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Entrectinib

Entrectinib is an innovative targeted therapy drug being studied in clinical trials for the treatment of various solid tumors and non-small cell lung cancer (NSCLC), particularly in patients with specific genetic alterations. These trials aim to evaluate the safety, efficacy, and potential benefits of entrectinib in different patient populations and treatment scenarios.

Table of Contents

What is Entrectinib?

Entrectinib is an oral medication used in the treatment of certain types of cancer. It is also known by its brand name Rozlytrek[1]. Entrectinib belongs to a class of drugs called tyrosine kinase inhibitors, which work by targeting specific proteins in cancer cells to slow down or stop their growth[2].

How Does Entrectinib Work?

Entrectinib specifically targets and inhibits three types of proteins in cancer cells:

  • TrkA, TrkB, and TrkC: These proteins are coded by genes called NTRK1, NTRK2, and NTRK3.
  • ROS1: This protein is coded by the ROS1 gene.
  • ALK: This protein is coded by the ALK gene.

When these proteins are altered or fused with other genes, they can cause uncontrolled cell growth, leading to cancer. By blocking the action of these proteins, entrectinib can help slow down or stop the growth of cancer cells[2].

What Conditions Does Entrectinib Treat?

Entrectinib is used to treat several types of cancers that have specific genetic alterations. These include:

  • Non-small cell lung cancer (NSCLC) with ROS1 gene fusions
  • Solid tumors with NTRK gene fusions, including:
    • Colorectal cancer
    • Salivary gland cancers
    • Thyroid cancer
    • Pancreatic cancer
    • Brain tumors
    • Sarcomas

Entrectinib is particularly effective in treating cancers that have spread to the brain (brain metastases) because it can cross the blood-brain barrier, a protective layer that prevents many drugs from reaching the brain[1][2].

Clinical Trials and Research

Several clinical trials have been conducted or are ongoing to evaluate the effectiveness and safety of entrectinib:

  • STARTRK-2 Study: This global Phase 2 trial investigated entrectinib in patients with solid tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions[1].
  • STARTRK-NG Study: This Phase 1/2 trial evaluated entrectinib in children and adolescents with recurrent or refractory solid tumors and primary CNS tumors[3].
  • ALKA-372-001 and STARTRK-1 Studies: These Phase 1 trials assessed the safety and efficacy of entrectinib in adult patients with locally advanced or metastatic solid tumors[2].

These trials have shown promising results, particularly in patients with ROS1-positive NSCLC and NTRK fusion-positive solid tumors[1][2][3].

How is Entrectinib Administered?

Entrectinib is taken orally in the form of capsules. The typical dosage for adults is 600 mg (three 200 mg capsules) once daily. For children and adolescents, the dosage is based on body surface area. The medication can be taken with or without food[1][3].

Potential Side Effects

Like all medications, entrectinib can cause side effects. Common side effects may include:

  • Fatigue
  • Constipation
  • Altered sense of taste
  • Swelling (edema)
  • Dizziness
  • Diarrhea
  • Nausea
  • Shortness of breath
  • Muscle pain
  • Cognitive changes

It’s important to report any side effects to your healthcare provider. They can help manage these effects and may adjust your dosage if necessary[1][2].

Special Considerations

There are some special considerations to keep in mind when taking entrectinib:

  • Genetic Testing: Before starting entrectinib, patients typically undergo genetic testing to confirm the presence of NTRK, ROS1, or ALK gene fusions in their tumors[1].
  • Liver Function: Entrectinib is processed by the liver, so patients with liver problems may need dose adjustments[4].
  • Pregnancy and Breastfeeding: The effects of entrectinib on unborn babies and breastfed infants are not well known. Patients who are pregnant, planning to become pregnant, or breastfeeding should discuss this with their doctor[1].
  • Drug Interactions: Entrectinib may interact with other medications. It’s important to inform your healthcare provider about all medications, supplements, and herbal products you are taking[1].
Aspect Details
Drug Name Entrectinib (also known as RXDX-101)
Mechanism of Action Inhibitor of tyrosine kinases TrkA, TrkB, TrkC, ROS1, and ALK
Target Patient Population Patients with solid tumors harboring NTRK1/2/3, ROS1, or ALK gene rearrangements
Key Cancer Types Studied NSCLC, colorectal cancer, brain tumors, and various other solid tumors
Administration Oral (capsules or tablets), typically daily dosing
Primary Outcomes Measured Objective response rate, progression-free survival, safety and tolerability
Secondary Outcomes Duration of response, overall survival, CNS efficacy in patients with brain metastases
Special Considerations Efficacy in patients with CNS metastases, comparison with other targeted therapies (e.g., crizotinib)
Patient Age Groups Studies include adult, pediatric, and adolescent patients
Quality of Life Assessments Included in some trials using standardized questionnaires

