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Crizotinib

Crizotinib, marketed under the brand name Xalkori, is an orally administered small-molecule tyrosine kinase inhibitor that primarily targets anaplastic lymphoma kinase (ALK), ROS1, and hepatocyte growth factor receptor (c-MET).^[1] It is approved for treating metastatic non-small cell lung cancer (NSCLC) in patients with ALK or ROS1 gene rearrangements, as well as relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma (ALCL) in adults and pediatric patients aged 1 year and older, and ALK-positive unresectable inflammatory myofibroblastic tumor (IMT) in adults and pediatric patients aged 1 year and older.^[2]^[3]^[4] Developed by Pfizer, crizotinib received its initial U.S. Food and Drug Administration (FDA) accelerated approval in August 2011 for locally advanced or metastatic ALK-positive NSCLC, based on phase I and II clinical trials demonstrating objective response rates of 50-61%.^[5]^[1] Subsequent approvals expanded its indications, including full approval for ALK-positive NSCLC in 2013, ROS1-positive metastatic NSCLC in 2016, pediatric and young adult ALCL in 2021, and IMT in 2022.^[6]^[7]^[4] In 2023, the FDA approved an oral pellet formulation to improve administration in pediatric patients unable to swallow capsules.^[8] Crizotinib works by competitively binding to the ATP-binding site of ALK, ROS1, and c-MET kinases, thereby inhibiting their phosphorylation and downstream signaling pathways that promote cancer cell proliferation, survival, and metastasis.^[9] In ALK-positive cells, this leads to G1-S cell cycle arrest and apoptosis, with high selectivity demonstrated in preclinical models.^[1] The drug exhibits favorable pharmacokinetics, achieving steady-state plasma concentrations after twice-daily dosing of 250 mg, with a bioavailability of approximately 43% and a half-life of about 42 hours.^[1] Clinical efficacy in NSCLC is highlighted by phase III trials such as PROFILE 1014, where crizotinib extended median progression-free survival to 10.9 months compared to 7.0 months with standard chemotherapy in first-line ALK-positive patients.^[10] In ROS1-positive NSCLC, it achieved a 72% objective response rate in phase II studies.^[7] For ALCL and IMT, approvals were supported by trials showing overall response rates of 81-90% in relapsed/refractory cases.^[3]^[4] However, acquired resistance often develops within 12 months, primarily through secondary ALK mutations like L1196M or amplification of the target gene, prompting the development of next-generation inhibitors.^[1] Common adverse effects include vision disorders (up to 62%), nausea (53%), diarrhea (51%), and edema (28%), while serious risks encompass pneumonitis (1.6%), QT interval prolongation (2.1%), and severe liver enzyme elevations.^[2]^[1] Patients require regular monitoring of vision, cardiac function, and pulmonary status, and the drug is contraindicated with strong CYP3A inhibitors or inducers due to metabolic interactions.^[11] Crizotinib's role as a pioneering targeted therapy underscores advances in precision oncology for fusion-driven malignancies.^[9]

Medical uses

Non-small cell lung cancer

Crizotinib received accelerated approval from the U.S. Food and Drug Administration (FDA) on August 26, 2011, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive and has progressed following platinum-based chemotherapy or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy if applicable.^[12] This approval was based on antitumor activity observed in phase 1 and 2 trials, with full approval granted in 2013 following confirmatory data. The indication was expanded on March 11, 2016, to include ROS1-positive metastatic NSCLC, making crizotinib the first approved therapy for this subtype.^[13] The recommended dosing regimen for crizotinib in NSCLC is 250 mg taken orally twice daily, with or without food, until disease progression or unacceptable toxicity. Patient selection requires confirmation of ALK or ROS1 positivity using FDA-approved companion diagnostic tests, such as the Vysis ALK Break Apart FISH Probe Kit for ALK rearrangements, which was approved concurrently with crizotinib in 2011.^[14] For ROS1, laboratory-developed tests or assays like the VENTANA ROS1 (SP384) RxDx Assay are used to identify eligible patients.^[15] In the phase 1 PROFILE 1001 trial, crizotinib demonstrated an objective response rate (ORR) of 50% (95% CI, 42-58) among 149 patients with previously treated ALK-positive NSCLC, establishing its efficacy in this population.^[12] For ROS1-positive cases in the same trial, the ORR was 72% with a median progression-free survival (PFS) of 19.2 months. The phase 3 PROFILE 1014 trial, evaluating first-line crizotinib versus pemetrexed-plus-platinum chemotherapy in 343 treatment-naive ALK-positive patients, showed a median PFS of 10.9 months with crizotinib compared to 7.0 months with chemotherapy (hazard ratio 0.45; 95% CI, 0.35-0.60; P<0.001).^[10] In contemporary treatment sequences for ALK-positive metastatic NSCLC as of 2025, crizotinib is often reserved for second-line or later use following progression on next-generation ALK inhibitors like alectinib or lorlatinib, which offer superior central nervous system penetration and longer PFS in first-line settings per National Comprehensive Cancer Network (NCCN) guidelines.^[16] For ROS1-positive NSCLC, however, crizotinib remains a preferred first-line option due to its established efficacy and lack of superior alternatives.^[17]

