Crizotinib in ROS1-Positive Metastatic Non–Small Cell Lung Cancer

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On March 11, 2016, crizotinib (Xalkori) was approved for treatment of patients with metastatic non–small cell lung cancer (NSCLC) with ROS1 rearrangement–positive tumors.1,2 A U.S. Food and Drug Administration–approved test for the detection of ROS1 rearrangements in NSCLC is not currently available.

Supporting Efficacy Data

The current approval was based on observation of durable responses in a multicenter, single-arm phase I trial expansion cohort in which 50 patients received oral crizotinib at 250 mg orally twice daily.2,3 Patients had a median age of 53 years (range = 25–77 years), 56% were female, 98% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 54% were white and 42% were Asian, 22% were past and 78% were never smokers, 92% had metastatic disease, 96% had adenocarcinoma, 14% had no prior systemic therapy for metastatic disease, and 80% had prior platinum-based chemotherapy for metastatic disease. Tumors were determined to be ROS1-positive by fluorescence in situ hybridization in 96% of cases and by reverse transcription polymerase chain reaction in 4%. The median duration of exposure to crizotinib was 34.4 months.

The response rate on independent review was 66% (95% confidence interval [CI] = 51%–79%), with a median duration of response of 18.3 months (95% CI = 12.7 months to not reached). The investigator-assessed response rate was 72% (95% CI = 58%–84%), with a median duration of response not reached (95% CI = 14.5 months to not reached).

Targeting ROS1 Rearrangements in Lung Cancer

  • Crizotinib (Xalkori) was approved for treatment of patients with metastatic non–small cell lung cancer with ROS1 rearrangement–positive tumors.
  • The recommended dose of crizotinib is 250 mg twice daily until disease progression or intolerance.

How It Works

Crizotinib inhibits multiple receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-Met), ROS1 (c-ros), and recepteur d’origine nantais (RON). Translocations that affect the ALK gene can result in expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of gene expression and signaling, contributing to increased cell proliferation and survival in tumors expressing the proteins. Crizotinib exhibits concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in tumor cell lines and antitumor activity in xenografts expressing EML4-or NPM-ALK fusion proteins or c-Met.

How It Is Given

The recommended dose of crizotinib is 250 mg twice daily until disease progression or intolerance. In patients with severe renal impairment not requiring dialysis, the recommended dose is 250 mg once daily. Dose reductions due to grade 3 or 4 toxicities are, sequentially, to 200 mg twice daily and 250 mg once daily, with treatment discontinuation thereafter.

For hematologic toxicity, treatment should be interrupted until recovery to grade ≤ 2 and resumed at the same dose in patients with grade 3 toxicity and resumed at the next lower dose in those with grade 4 toxicity. Complete blood cell counts should be monitored monthly and as clinically indicated, with more frequent testing in patients with grade 3 or 4 toxicities or who develop fever or infection.

For nonhematologic toxicity, the following modifications are recommended. For alanine transaminase (ALT) or aspartate transaminase (AST) elevation more than 5 times the upper limit of normal (ULN) with total bilirubin ≤ 1.5 times ULN, treatment should be withheld until recovery to baseline or ≤ 3 times ULN and then resumed at a reduced dose. For QTc > 500 ms on at least two separate electrocardiograms, treatment should be withheld until recovery to baseline or a QTc < 481 ms and resumed at a reduced dose.

For symptomatic bradycardia, treatment should be withheld until recovery to asymptomatic bradycardia or a heart rate of ≥ 60 beats per minute. Upon recovery, treatment can be resumed at the same dose if a contributing concomitant medication has been discontinued or appropriately dose adjusted or at a lower dose if there is no contributing medication. For life-threatening bradycardia, treatment should be permanently discontinued if no contributing concomitant medication is identified; in cases in which such medication is identified and discontinued or dose adjusted, crizotinib can be resumed at 250 mg once daily.

Treatment should be permanently discontinued for ALT or AST elevation > 3 times ULN with concurrent total bilirubin elevation > 1.5 times ULN (in the absence of cholestasis or hemolysis), any-grade drug-related interstitial lung disease/pneumonitis, or a QTc > 500 ms or ≥ 60 ms change from baseline with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. For visual loss (grade 4 ocular disorder), treatment should be discontinued during evaluation of vision loss.

Coadministration with strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole) should be avoided, as should grapefruit or grapefruit juice. Caution should be used with concomitant use of moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort) should be avoided.

Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Safety Profile

The safety results of the study supporting the current approval were generally consistent with those of crizotinib in patients with ALK-positive metastatic NSCLC. The most common adverse events associated with crizotinib overall (any grade in > 25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. Vision disorders occurred in 92% of patients in the study supporting the current approval, with 90% being grade 1 and 2% being grade 2.

Crizotinib carries warnings/precautions for hepatotoxicity (fatal in 0.1% of patients), interstitial lung disease/pneumonitis (observed in 2.9% of patients), QT prolongation (observed in 2.1%), bradycardia, severe visual loss (observed in 0.2%), and embryofetal toxicity. Patients should receive periodic liver function testing. Electrocardiography and electrolyte monitoring should be performed in patients with a history of or predisposition to QTc prolongation or who are taking medications that prolong QTc. Heart rate and blood pressure should be monitored regularly. Patients should undergo ophthalmologic evaluation. ■


1. U.S. Food and Drug Administration: Crizotinib (Xalkori) capsules. Available at Accessed March 22, 2016.

2. Xalkori (crizotinib) capsules prescribing information. Pfizer Inc, March 2016. Available at Accessed March 22, 2016.

3. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-1971, 2014.