Crizotinib (Xalkori): Understanding Its Mechanism, Dosing, Clinical Uses, and Role in ALK- and ROS1-Positive Cancers

Crizotinib (Xalkori) is an oral, multitargeted tyrosine kinase inhibitor that inhibits ALK, ROS1, and MET signaling. It was one of the first precision-oncology drugs to transform the treatment of molecularly defined non-small cell lung cancer (NSCLC), initially establishing the clinical value of targeting ALK rearrangements and later becoming the first FDA-approved therapy for ROS1-positive metastatic NSCLC.

Crizotinib is also FDA approved outside lung cancer, including relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma (ALCL) in pediatric patients and young adults and unresectable, recurrent, or refractory ALK-positive inflammatory myofibroblastic tumor (IMT). Although newer-generation ALK inhibitors have largely replaced crizotinib as preferred first-line therapy for ALK-positive metastatic NSCLC, crizotinib remains clinically relevant, particularly in ROS1-positive NSCLC and ALK-driven ALCL and IMT.

Key Facts

• Generic name: Crizotinib
• Brand name: Xalkori
• Drug class: Multitargeted tyrosine kinase inhibitor
• Route: Oral
• Initial US approval: August 26, 2011
• Major targets: ALK, ROS1, MET/HGFR
• Adult NSCLC dose: 250 mg orally twice daily
• Adult IMT dose: 250 mg orally twice daily
• Pediatric/young adult ALCL dose: 280 mg/m² orally twice daily
• Pediatric IMT dose: 280 mg/m² orally twice daily
• Administration: With or without food
• Adult capsule strengths: 200 mg and 250 mg
• Oral pellet strengths: 20 mg, 50 mg, and 150 mg
• Adult dose reductions: 200 mg twice daily → 250 mg once daily
• Major toxicities: Visual disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness, and neuropathy
• Important serious toxicities: Hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, bradycardia, and severe visual loss
• Major interactions: Strong CYP3A inhibitors and inducers
• Half-life: Approximately 42 hours
• Current US status: FDA approved

What Is Crizotinib?

Crizotinib is a small-molecule kinase inhibitor targeting several receptor tyrosine kinases involved in oncogenic signaling.

Its principal clinically relevant targets include:

• ALK
• ROS1
• MET/HGFR

Crizotinib was initially developed as a MET inhibitor, but its activity against ALK became particularly important after the discovery of ALK rearrangements in NSCLC.

ALK fusions, most commonly involving EML4-ALK, generate constitutively active fusion proteins that continuously stimulate signaling pathways involved in malignant-cell proliferation and survival.

Similarly, ROS1 rearrangements create oncogenic fusion proteins that activate downstream signaling independently of normal regulatory control.

By inhibiting these abnormal kinases, crizotinib can suppress oncogenic signaling and induce tumor regression.

What Is the Mechanism of Action of Crizotinib?

1. Oncogenic Kinase Fusions Drive Tumor Growth

ALK and ROS1 rearrangements generate fusion proteins with constitutively active kinase domains.

These activated proteins stimulate intracellular signaling pathways that promote:

• Cell proliferation
• Survival
• Migration
• Invasion
• Resistance to apoptosis

2. Crizotinib Binds the ATP-Binding Site

Crizotinib is an:

ATP-competitive tyrosine kinase inhibitor.

It binds to the kinase domains of:

ALK, ROS1, and MET.

This prevents ATP-dependent phosphorylation and blocks kinase activation.

3. Receptor and Fusion-Protein Phosphorylation Falls

Inhibition of kinase activity suppresses autophosphorylation and signaling from abnormal ALK or ROS1 fusion proteins.

4. Downstream Signaling Is Suppressed

Important pathways affected include:

RAS–RAF–MEK–ERK

PI3K–AKT–mTOR

and:

JAK–STAT.

These pathways normally support cancer-cell proliferation and survival.

5. Tumor-Cell Growth Is Inhibited

Reduced oncogenic signaling leads to:

• Decreased tumor-cell proliferation
• Reduced survival
• Increased apoptosis
• Tumor regression in sensitive cancers

The mechanism can therefore be summarized as:

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

What Is the Dose of Crizotinib?

Adult ALK- or ROS1-Positive Metastatic NSCLC

The recommended dose is:

250 mg orally twice daily.

Treatment continues until:

• Disease progression
• Unacceptable toxicity

Crizotinib may be taken:

With or without food.