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm characterized by myofibroblastic spindle cell proliferation accompanied by inflammatory cells, most commonly arising in the lungs, abdomen, or soft tissues. These tumors occur across all age groups, with a higher incidence in children and young adults, and exhibit intermediate malignant potential with risks of local recurrence (up to 25%) but low metastatic potential (less than 5%). Approximately 50% of IMT cases harbor ALK gene rearrangements or fusions, which drive oncogenesis and serve as a key therapeutic target for ALK inhibitors like crizotinib.^[18]^[19] Crizotinib received accelerated approval from the U.S. Food and Drug Administration on July 14, 2022, for the treatment of unresectable, recurrent, or refractory ALK-positive IMT in adult and pediatric patients 1 year of age and older. This approval was based on objective response rates (ORR) as the primary efficacy measure from two multicenter, single-arm, open-label trials: ADVL0912 (enrolling 14 pediatric patients aged 2 to less than 18 years) and A8081013 (enrolling 7 adults). In the pediatric cohort, the confirmed ORR was 86% (95% CI: 57-98) per independent radiology review, with 43% complete responses and 43% partial responses; in adults, the ORR was 71% (5 of 7 patients), including 14% complete and 57% partial responses. An earlier phase 1/2 study (NCT00585164) in 12 patients with ALK-positive IMT reported an ORR of 50% (95% CI: 21-79), establishing early evidence of antitumor activity.^[4]^[2] The recommended dosage of crizotinib for adults is 250 mg orally twice daily on an empty stomach (at least 2 hours before or after a meal) until disease progression or unacceptable toxicity. For pediatric patients 1 year and older, the dosage is 280 mg/m² orally twice daily, calculated based on body surface area (BSA); an oral pellet formulation approved by the FDA in August 2023 allows precise dosing for patients unable to swallow capsules, while capsules may require adjustment (e.g., for BSA less than 1.5 m², doses may be approximated to 200 mg twice daily or as per the dosing table); the maximum dose is 250 mg twice daily.^[8]^[2]^[20] Efficacy outcomes, including high ORR and durable responses, were comparable between pediatric (median age 10 years) and adult subgroups across studies, with durations of response exceeding 12 months in over 50% of pediatric responders in ADVL0912. In longer-term analyses from phase 1b studies and expanded access programs involving ALK-positive IMT, the median treatment duration was approximately 25 to 33 months, reflecting sustained clinical benefit in responsive cases.^[2]^[4]^[21]

