Entrectinib (Rozlytrek): Understanding Its Mechanism, Dosing, Clinical Uses, and Role in ROS1-Positive NSCLC and NTRK Fusion-Positive Tumors

Entrectinib (Rozlytrek) is an oral, CNS-active tyrosine kinase inhibitor targeting ROS1 and the tropomyosin receptor kinases TRKA, TRKB, and TRKC, encoded by NTRK1, NTRK2, and NTRK3. It was designed to achieve meaningful systemic and intracranial activity, making it particularly relevant in cancers driven by ROS1 or NTRK gene fusions.

Entrectinib is FDA approved for adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC)and for adult and pediatric patients older than 1 month with qualifying NTRK gene fusion-positive solid tumors. The NTRK indication is tumor-agnostic and remains under accelerated approval based on response rate and durability of response.

Key Facts

• Generic name: Entrectinib
• Brand name: Rozlytrek
• Drug class: Multitargeted tyrosine kinase inhibitor
• Primary targets: ROS1, TRKA, TRKB, TRKC
• Route: Oral
• Initial US approval: 2019
• Adult dose: 600 mg orally once daily
• Administration: With or without food
• Dose reductions in adults: 600 mg → 400 mg → 200 mg once daily
• Capsule strengths: 100 mg and 200 mg
• Oral pellets: 50 mg per packet
• FDA indications: ROS1-positive metastatic NSCLC; qualifying NTRK fusion-positive solid tumors
• Major safety concerns: Congestive heart failure, CNS effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and visual disorders
• Major metabolism: CYP3A4
• Active metabolite: M5
• Current US status: FDA approved

What Is Entrectinib?

Entrectinib is a small-molecule inhibitor of oncogenic kinases produced by rearrangements involving:

• ROS1
• NTRK1
• NTRK2
• NTRK3

NTRK rearrangements result in abnormal fusion proteins involving:

• TRKA
• TRKB
• TRKC

These fusion proteins become constitutively active and continuously stimulate pathways responsible for:

• Cell proliferation
• Survival
• Differentiation
• Migration
• Tumor growth

Similarly, ROS1 fusion proteins function as constitutively activated tyrosine kinases and act as oncogenic drivers in a subset of NSCLC.

Entrectinib was specifically developed with the ability to penetrate the central nervous system, which is clinically important because brain metastases are frequent in oncogene-driven NSCLC.

What Is the Mechanism of Action of Entrectinib?

1. ROS1 or NTRK Fusions Create Constitutively Active Kinases

Genomic rearrangements can create abnormal fusion proteins involving:

ROS1

or:

TRKA / TRKB / TRKC.

These fusion proteins signal continuously without normal ligand regulation.

2. Entrectinib Binds the Kinase Domain

Entrectinib is an:

ATP-competitive tyrosine kinase inhibitor.

It binds to the ATP-binding site of:

• ROS1
• TRKA
• TRKB
• TRKC

and inhibits kinase activity.

3. Autophosphorylation Is Reduced

By blocking ATP-dependent kinase activity, entrectinib reduces phosphorylation of the oncogenic fusion proteins.

4. Downstream Signaling Is Suppressed

Key signaling pathways affected include:

RAS–RAF–MEK–ERK

PI3K–AKT–mTOR

and:

JAK–STAT.

5. Tumor Growth Is Inhibited

The result is:

• Reduced tumor-cell proliferation
• Reduced survival signaling
• Increased apoptosis
• Reduced migration and invasion
• Tumor regression in fusion-driven cancers

The mechanism can be summarized as:

Entrectinib → inhibition of ROS1/TRK fusion kinase activity → reduced phosphorylation → suppression of MAPK, PI3K/AKT, and JAK/STAT signaling → decreased tumor-cell proliferation and survival.

What Is the Dose of Entrectinib?

Adults

The recommended dose for adult patients with:

• ROS1-positive metastatic NSCLC
• NTRK fusion-positive solid tumors

is:

600 mg orally once daily.

Entrectinib may be taken:

With or without food.

Treatment is continued until:

Disease progression
Unacceptable toxicity.

