FDA expands use of Xalkori (crizotinib) to treat rare form of advanced non-small cell lung cancer.

March 11, 2016


The U.S. Food and Drug Administration approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration.

Xalkori is the first and only FDA approved treatment for patients with ROS-1 positive NSCLC.

ROS-1 gene alterations are present in approximately 1 percent of patients with NSCLC.

The overall patient and disease characteristics of NSCLC with ROS-1 gene alterations appear similar to NSCLC with anaplastic lymphoma kinase (ALK) gene alterations, for which crizotinib use was previously approved.

Earlier, U.S. Food and Drug Administration on 26 Aug 2011 had approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.


  • XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor.
  • The molecular formula for crizotinib is C21H22Cl2FN5O.
  • The molecular weight is 450.34 Daltons. Crizotinib is described chemically as (R)-3-[1-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.



Mechanism of Action

  • Crizotinib is an inhibitor of receptor tyrosine kinases including ALK,Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON).


Carrizosa DR, Mileham KF, Haggstrom DE. New targets and new mechanisms in lung cancer. Oncology (Williston Park, NY). 2013 May;27(5):396-404.
  • Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins.
  • Crizotinib demonstrated concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
  • Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.
  • Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.
  • In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient. Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro.(1)
  • Xalkori is an oral medication that blocks the activity of the ROS-1 protein in tumors that have ROS-1 gene alterations.
  • This effect on ROS-1 may prevent NSCLC from growing and spreading.


Treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration.


  • 250 mg taken orally twice daily with or without food.
  • Dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required based on individual safety and tolerability, then to 250 mg taken orally once daily if further reduction is necessary.


  • Pneumonitis: Severe, including fatal, treatment-related pneumonitis has been observed. Monitor patients for pulmonary symptoms indicative of pneumonitis. Permanently discontinue in patients diagnosed with treatment-related pneumonitis.
  • Hepatic Laboratory Abnormalities: Concurrent elevations in ALT and total bilirubin have occurred. Monitor monthly and as clinically indicated with more frequent testing in patients with Grade 2-4 elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated.
  • QT Interval Prolongation: In patients who have a history of or predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered.
  • ALK Testing: Detection of ALK-positive NSCLC using an FDAapproved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.
  •  Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman.

Safety and Efficacy

  • The safety and efficacy of Xalkori for the treatment of patients with ROS-1 positive tumors were evaluated in a multi-center, single-arm study of 50 patients with ROS-1 positive metastatic NSCLC. Patients received Xalkori twice daily to measure the drug’s effect on their lung cancer tumors.
  • The studies were designed to measure overall response rate, the percentage of patients who experienced complete or partial shrinkage of their tumors.
  • Results showed 66 percent of participants experienced a complete or partial shrinkage of their NSCLC tumors, an effect that lasted a median of 18.3 months.
  • The safety results of this study were generally consistent with the safety profile of Xalkori evaluated in 1,669 patients with ALK-positive metastatic NSCLC.


  • The most common side effects of Xalkori are vision disorders, nausea, diarrhea, vomiting, swelling (edema), constipation, liver problems (elevated transaminases), fatigue, decreased appetite, upper respiratory infection, and dizziness and numbness or tingling in the hands or feet (neuropathy).
  • Xalkori may cause serious side effects, including liver problems, life-threatening or fatal inflammation of the lungs, abnormal heartbeats and partial or complete loss of vision in one or both eyes.


  • CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors.
  •  CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers.
  •  CYP3A Substrates: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices.

The FDA granted the Xalkori expanded use application breakthrough therapy designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

Xalkori also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Xalkori is marketed by Pfizer, based in New York, New York.


1. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y (Mar 2012). “RET, ROS1 and ALK fusions in lung cancer”. Nature Medicine 18 (3): 378–81.


3. Prescribing Information