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is an aggressive subtype of peripheral T-cell non-Hodgkin lymphoma that predominantly affects children and young adults, with approximately 85% of pediatric cases harboring anaplastic lymphoma kinase (ALK) gene fusions driving oncogenesis.^[22] Systemic ALK-positive ALCL often presents with advanced-stage disease, B symptoms, and extranodal involvement, leading to relapse rates of 25-30% despite initial multiagent chemotherapy.^[23] Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, received U.S. Food and Drug Administration (FDA) approval on January 14, 2021, for the treatment of relapsed or refractory systemic ALK-positive ALCL in pediatric patients aged 1 year and older, as well as young adults up to 21 years, following progression after one or more prior lines of therapy.^[3] This approval was supported by data from the ADVL0912 trial (NCT00939770), a multicenter, single-arm, open-label phase 1/2 study evaluating crizotinib in 26 patients aged 1 to 21 years with relapsed or refractory ALK-positive ALCL.^[24] In this cohort, crizotinib administered at doses of 165 mg/m² or 280 mg/m² orally twice daily yielded an objective response rate (ORR) of 88% (95% CI: 71-96), including a complete response (CR) rate of 81%, with responses observed across various prior treatment exposures.^[25] Among responders, 39% maintained their response for at least 6 months and 22% for at least 12 months, highlighting durable disease control in a subset of patients.^[3] The recommended dosage for this indication is 280 mg/m² orally twice daily, calculated based on body surface area (BSA) and administered on an empty stomach to optimize bioavailability, with a maximum of 250 mg per dose for patients whose BSA-based calculation exceeds this threshold; an oral pellet formulation approved by the FDA in August 2023 supports precise dosing for those unable to swallow capsules.^[8]^[25] Dose adjustments are made for toxicities, such as grade 3 or 4 adverse events, or organ impairment. In responders, crizotinib frequently serves as a bridge to consolidative hematopoietic stem cell transplantation, improving long-term outcomes in this high-risk population.^[26] In adults with relapsed or refractory ALK-positive ALCL, crizotinib use remains off-label, as safety and efficacy have not been formally established beyond young adults in regulatory approvals.^[3] However, real-world and prospective data, such as from the French AcSé-crizotinib trial, demonstrate comparable activity with an 8-week response rate of 57% in adult patients (n=14), supporting its consideration in this setting despite lower durability compared to pediatric cases.^[27]

Adverse effects

Common adverse effects

Crizotinib treatment is associated with several common adverse effects occurring in at least 25% of patients, primarily derived from data in the PROFILE clinical trials for non-small cell lung cancer (NSCLC).^[2] These effects are generally manageable and impact quality of life, often leading to dose adjustments in approximately 6-16% of patients.^[2] Vision disorders, reported in 60-71% of patients, include symptoms such as diplopia, blurred vision, and photopsia, which typically onset within the first week of treatment and affect retinal ganglion cells.^[2]^[28] These disturbances can impair daily activities like driving or operating machinery, and patients are advised to undergo baseline and monthly ophthalmologic examinations, with referral to a specialist for severe cases; discontinuation is recommended if significant visual loss occurs.^[2] Gastrointestinal issues are frequent, with nausea affecting 55-56% of patients, diarrhea in 60-61%, vomiting in 46-47%, and constipation in 42-43%.^[2] These symptoms are mostly grade 1 or 2 and can disrupt eating and hydration; management involves prophylactic or as-needed antiemetics, antidiarrheal agents, and dietary modifications, with dose withholding or reduction for grade 3 or 4 severity.^[2]^[29] Peripheral or facial edema occurs in 31-49% of patients and is typically mild and self-limiting, resolving with conservative measures such as elevation and compression if needed.^[2] Fatigue is experienced by 27-29% of patients, contributing to reduced energy levels and daily functioning, and is managed through supportive care and dose adjustments if persistent.^[2] Elevations in transaminases, with ALT increases in 76-79% and AST in 61-66% of patients (grade 3-4 in 8-17%), necessitate regular liver function monitoring every two weeks for the first two months, then monthly, with dose interruption or reduction for significant elevations.^[2] In patients with anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT), the profile is similar overall but gastrointestinal effects occur at higher rates, particularly in pediatric patients (e.g., vomiting in 92% of ALCL cases and 93% in pediatric IMT; diarrhea in 92% of ALCL and 64% in pediatric IMT).^[30] Overall, more than 80% of patients in the PROFILE trials reported at least one common adverse effect, though most were grade 1 or 2 and reversible upon dose modification.^[31]^[2]