Pediatric Dose for NTRK Fusion-Positive Tumors

For pediatric patients:

Older than 1 month to ≤6 months
250 mg/m² once daily.

Older than 6 months
Dose is based on body surface area:

• BSA ≤0.50 m²: 300 mg/m² once daily
• BSA 0.51–0.80 m²: 200 mg once daily
• BSA 0.81–1.10 m²: 300 mg once daily
• BSA 1.11–1.50 m²: 400 mg once daily
• BSA ≥1.51 m²: 600 mg once daily.

What If a Dose Is Missed?

If a dose is missed:

Take it when remembered unless the next dose is due within 12 hours.

If the next dose is due within 12 hours:

Skip the missed dose.

If vomiting occurs immediately after taking entrectinib:

Repeat the dose.

How Are Entrectinib Dose Reductions Made?

For adults starting at:

600 mg once daily

the first dose reduction is:

400 mg once daily.

The second reduction is:

200 mg once daily.

If the patient cannot tolerate treatment after two dose reductions:

Permanently discontinue entrectinib.

For pediatric patients, dose reductions depend on the starting dose and may involve reducing to:

• Two-thirds of the starting dose
• One-third of the starting dose

depending on age, BSA, and formulation.

How Is Entrectinib Administered?

Entrectinib is available as:

• 100 mg capsules
• 200 mg capsules
• 50 mg oral pellet packets

It can be administered as:

• Whole capsules
• Capsules prepared as an oral suspension
• Oral pellets sprinkled onto soft food

Capsules prepared as suspension can also be administered through an:

Enteral feeding tube.

However:

Oral pellets should not be administered through an enteral tube, because they may clog the tube.

Entrectinib is taken:

Once daily, with or without food.

What Are the Important Drug Interactions With Entrectinib?

Strong and Moderate CYP3A Inhibitors

Entrectinib is primarily metabolized through:

CYP3A4.

Strong or moderate CYP3A inhibitors can increase entrectinib exposure.

For adults and pediatric patients aged ≥2 years:

Dose modification is required if concomitant use cannot be avoided.

For pediatric patients younger than 2 years:

Avoid concomitant administration. 

Examples include:

• Clarithromycin
• Ketoconazole
• Itraconazole
• Certain protease inhibitors

CYP3A Inducers

Moderate or strong CYP3A inducers can substantially reduce entrectinib exposure.

These should be:

Avoided.

Examples include:

• Rifampin
• Carbamazepine
• Phenytoin
• St. John’s wort

QT-Prolonging Drugs

Because entrectinib can prolong the QT interval:

Avoid concomitant use with other QT-prolonging medications when possible. 

Does Entrectinib Require Renal or Hepatic Dose Adjustment?

Renal Impairment

No clinically meaningful effect on entrectinib pharmacokinetics has been demonstrated in:

Mild or moderate renal impairment.

Data remain limited in patients with:

Severe renal impairment.

Hepatic Impairment

No standard dose adjustment is generally required for mild hepatic impairment.

Clinical data in moderate-to-severe hepatic dysfunction are more limited, and treatment should be used cautiously with appropriate monitoring.

What Is the Pharmacokinetic Profile of Entrectinib?

Absorption

Median time to maximum plasma concentration is approximately:

4–6 hours.

Steady State

Steady-state exposure is generally achieved within:

• Approximately 1 week for entrectinib
• Approximately 2 weeks for its active metabolite M5

Protein Binding

Entrectinib and M5 are:

>99% protein bound.

Distribution

The apparent volume of distribution is approximately:

• 551 L for entrectinib
• 81.1 L for M5

indicating extensive tissue distribution.

Metabolism

Entrectinib is predominantly metabolized by:

CYP3A4.

Its major active metabolite is:

M5.

M5 exposure is approximately:

40% of parent-drug exposure.

Half-Life

Approximate terminal half-lives are:

• Entrectinib: 20 hours
• M5: 40 hours

Elimination

Approximately:

• 83% is recovered in feces
• 3% in urine

indicating predominantly hepatobiliary/fecal elimination.

What Are the Clinical Uses of Entrectinib?