Adult ALK-Positive Inflammatory Myofibroblastic Tumor

The recommended adult dose is:

250 mg orally twice daily.

Pediatric and Young Adult ALK-Positive ALCL

The recommended dose is:

280 mg/m² orally twice daily

with the actual dose selected according to body surface area.

Pediatric ALK-Positive IMT

The recommended dose is also:

280 mg/m² orally twice daily

based on body surface area.

What If a Dose Is Missed?

If a dose is missed, it may be taken when remembered unless the next scheduled dose is due within approximately:

6 hours.

If less than 6 hours remain before the next dose:

Skip the missed dose.

Patients should not take two doses at the same time.

If vomiting occurs after taking crizotinib:

Do not take an additional dose.

Continue with the next regularly scheduled dose.

How Are Crizotinib Dose Reductions Made?

For adults with NSCLC or IMT, the standard dose is:

250 mg twice daily.

The first dose reduction is:

200 mg twice daily.

The second dose reduction is:

250 mg once daily.

If the patient cannot tolerate:

250 mg once daily

crizotinib should generally be permanently discontinued.

Dose interruption or reduction may be required for clinically important toxicities including:

• Hepatotoxicity
• Neutropenia
• QT prolongation
• Bradycardia
• Visual toxicity
• Severe gastrointestinal adverse effects
• Other clinically significant treatment-related adverse events

How Is Crizotinib Administered?

Crizotinib can be administered as:

• Capsules
• Oral pellets

Adult capsule strengths include:

200 mg

and:

250 mg.

Oral pellet strengths include:

20 mg

50 mg

and:

150 mg.

Crizotinib can be taken:

With or without food.

Unlike intravenous therapy, it requires:

• No IV access
• No infusion preparation
• No infusion-related premedication

For pediatric ALCL and IMT, dose selection is based on body surface area.

What Are the Important Drug Interactions With Crizotinib?

Strong CYP3A Inhibitors

Crizotinib is primarily metabolized by:

CYP3A.

Strong CYP3A inhibitors can increase crizotinib exposure and increase toxicity.

These should generally be:

Avoided.

If unavoidable, dose reduction may be required.

Strong CYP3A Inducers

Strong CYP3A inducers can substantially lower crizotinib exposure and potentially reduce efficacy.

Concomitant use should generally be:

Avoided.

CYP3A Substrates

Crizotinib can affect exposure to certain CYP3A substrates.

Particular caution is required when even small changes in substrate concentration could lead to serious toxicity.

QT-Prolonging Drugs

Crizotinib can prolong the QT interval.

Concomitant QT-prolonging medications should therefore be used cautiously or avoided when possible.

Drugs That Cause Bradycardia

Crizotinib can reduce heart rate.

Concurrent use of medications that cause bradycardia may increase this effect and requires clinical monitoring.

Does Crizotinib Require Renal or Hepatic Dose Adjustment?

Renal Impairment

No routine dose adjustment is recommended for:

Mild or moderate renal impairment

with creatinine clearance approximately:

30–89 mL/min.

In severe renal impairment:

CrCl <30 mL/min

not requiring dialysis, crizotinib exposure increases substantially.

The recommended adult dose is therefore reduced to:

250 mg once daily.

Following a single 250 mg dose, severe renal impairment increased:

• AUC by approximately 79%
• Cmax by approximately 34%

Hepatic Impairment

No dose adjustment is recommended for:

Mild hepatic impairment.

For moderate hepatic impairment, the adult dose is reduced to:

200 mg twice daily.

For severe hepatic impairment, the adult dose is reduced to:

250 mg once daily.

What Is the Pharmacokinetic Profile of Crizotinib?

Absorption

Crizotinib is orally absorbed after administration.

Peak concentrations are generally reached within several hours.

It may be administered:

With or without food.

Distribution

Crizotinib demonstrates extensive tissue distribution.

Plasma protein binding is high.

Metabolism

Crizotinib is predominantly metabolized by:

CYP3A.

Drug interactions affecting CYP3A activity can therefore meaningfully alter systemic exposure.

Half-Life

The mean apparent terminal plasma half-life is approximately:

42 hours.

Elimination

Elimination occurs mainly through:

Fecal excretion

with a smaller proportion excreted in urine.

What Are the Clinical Uses of Crizotinib?