Serious adverse effects

Crizotinib is associated with several serious adverse effects that require vigilant monitoring and may necessitate dose adjustments or treatment discontinuation.^[2] These include interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, QT interval prolongation, bradycardia, severe vision disorders, and renal impairment, each with specific incidence rates derived from clinical trials in patients with non-small cell lung cancer (NSCLC).^[2] Management strategies follow Common Terminology Criteria for Adverse Events (CTCAE) grading, with permanent discontinuation recommended for grade 4 toxicities and dose reduction for grade 3 events.^[2] Interstitial lung disease (ILD) or pneumonitis occurs in 2.9% of patients treated with crizotinib, with grade 3 or 4 events in 1.4% and fatal outcomes in 0.4%.^[30] The median onset is 23 days after initiation (range, 3-763 days), often presenting with dyspnea, cough, or fever.^[32] Although not an absolute contraindication, crizotinib should be used cautiously in patients with preexisting lung injury due to heightened risk, and any suspected ILD requires immediate evaluation to exclude infectious causes.^[2] If confirmed as drug-related, treatment must be permanently discontinued, with close pulmonary monitoring advised for all patients, particularly in the first few weeks.^[2] Hepatotoxicity manifests as severe elevations in liver enzymes, with alanine aminotransferase (ALT) exceeding 5 times the upper limit of normal (ULN) in 11% of patients and aspartate aminotransferase (AST) in 6%, alongside fatal hepatic failure in 0.1%.^[2] Monitoring guidelines recommend assessing liver function tests (LFTs), including ALT, AST, and bilirubin, every 2 weeks for the first 2 months of therapy, followed by monthly thereafter and as clinically indicated.^[2] For grade 3 elevations, withhold treatment until recovery to baseline or grade 1, then resume at a reduced dose; grade 4 events warrant permanent discontinuation.^[2] QT interval prolongation affects about 2.1% of patients with QTcF ≥500 ms, while a change from baseline ≥60 ms occurs in 5%, potentially leading to torsades de pointes or sudden death.^[2] Bradycardia, defined as heart rate <50 beats per minute, is reported in 13% overall, with symptomatic or severe cases in 5-7%.^[2] Baseline electrocardiogram (ECG) and electrolyte monitoring (potassium, calcium, magnesium, phosphorus) are essential prior to starting therapy, with follow-up ECGs and heart rate assessments during treatment.^[2] Concomitant use of strong CYP3A inhibitors, which increase crizotinib exposure, should be avoided to mitigate these risks; for grade 3 events, withhold until resolution, then reduce dose, and discontinue for grade 4.^[2] Severe vision disorders, including permanent vision loss, occur in 1-2% of patients, often involving diplopia, blurred vision, or visual field defects that may not fully resolve.^[2] Renal impairment, characterized by elevated serum creatinine or decreased estimated glomerular filtration rate (eGFR), affects 1.4% with grade 3 or 4 severity, with dose reduction required for creatinine clearance <30 mL/min.^[30] Monthly ophthalmologic monitoring is advised, with prompt referral to a specialist for new visual symptoms and discontinuation for grade 4 vision loss; renal function should be assessed periodically, especially in patients with baseline impairment.^[2] In ALCL and IMT patients, rates of serious effects like ILD/pneumonitis (0.8% in pediatric studies), QT prolongation (7-8%), and bradycardia (14-19%) are comparable to NSCLC, but with increased gastrointestinal severity in pediatrics.^[30] Crizotinib poses risks during pregnancy, with animal studies demonstrating embryofetal toxicity and reduced fertility at exposures below human therapeutic levels, necessitating effective contraception and consideration of pregnancy testing prior to initiation.^[2]

Pharmacology

Pharmacodynamics

Crizotinib is an orally available small-molecule tyrosine kinase inhibitor that primarily targets anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1), and MET proto-oncogene receptor tyrosine kinase (MET) by competitively binding to their ATP-binding sites.^[33] As a type I kinase inhibitor, it stabilizes the active conformation of these kinases, preventing ATP binding and subsequent autophosphorylation. In biochemical assays, crizotinib exhibits high potency against these targets, with IC₅₀ values of approximately 0.6 nM for wild-type ALK, 0.11 nM for ROS1, and 4 nM for MET.^[34]^[33] By inhibiting these kinases, crizotinib disrupts fusion-driven oncogenic signaling, such as that mediated by NPM-ALK in anaplastic large cell lymphoma, leading to blockade of downstream pathways including PI3K/AKT, MAPK/ERK, and STAT3.^[33] This inhibition results in reduced cell proliferation, decreased cell survival through induction of apoptosis, and suppression of angiogenesis in tumor models expressing activated ALK, ROS1, or MET.^[33] Though its clinical relevance is primarily tied to ALK, ROS1, and MET inhibition. Resistance to crizotinib can emerge through secondary mutations, such as L1196M in the ALK kinase domain, which alters the ATP-binding pocket and reduces inhibitor affinity.