FAQ

  • What is entrectinib and how does it work? Entrectinib is an oral medication that works as an inhibitor of the tyrosine kinases TrkA, TrkB, TrkC, ROS1, and ALK. It targets specific genetic alterations found in some cancers, potentially stopping or slowing down cancer growth.
  • What types of cancers are being studied with entrectinib? Entrectinib is being studied in various solid tumors, including non-small cell lung cancer (NSCLC), colorectal cancer, breast cancer, melanoma, and brain tumors. It's particularly focused on cancers with NTRK1/2/3, ROS1, or ALK gene rearrangements.
  • How is entrectinib administered in clinical trials? Entrectinib is typically given orally, either as capsules or tablets. The dosage may vary depending on the specific trial and patient characteristics, but it's often administered daily.
  • What are some potential side effects of entrectinib? While side effects can vary, some potential adverse events being monitored in trials include fatigue, nausea, dizziness, and changes in taste. The trials are carefully assessing the safety profile of entrectinib.
  • How long do patients typically stay on entrectinib treatment in clinical trials? In many trials, patients continue treatment with entrectinib until disease progression, unacceptable toxicity, or withdrawal from the study. The duration can vary widely depending on individual patient response and tolerance.

Ongoing Clinical Trials on Entrectinib

  • Study on the Effectiveness of Tepotinib and Drug Combination for Patients with Advanced Cancer

    Recruiting

    1 1 1
    Investigated drugs:
    Norway

  • Study of Drug Combination for Advanced Cancer Patients with Known Molecular Profile – FINPROVE Study

    Recruiting

    1 1 1
    Investigated drugs:
    Finland

  • Study on the Effectiveness of Entrectinib and Other Drug Combinations for Patients with Advanced Solid Tumors, Multiple Myeloma, or Non-Hodgkin Lymphoma

    Recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    The Netherlands

  • Study of Entrectinib for Patients with Advanced or Metastatic Solid Tumors with Specific Gene Changes

    Recruiting

    1 1 1
    Investigated drugs:
    France Germany Italy The Netherlands Poland Spain

  • Continued Cancer Treatment Study with Abiraterone, Ipatasertib, Tiragolumab, and Drug Combination for Patients from Previous Genentech/Roche Trials

    Recruiting

    1 1 1 1
    Investigated diseases:
    Investigated drugs:
    Belgium France Greece Poland

  • Study Comparing Entrectinib and Crizotinib for Patients with Advanced Non-Small Cell Lung Cancer with ROS1 Gene Changes, With or Without Brain Metastases

    Not recruiting

    1 1 1 1
    Investigated diseases:
    Investigated drugs:
    Croatia France Germany Greece Italy The Netherlands +4

  • Study of Entrectinib in Children and Adolescents with Advanced or Metastatic Solid Tumors or Primary CNS Tumors with No Satisfactory Treatment Options

    Not recruiting

    1 1
    Investigated drugs:
    France Germany Italy Spain

  • Study on the Effectiveness of Inavolisib, Atezolizumab, and Entrectinib in Patients with Advanced or Metastatic Solid Tumors

    Not recruiting

    1 1 1
    Investigated drugs:
    Belgium Denmark France Germany Italy Poland +2

Glossary

  • NTRK1/2/3: Genes that code for tropomyosin receptor kinases (TRK) involved in cell signaling. Alterations in these genes can lead to cancer growth.
  • ROS1: A gene that, when altered, can drive cancer growth. ROS1 gene rearrangements are found in some lung cancers and other tumor types.
  • ALK: Anaplastic Lymphoma Kinase, a gene that can become altered in some cancers, leading to uncontrolled cell growth.
  • NSCLC: Non-Small Cell Lung Cancer, a type of lung cancer that is the most common form of the disease.
  • Tyrosine kinase inhibitor: A type of targeted therapy that blocks specific enzymes called tyrosine kinases, which are involved in cancer cell growth and survival.
  • Gene fusion: An abnormal joining of two otherwise separate genes, which can lead to cancer development in some cases.
  • Progression-free survival (PFS): The length of time during and after treatment that a patient lives without the cancer progressing or getting worse.
  • Overall response rate (ORR): The proportion of patients whose cancer shrinks or disappears after treatment.
  • Duration of response (DOR): The length of time that a tumor continues to respond to treatment without growing or spreading.
  • Central Nervous System (CNS) metastases: Cancer that has spread from its original location to the brain or spinal cord.

References

  1. https://clinicaltrials.eu/trial/study-of-entrectinib-for-patients-with-advanced-or-metastatic-solid-tumors-with-specific-gene-changes/
  2. https://clinicaltrials.gov/study/NCT02097810
  3. https://clinicaltrials.gov/study/NCT02650401
  4. https://clinicaltrials.gov/study/NCT04226833