❓What Is Targeted Therapy? What Is Targeted Monotherapy?
Targeted therapy is a medical treatment aiming to target specific molecules or pathways essential for the growth and survival of cancer or diseased cells. This treatment differs from traditional chemotherapy, which affects both healthy and cancerous cells.
Targeted therapy is designed to selectively target the cancer cells, resulting in fewer side effects and improved treatment effectiveness.
Targeted monotherapy refers to using a single targeted therapy drug as a standalone treatment for a particular disease rather than combining it with other treatments such as chemotherapy or radiation therapy.
In oncology, targeted monotherapy is often used when a patient's cancer is found to have specific genetic mutations or molecular characteristics that make it susceptible to a particular targeted therapy drug. For example, some cancers have mutations in genes such as EGFR or ALK, which can be targeted with specific drugs to slow or stop the growth of cancer cells.
⚕️ Is Larotrectinib FDA Approved? Is Vitrakvi FDA Approved?
Larotrectinib was granted accelerated approval on November 26, 2018, for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation that is either metastatic or where surgical resection is likely to result in severe morbidity alternative treatments or whose cancer has progressed following treatment [citation]. Vitrakvi (Larotrectinib) is produced by Bayer [citation].
🧪Do We Have to Do a Genetic Test for the NTRK Gene Mutations if One Would Have to Take Vitrakvi (Larotrectinib), and Why?
A genetic test before taking Vitrakvi is mandatory because it affects only NTRK fusion-positive cancers and is prescribed only in cases where no other treatment is possible. You can read more about the genetic testing for NTRK gene fusions HERE.
The adverse effects and consequences of taking Vitrakvi are severe; hence, it is never administered in case there is no NTRK fusion that it can target [citation]. You can read more about the NTRK gene fusion testing in our first blog posts you can read here.
What Type of Drug Is Rozlytrek (Entrectinib)? What Is the Relation Between the NTRK Gene and Entrectinib?
Entrectinib is a selective inhibitor of NTRK and ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1). Entrectinib is, in fact, a very potent tyrosine kinase inhibitor [citation].
Entrectinib is FDA-approved [citation]. Rozlytrek is a pharmacy name for entrectinib, so it is used for the same purpose in target therapy for inhibiting NTRK and ROS1. It is used to treat metastatic non-small lung cancer whose tumors are ROS1 positive.
Additionally, it is used to treat pediatric patients older than 12 or adults with solid tumors that are NTRK fusion-positive without a known acquired resistance mutation, whose surgical resection is likely to cause morbidity or have either progressed following treatment or have no satisfactory alternative therapy [citation].
Rozlytrek is used to inhibit the products of NTRK gene mutations, thus counteracting the effects of these mutations. Rozlytrek is produced by Roche GmbH [citation].
Do We Have to Do a Genetic Test for the NTRK Gene Mutations if One Would Have to Take Rozlytrek (Entrectinib), and Why?
A genetic test for NTRK mutations is crucial before administering Rozlytrek, and this is because it affects only NTRK fusion-positive cancers, and it is prescribed only in cases where no other treatment is possible.
The adverse effects and consequences of taking Rozlytrek are very severe; hence it is never administered in case there is no NTRK fusion that it can target or if the patient has a genetic mutation rendering him resistant to therapy [citation].
You can read more about the NTRK gene fusion testing in our first blog posts you can read here.