Pharmacokinetics

Crizotinib is administered orally as capsules and exhibits an absolute bioavailability of approximately 43% (range 32%–66%). Following oral administration of a 250 mg dose, the median time to reach maximum plasma concentration (T_max) is 4 to 6 hours. A high-fat meal decreases the area under the plasma concentration-time curve from zero to infinity (AUC_0-INF) and maximum plasma concentration (C_max) by about 14%, an effect considered not clinically significant; thus, crizotinib may be taken with or without food.^[2] The steady-state volume of distribution of crizotinib is 1773 L following intravenous administration, suggesting extensive tissue distribution. It is highly bound to plasma proteins (91%), independent of concentration, with binding primarily to albumin and alpha-1-acid glycoprotein. Crizotinib demonstrates limited penetration across the blood-brain barrier, achieving cerebrospinal fluid concentrations of approximately 0.3% relative to plasma levels, which contributes to reduced efficacy against central nervous system metastases.^[2]^[35] Crizotinib undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes CYP3A4 and CYP3A5 (accounting for about 85% of clearance), with a minor role played by aldehyde oxidase. The major metabolites include the inactive O-desmethyl and desalkyl forms, formed through O-dealkylation followed by phase II conjugation; another circulating metabolite, crizotinib lactam (formed by oxidation of the piperidine ring), exhibits reduced potency compared to the parent compound.^[2]^[36] Elimination of crizotinib occurs mainly via feces, with 63% of the administered dose recovered unchanged (53%) and the remainder as metabolites; urinary excretion accounts for 22% of the dose, including only 2.3% as unchanged drug. The mean terminal half-life is 42 hours, with apparent oral clearance of 100 L/h after a single dose and 60 L/h at steady state (250 mg twice daily). Crizotinib displays time-dependent pharmacokinetics due to auto-inhibition of CYP3A4, resulting in a 40% reduction in clearance upon repeated dosing.^[2]^[36] In special populations, no dose adjustments are recommended for mild hepatic impairment (Child-Pugh A; AUC decrease of 9%) or mild to moderate renal impairment (creatinine clearance ≥30 mL/min; no significant change). For moderate hepatic impairment (Child-Pugh B; AUC increase of 14%), reduce dose to 200 mg twice daily; for severe hepatic impairment (Child-Pugh C; AUC decrease of 35%), reduce to 250 mg once daily; for severe renal impairment (creatinine clearance <30 mL/min; AUC increase of 79%), reduce to 250 mg once daily. Strong CYP3A4 inhibitors, such as ketoconazole, substantially increase crizotinib exposure (AUC increase of 3.2-fold after single dose, 1.6-fold at steady state), requiring dose reduction to avoid toxicity; conversely, strong inducers decrease exposure by up to 84%. No clinically relevant effects on pharmacokinetics are observed based on age, sex, ethnicity, or body weight in adults.^[2]^[37]

History

Development

Crizotinib, initially designated as PF-02341066, was discovered by researchers at Pfizer in 2005 as part of a program targeting the c-Met (hepatocyte growth factor receptor) tyrosine kinase, utilizing structure-based drug design to optimize inhibitors for this pathway implicated in tumor growth and metastasis.^[38] During subsequent screening, the compound was identified as a potent inhibitor of anaplastic lymphoma kinase (ALK), expanding its potential therapeutic scope to ALK-driven malignancies. In preclinical development, crizotinib exhibited strong antitumor activity in models harboring ALK fusions, including significant tumor regression in ALK-positive Karpas299 anaplastic large cell lymphoma xenografts and H2228 non-small cell lung cancer xenografts, with selective inhibition of ALK phosphorylation at low nanomolar concentrations. The molecule's aminopyridine core structure facilitated key interactions with the ATP-binding sites of both c-Met and ALK kinases. Due to chirality at the benzylic position, the (R)-enantiomer was selected for further development based on its superior potency, selectivity, and pharmacokinetic profile compared to the (S)-enantiomer.^[39] The first-in-human phase I trial (PROFILE 1001) began enrolling patients in late 2007, with dosing initiated in 2008 for individuals with advanced solid tumors refractory to standard therapies, focusing initially on those with c-Met amplification and later expanded to include ALK-positive cases.^[40] Preliminary data from this dose-escalation study, reported in 2009, revealed rapid and durable objective responses in the subset of patients with ALK-rearranged non-small cell lung cancer, with tumor shrinkage observed in over 50% of evaluable cases, prompting an accelerated development pathway toward regulatory submission. In recognition of its potential for rare ALK-driven cancers, the U.S. Food and Drug Administration granted orphan drug designation to crizotinib in September 2010 for the treatment of ALK-positive non-small cell lung cancer.^[41]