Crizotinib currently has several FDA-approved oncology indications.

ALK-Positive Metastatic NSCLC

Crizotinib is approved for adults with:

Metastatic NSCLC whose tumors are ALK-positive, detected by an FDA-approved test.

ROS1-Positive Metastatic NSCLC

Crizotinib is also approved for:

Metastatic ROS1-positive NSCLC.

This indication was approved in:

March 2016.

ALK-Positive Anaplastic Large Cell Lymphoma

Crizotinib is approved for:

Pediatric patients aged 1 year and older and young adults with relapsed or refractory systemic ALK-positive ALCL.

ALK-Positive Inflammatory Myofibroblastic Tumor

Crizotinib is approved for:

Adult and pediatric patients aged 1 year and older with unresectable, recurrent, or refractory ALK-positive IMT.

What Did Crizotinib Clinical Trials Show?

PROFILE 1007 — Previously Treated ALK-Positive NSCLC

PROFILE 1007 was a phase III study comparing crizotinib with chemotherapy in patients with advanced ALK-positive NSCLC who had previously received platinum-based chemotherapy.

A total of:

347 patients

were randomized to:

• Crizotinib 250 mg twice daily
• Pemetrexed or docetaxel chemotherapy

Median Progression-Free Survival

Median PFS was:

• Crizotinib: 7.7 months
• Chemotherapy: 3.0 months

Hazard ratio:

0.49

P < 0.001.

Objective Response Rate

ORR was:

• Crizotinib: 65%
• Chemotherapy: 20%

P < 0.001.

These findings established superior disease control with crizotinib compared with conventional chemotherapy.

PROFILE 1014 — First-Line ALK-Positive NSCLC

PROFILE 1014 evaluated crizotinib as first-line treatment for advanced ALK-positive nonsquamous NSCLC.

A total of:

343 patients

were randomized to:

Crizotinib 250 mg twice daily
Pemetrexed plus cisplatin or carboplatin

Median Progression-Free Survival

Median PFS was approximately:

• Crizotinib: 10.9 months
• Chemotherapy: 7.0 months

Hazard ratio:

0.45.

Objective Response Rate

Response rates were approximately:

• Crizotinib: 74%
• Chemotherapy: 45%

Crizotinib also improved lung-cancer symptoms and quality of life compared with chemotherapy.

What About Overall Survival in PROFILE 1014?

At final analysis:

Median OS was:

• Not reached with crizotinib
• 47.5 months with chemotherapy

The unadjusted hazard ratio was:

0.76

with substantial crossover from chemotherapy to crizotinib complicating interpretation.

Approximately:

84%

of chemotherapy-treated patients subsequently received crizotinib.

Four-year survival was approximately:

• 56.6% with crizotinib
• 49.1% with chemotherapy

What About Brain Metastases?

The central nervous system represents an important limitation of crizotinib in ALK-positive NSCLC.

Crizotinib has intracranial activity, but its CNS penetration and durability are inferior to those of newer-generation ALK inhibitors.

In PROFILE 1014:

23%

of patients had treated brain metastases at baseline.

The CNS became a frequent site of disease progression during crizotinib therapy.

This contributed substantially to the development and adoption of newer ALK inhibitors with stronger intracranial activity, including:

• Alectinib
• Brigatinib
• Lorlatinib

Therefore, crizotinib is generally no longer preferred first-line for ALK-positive metastatic NSCLC when these agents are available.

What Did Crizotinib Show in ROS1-Positive NSCLC?

PROFILE 1001

Crizotinib demonstrated substantial activity in patients with ROS1-rearranged advanced NSCLC.

In an updated analysis of:

53 patients

treated with crizotinib 250 mg twice daily:

Objective Response Rate

ORR was:

72%

95% CI:

58%–83%.

Median Duration of Response

Median DoR was:

24.7 months.

Median Progression-Free Survival

Median PFS was:

19.3 months.

These findings established crizotinib as an effective targeted therapy for ROS1-positive metastatic NSCLC.

Is Crizotinib FDA Approved?

Yes.

Crizotinib received its initial accelerated FDA approval on:

August 26, 2011

for ALK-positive advanced NSCLC.

Regular approval followed after randomized evidence confirmed clinical benefit.

Subsequent FDA approvals expanded its use to:

• ROS1-positive metastatic NSCLC
• ALK-positive relapsed/refractory systemic ALCL
• ALK-positive unresectable, recurrent, or refractory IMT

What Is the Current Clinical Role of Crizotinib?