ROS1-Positive Metastatic NSCLC

Entrectinib is FDA approved for:

Adult patients with ROS1-positive metastatic NSCLC detected by an FDA-approved test. 

Its strong CNS penetration makes it especially relevant when:

• Brain metastases are present
• CNS control is an important therapeutic priority

NTRK Fusion-Positive Solid Tumors

Entrectinib is also approved for:

Adult and pediatric patients older than 1 month with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgery would likely result in severe morbidity, and have progressed after treatment or have no satisfactory alternative therapy. 

This is a:

Tumor-agnostic indication.

That means treatment is selected based on the molecular alteration rather than the organ of origin.

What Did Entrectinib Clinical Trials Show?

Entrectinib was evaluated across several early-phase trials, particularly:

• ALKA-372-001
• STARTRK-1
• STARTRK-2

Data from these studies were pooled to evaluate activity in ROS1-positive NSCLC and NTRK fusion-positive tumors.

ROS1-Positive NSCLC — Initial Integrated Analysis

In the initial pooled analysis, the efficacy-evaluable population included:

53 patients

with ROS1 fusion-positive NSCLC.

Objective response occurred in approximately:

77%

of patients in the original integrated analysis.

These data helped establish entrectinib as a highly active ROS1-directed therapy.

Updated ROS1 Integrated Analysis

A later integrated analysis included:

161 patients

with locally advanced or metastatic ROS1 fusion-positive NSCLC.

Objective Response Rate

ORR was:

67.1%.

Median Duration of Response

Median DoR was:

15.7 months.

Median Progression-Free Survival

Median PFS was:

15.7 months.

12-Month Overall Survival

The 12-month OS rate was:

81%.

What About Brain Metastases?

Entrectinib was specifically designed to penetrate the CNS.

Among:

24 patients with measurable baseline CNS metastases

in the updated ROS1 analysis:

Intracranial ORR
79.2%.

Median Intracranial PFS
12.0 months.

Median Intracranial Duration of Response
12.9 months.

These findings demonstrate substantial intracranial activity.

A later long-term analysis also reported an intracranial ORR of approximately:

80%

in patients with measurable baseline CNS metastases.

NTRK Fusion-Positive Solid Tumors — Initial Integrated Analysis

The initial efficacy population included:

54 adults

with advanced or metastatic NTRK fusion-positive tumors spanning:

• 10 tumor types
• 19 histologies

Objective response occurred in:

57%

of patients.

Responses included:

• Complete response: 7%
• Partial response: 50%

Median duration of response was approximately:

10 months.

Updated NTRK Integrated Analysis

An expanded analysis included:

121 adults

with NTRK fusion-positive solid tumors across:

• 14 tumor types
• More than 30 histologies

The confirmed response rate was:

61.2%.

Median duration of response was:

20.0 months.

Median PFS was:

13.8 months.

Among patients with measurable CNS disease:

Intracranial ORR was 63.6%.

Pediatric NTRK Fusion-Positive Tumors

Entrectinib also demonstrated substantial activity in pediatric patients with NTRK fusion-positive tumors.

Updated pediatric analyses reported an ORR of approximately:

72.7%

with durable responses and meaningful activity across several pediatric tumor types.

The expansion of FDA approval to patients:

Older than 1 month

reflects these pediatric efficacy and pharmacokinetic data.

Is Entrectinib FDA Approved?

Yes.

Entrectinib received FDA approval on:

August 15, 2019.

It was approved for:

• ROS1-positive metastatic NSCLC
• NTRK fusion-positive solid tumors

The NTRK indication was subsequently expanded in:

October 2023

to include pediatric patients:

Older than 1 month.

The NTRK tumor-agnostic indication remains under:

Accelerated approval.

What Is the Current Clinical Role of Entrectinib?

ROS1-Positive NSCLC

Entrectinib remains an important targeted treatment for:

ROS1-positive metastatic NSCLC.

Its key advantage is:

CNS activity.