Regulatory approvals

Crizotinib received accelerated approval from the U.S. Food and Drug Administration (FDA) on August 26, 2011, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive, as detected by an FDA-approved test.^[6] This approval was based on the drug's demonstration of substantial clinical benefit in addressing an unmet need for this subset of patients.^[42] Subsequent FDA expansions included approval on March 11, 2016, for ROS1-positive metastatic NSCLC.^[13] On January 14, 2021, the FDA approved crizotinib for pediatric patients aged 1 year and older with relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma (ALCL). Accelerated approval was granted on July 14, 2022, for adult and pediatric patients aged 1 year and older with unresectable, recurrent, or refractory ALK-positive inflammatory myofibroblastic tumor (IMT). On August 8, 2023, the FDA approved an oral pellet formulation of crizotinib for use in pediatric patients who cannot swallow capsules, across its approved indications.^[8] The European Medicines Agency (EMA) granted conditional marketing authorization for crizotinib on October 23, 2012, for the treatment of adults with previously treated ALK-positive advanced NSCLC.^[43] This was expanded on August 31, 2016, to include ROS1-positive advanced NSCLC.^[44] In 2024, the EMA extended marketing authorization to include treatment of pediatric patients aged 1 year and older with relapsed or refractory systemic ALK-positive ALCL and unresectable ALK-positive IMT.^[43] Crizotinib was approved in Japan in 2012 for ALK-positive unresectable advanced or recurrent NSCLC by the Pharmaceuticals and Medical Devices Agency.^[45] In China, the National Medical Products Administration approved it in February 2013 for locally advanced or metastatic ALK-positive NSCLC.^[46] By 2015, crizotinib had received regulatory approval in more than 80 countries worldwide, including Canada, South Korea, and Australia.^[47] The FDA prescribing information includes boxed warnings for severe, potentially fatal hepatotoxicity and interstitial lung disease/pneumonitis, with updates to these warnings incorporated in the July 2022 label revision.^[2] Use of crizotinib requires confirmation of ALK or ROS1 positivity via FDA-approved companion diagnostic tests, such as the Vysis ALK Break Apart FISH Probe Kit.^[15]

Society and culture

Legal status

Crizotinib is classified as a prescription-only medicine (Rx) in all major markets worldwide, including the United States, European Union, and other regions, requiring a physician's authorization for dispensing. It is not a controlled substance and is not subject to scheduling under international drug control conventions, such as those administered by the United Nations Office on Drugs and Crime.^[48]^[25] In the United States, crizotinib has received orphan drug designation from the Food and Drug Administration (FDA) for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) since 2010, as well as for inflammatory myofibroblastic tumor (IMT) in 2021 and anaplastic large cell lymphoma (ALCL) in 2012. This status confers seven years of market exclusivity upon approval to encourage development for rare diseases affecting fewer than 200,000 individuals in the US. In the European Union, the European Medicines Agency (EMA) has granted orphan designation for ALK-positive ALCL and IMT in pediatric patients, providing up to 10 years of market exclusivity following authorization to support therapies for conditions with an incidence of less than 5 per 10,000 persons.^[41]^[49]^[50]^[43] As of 2025, the primary composition-of-matter patent for crizotinib in the US (U.S. Patent No. 7,498,341) expired in 2026, though pediatric exclusivity extensions have delayed full generic entry until at least 2027 in some formulations; however, certain method-of-use patents extend protection beyond this date, with overall generic launch projected for November 2029. In contrast, generic versions of crizotinib became available in India in September 2025, improving access in that region through local manufacturing.^[51]^[52]^[53] Access to crizotinib remains limited by its high cost, with the wholesale acquisition cost approximately $11,000 to $13,000 per month in the US as of 2025, equating to about $132,000 to $156,000 annually for typical dosing regimens, which can pose significant barriers for patients without insurance coverage. Pfizer, the manufacturer, provides patient assistance programs such as Pfizer Oncology Together and RxPathways, offering co-pay support, free medication for eligible uninsured or underinsured individuals, and enrollment in Medicare Part D payment plans to mitigate out-of-pocket expenses.^[54]^[55]^[56] Crizotinib has no established recreational use due to its targeted anticancer mechanism and potential for severe adverse effects, and off-label prescribing is strictly regulated, permitted only under licensed medical supervision with informed consent and institutional review where required.^[25]