Crizotinib remains FDA approved, but its role differs substantially by molecular subtype.

ALK-Positive NSCLC

In 2026, preferred first-line options for metastatic ALK-positive NSCLC include:

• Alectinib
• Brigatinib
• Lorlatinib

Crizotinib is generally an alternative when preferred newer-generation agents are unavailable or unsuitable.

The reduced first-line role of crizotinib largely reflects the superior:

• Systemic disease control
• CNS penetration
• Intracranial efficacy
• Durability

of later-generation ALK inhibitors.

ROS1-Positive NSCLC

Crizotinib remains an important treatment option for:

ROS1-positive metastatic NSCLC.

The ROS1 treatment landscape now also includes newer CNS-active agents, so drug selection depends on:

• CNS disease
• Previous treatment
• Resistance mechanisms
• Access
• Tolerability

ALCL and IMT

Crizotinib continues to have an important role in:

• Relapsed/refractory systemic ALK-positive ALCL
• Unresectable, recurrent, or refractory ALK-positive IMT

Read more about how targeted treatment is evolving across 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.

What Are the Major Side Effects of Crizotinib?

The most common adverse effects in adults with NSCLC include:

• Visual disorders
• Nausea
• Diarrhea
• Vomiting
• Edema
• Constipation
• Elevated transaminases
• Fatigue
• Decreased appetite
• Dizziness
• Neuropathy

Visual Disorders

Visual disturbances are among the most characteristic adverse effects of crizotinib.

They may include:

• Photopsia
• Blurred vision
• Diplopia
• Floaters
• Reduced visual acuity
• Visual impairment

Most are mild, but severe visual loss has been reported.

Patients developing new or severe visual symptoms require prompt ophthalmologic assessment.

Hepatotoxicity

Crizotinib can cause clinically significant hepatotoxicity.

Monitoring should include:

• ALT
• AST
• Bilirubin

particularly during the first months of therapy.

Severe liver injury and rare fatal hepatic failure have been reported.

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

Interstitial Lung Disease/Pneumonitis

Crizotinib can cause:

Interstitial lung disease or pneumonitis.

Symptoms may include:

• Dyspnea
• Cough
• Fever
• Hypoxia
• New pulmonary infiltrates

Patients with suspected treatment-related ILD should have crizotinib withheld while the diagnosis is evaluated.

Confirmed drug-related ILD may require permanent discontinuation.

QT Interval Prolongation

Crizotinib can prolong the:

QTc interval.

Risk may be increased in patients with:

• Baseline QT prolongation
• Electrolyte abnormalities
• Bradyarrhythmias
• Concomitant QT-prolonging medications

ECG and electrolyte monitoring should be considered in patients at risk.

Bradycardia

Crizotinib can reduce heart rate.

Clinically significant bradycardia may present with:

• Dizziness
• Syncope
• Fatigue
• Hypotension

Other medications that lower heart rate should be reviewed carefully.

Gastrointestinal Toxicity

Common gastrointestinal adverse effects include:

• Nausea
• Vomiting
• Diarrhea
• Constipation

Appropriate:

• Antiemetic therapy
• Hydration
• Nutritional support

may be required.

GI toxicity may be particularly important in pediatric and young adult patients receiving crizotinib for ALCL or IMT.

Embryo-Fetal Toxicity

Crizotinib can cause fetal harm.

Patients of reproductive potential should receive counseling regarding appropriate contraception.

Breastfeeding is not recommended during crizotinib therapy.

What Monitoring Is Required?

Monitoring during crizotinib therapy should include:

• Liver function tests
• ALT
• AST
• Bilirubin
• CBC when clinically appropriate
• ECG in patients at risk for QT prolongation
• Potassium
• Magnesium
• Calcium
• Heart rate
• Blood pressure
• Respiratory symptoms suggesting ILD/pneumonitis
• Visual symptoms
• Gastrointestinal toxicity
• Hydration and nutritional status
• Renal function
• Concomitant CYP3A inhibitors
• Concomitant CYP3A inducers
• QT-prolonging medications
• Drugs that cause bradycardia

Patients receiving crizotinib for pediatric ALCL or IMT may require particularly close monitoring for:

• Gastrointestinal toxicity
• Hematologic abnormalities
• Visual effects
• Growth-related considerations