This makes it especially valuable in patients with:

• Baseline brain metastases
• High risk of CNS progression
• Need for systemic and intracranial disease control

The ROS1 treatment landscape has evolved with newer agents, so selection now depends on:

• CNS disease
• Previous ROS1 therapy
• Resistance profile
• Toxicity
• Drug availability

Read more about the evolving role of targeted therapy in molecularly defined lung cancer in OncoDaily’s Targeted Therapy in Advanced NSCLC: From Driver Matching to Adaptive Precision Oncology.

Watch more: Explore OncoDaily’s discussion on targeted therapies in lung cancer and the evolving treatment landscape for oncogene-driven NSCLC.

NTRK Fusion-Positive Tumors

Entrectinib remains a major tumor-agnostic targeted therapy for:

NTRK fusion-positive cancers.

Treatment depends on identification of a genuine:

NTRK1, NTRK2, or NTRK3 fusion

rather than isolated TRK expression.

What Are the Major Side Effects of Entrectinib?

Common adverse effects include:

• Fatigue
• Constipation
• Dysgeusia
• Edema
• Dizziness
• Diarrhea
• Nausea
• Dysesthesia
• Dyspnea
• Myalgia
• Cognitive impairment
• Weight gain
• Cough
• Vomiting
• Pyrexia
• Arthralgia
• Visual disorders.

Congestive Heart Failure

Entrectinib can cause:

Congestive heart failure.

Before treatment:

Assess left ventricular ejection fraction.

Patients should be monitored for:

• Dyspnea
• Edema
• Rapid weight gain
• Exercise intolerance

For new or worsening CHF:

• Withhold entrectinib
• Reassess LVEF
• Treat appropriately
• Resume at reduced dose or permanently discontinue depending on severity.

Central Nervous System Effects

CNS adverse effects may include:

• Cognitive impairment
• Dizziness
• Mood changes
• Sleep disturbances

Dose interruption, reduction, or permanent discontinuation may be required depending on severity.

Skeletal Fractures

Entrectinib increases the risk of:

Skeletal fractures.

Patients with:

• New bone pain
• Reduced mobility
• Trauma-associated pain

should be promptly evaluated.

This is particularly important in:

Pediatric patients. 

Hepatotoxicity

Entrectinib can cause elevations in:

• ALT
• AST

Liver tests should be obtained:

Every 2 weeks during the first month

then:

Monthly thereafter

and as clinically indicated.

Hyperuricemia

Entrectinib can cause:

Hyperuricemia.

Serum uric acid should be assessed:

• Before treatment
• Periodically during treatment

Patients should be monitored for clinical features of:

• Gout
• Renal complications
• Tumor lysis-associated uric acid elevation

Urate-lowering treatment may be required.

QT Interval Prolongation

Entrectinib can prolong:

QTc.

Before therapy:

• Assess QT interval
• Check electrolytes

During treatment:

• Repeat ECG when indicated
• Monitor potassium
• Monitor magnesium
• Monitor calcium
• Avoid concomitant QT-prolonging medications when possible.

Visual Disorders

Visual adverse effects can occur during entrectinib treatment.

Patients may experience:

• Blurred vision
• Photophobia
• Diplopia
• Visual impairment

New visual symptoms should prompt evaluation.

For clinically important visual toxicity:

• Withhold therapy
• Consider ophthalmologic assessment
• Resume at the same or reduced dose after improvement or stabilization.

Embryo-Fetal Toxicity

Entrectinib can cause fetal harm.

Patients of reproductive potential should receive counseling regarding:

• Pregnancy risks
• Effective contraception

Breastfeeding is not recommended during treatment.

What Monitoring Is Required?

Monitoring during entrectinib therapy should include:

• LVEF before treatment
• Signs and symptoms of heart failure
• Neurologic and cognitive symptoms
• Mood changes
• Signs of skeletal fracture
• ALT
• AST
• Bilirubin
• Serum uric acid
• ECG
• QT interval
• Potassium
• Magnesium
• Calcium
• Visual symptoms
• Weight
• Edema
• CYP3A drug interactions
• Concomitant QT-prolonging medications

Liver tests should specifically be checked:

Every 2 weeks during the first month and monthly thereafter.