Brand names and availability

Crizotinib is marketed under the brand name Xalkori by Pfizer and is available in the United States, European Union, and several Asian countries including China, Japan, and South Korea.^[57]^[43]^[2] It is available as oral capsules in 200 mg and 250 mg strengths and as oral pellets (20 mg, 50 mg, 150 mg) for pediatric patients, with no intravenous or other dosage forms approved.^[2]^[58]^[59] Capsules should be stored at controlled room temperature between 20°C to 25°C (68°F to 77°F), with excursions permitted to 15°C to 30°C (59°F to 86°F).^[2]^[60] As of November 2025, no generic versions of crizotinib are available in the US or EU, with key patents protecting the branded product until November 2029 in the US and October 2027 in the EU.^[51]^[61] The drug is widely distributed through standard pharmaceutical supply chains in approved markets, and no significant shortages have been reported since 2020.^[62]

Research

Lung cancer

In research exploring the adjuvant application of crizotinib for early-stage anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), the phase 3 ALCHEMIST E4512 trial (NCT02194738), presented at the 2025 World Conference on Lung Cancer, evaluated crizotinib versus observation following surgical resection. The study, involving patients with resected stage IB-IIIA ALK+ NSCLC, reported no improvement in disease-free survival (DFS), with a hazard ratio (HR) of 1.06 (90% CI 0.63-1.77; p=0.86) and immature overall survival data (HR 0.49; 90% CI 0.18-1.37; p=0.26).^[63] Given these findings, adjuvant crizotinib is not recommended for this setting, as observation outperformed the targeted therapy in preventing recurrence.^[64] Studies on resistance mechanisms following crizotinib treatment in ALK+ NSCLC have identified secondary ALK mutations as a primary driver of progression, occurring in approximately 20-30% of cases.^[65] Notable examples include the G1202R mutation, which confers resistance by altering the ALK kinase domain and is particularly challenging, often necessitating a switch to third-generation inhibitors like lorlatinib for effective management.^[66] These mutations highlight the limitations of first-generation ALK inhibitors and underscore the need for sequential therapy strategies to overcome acquired resistance. For central nervous system (CNS) metastases in ALK+ NSCLC, crizotinib exhibits limited intracranial efficacy, with an objective response rate (ORR) of 18% (95% CI 5-40%) in patients with measurable brain lesions.^[67] Comparative data from the ALEX trial indicate inferiority to next-generation agents like alectinib, which achieved a confirmed intracranial ORR of 59% versus 45% for crizotinib in treatment-naïve patients with measurable CNS metastases at baseline, alongside superior intracranial PFS.^[68] As of 2025, real-world analyses from the FDA Adverse Event Reporting System (FAERS) database, spanning 12 years of pharmacovigilance data, affirm the long-term safety profile of crizotinib in NSCLC, with consistent adverse event patterns including visual disturbances and gastrointestinal effects but no new safety signals emerging over extended use.^[69] Concurrently, its market share in first-line ALK+ NSCLC treatment has declined to approximately 15%, driven by the preferential adoption of more potent next-generation ALK inhibitors like alectinib and lorlatinib, which offer improved efficacy and CNS penetration.^[70]

Lymphomas

Research on crizotinib in lymphomas extends beyond its approved indication for relapsed or refractory pediatric anaplastic large cell lymphoma (ALCL), focusing on other ALK-positive subtypes where the drug targets oncogenic fusions driving disease progression. In non-ALCL lymphomas, such as ALK-positive diffuse large B-cell lymphoma (DLBCL), phase 2 trials have reported an objective response rate (ORR) of 44% among small cohorts of patients.^[71] The extreme rarity of ALK+ DLBCL, representing less than 1% of cases, has constrained larger-scale evaluations and long-term outcome assessments.^[21] For adult ALCL, retrospective analyses indicate an ORR of approximately 70-80% in relapsed settings, with median progression-free survival (PFS) reaching 12 months in select cohorts; these results align closely with efficacy observed in pediatric populations.^[72] Combination strategies integrating crizotinib with frontline chemotherapy have enhanced outcomes in pediatric ALK+ ALCL. The 2023 ANHL12P1 trial demonstrated that adding crizotinib to the ALCL99 regimen improved 3-year event-free survival (EFS) to 84.6% (95% CI 73.3-91.7), compared to historical ~70% with chemotherapy alone, by reducing early relapses and deepening responses.^[73] Key challenges include central nervous system (CNS) relapses, occurring in 10-15% of treated cases due to limited drug penetration across the blood-brain barrier.^[74] Ongoing trials are exploring combinations with CNS-penetrant agents to mitigate this risk and extend durable remissions. As of 2025, expanded access programs have documented durable responses in 50% of refractory lymphoma patients receiving crizotinib, highlighting its role in bridging to transplant or subsequent therapies in real-world settings.^[75]

Other cancers

Crizotinib has shown modest activity in phase 2 trials for ALK-aberrant relapsed or refractory neuroblastoma, particularly in high-risk cases. In the Children's Oncology Group (COG) study ADVL0912, which enrolled 20 patients treated with crizotinib at 280 mg/m² twice daily, the overall response rate (ORR) was 15% (3 partial or complete responses), with improved outcomes in those harboring the ALK R1275Q mutation, where 3 of 12 patients (25%) achieved responses and some experienced prolonged stable disease.^[76] The COG phase 3 trial ANBL1531, initially incorporating crizotinib for frontline therapy in ALK-mutated high-risk neuroblastoma, transitioned to lorlatinib for the ALK-targeted arm but remains recruiting as of November 2025, aiming to enhance event-free survival through targeted integration.^[77] In glioblastoma, a 2022 phase 1b study (GEINO 1402) combining crizotinib with temozolomide and radiotherapy in newly diagnosed patients reported an ORR of 28.6% (95% CI not specified) in 21 evaluable patients, with encouraging efficacy and acceptable safety, warranting prospective validation. No specific subgroup data for MET-driven cases was correlated with outcomes.^[78] Basket trials have explored crizotinib in ROS1 fusion-positive colorectal cancer, a rare alteration occurring in less than 1% of cases. In the NCI-MATCH trial (subprotocol E), crizotinib showed no objective responses (ORR 0%) in the 3 patients with non-NSCLC ROS1-aberrant tumors, highlighting limited activity outside lung cancer, though limited accrual and rarity of fusions restrict widespread applicability.^[79] For pediatric solid tumors beyond approved indications like inflammatory myofibroblastic tumors, the COG phase 1/2 study ADVL0921 (enrolling from 2011 to 2014, with follow-up through 2024) assessed crizotinib in refractory ALK-positive cases, yielding responses in select subtypes including IMT and neuroblastoma, but limited data for sarcomas specifically.^[80] Recent updates as of 2025 include ongoing phase 1/2 evaluations of crizotinib in MET-driven papillary renal cell carcinoma, building on the EORTC 90101 CREATE trial, which reported an ORR of 14% (3/21) and DCR of 71% overall in advanced PRCC with MET mutations/amplification, with median DCR duration of 18.3 months, suggesting utility for disease stabilization.^[81] Overall, approximately 15 active trials investigating crizotinib in various investigational cancer settings are listed on ClinicalTrials.gov as of November 2025, reflecting continued exploration in rare and fusion-driven tumors.

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