A kinase inhibitor indicated for treatment of patients with locally advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase (ALK) positive.
Non-small cell tumors of the lung that process a mutation in ROS1 are sensitive to inhibitory effects of this drug, directed at the molecular abnormality ALK rearrangement.
Has activity against ALK, MET, and ROS1
Has a superior progression free survival compared with cytotoxic chemotherapy in the front line treatment of patients with EML4-ALK positive lung adenocarcinoma
Resistance to Crizotinib invariably develops in NSCLC.
Unlike acquired resistance to EGFR inhibitors, where majority of patients develop a gatekeeper mutation T790M, resistance to crizotinib is more complex and mediated by mutations in the ALK kinase domain, ALK fusion gene amplification and up regulation of bypass signaling pathways.
Most responding patients relapse within 12 months.
Drug-induced hepatotoxicity occurs in less than 1% of patients in clinical trials, but drug-induced hepatotoxicity with fatal outcome has been reported.
Liver functions should be monitored monthly and more frequently if liver function test abnormalities are observed.
- tired feeling,
- diarrhea,
- constipation,
- rash or itching,
- cold symptoms
- numbness or tingling, or
- swelling in your hands or feet.
Has poor CNS penetration, and the CNS is the most common site of disease progression in ALK positive patients
Dose 250mg po bid, with adjustment in dosage with hepatic or severe renal insufficiency.
Drug interactions can occur with potent CYP3A inducers oy CYP3A substrates.
Monitoring with CBCs, LFTs, and EKGs recommended.
Ceritinib and alectinib are used for acquired resistance to crizotinib-these drugs demonstrated high response rates of 55-69% in patients with acquired resistance to crizotinib.
The FDA has approved crizotinib for the treatment of pediatric patients 1 year of age and older and young adults with ALK-positive relapsed or refractory, systemic anaplastic large cell lymphoma.
Study ADVL0912 (NCT00939770), showed encouraging antitumor activity with crizotinib in pediatric and adult patients with relapsed/refractory ALCL.
Patients who received crizotinib experienced an Overall response rate of 88%: 39% continued to respond for at least 6 months, while 22% continued to respond for at least 12 months.
Toxicity profile of the agent in children and young adults with ALK-positive ALCL proved to be comparable to its use in those with ALK-positive and ROS1-positive non–small cell lung cancer.
The most frequently reported toxicities included diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough and pruritis.
The most common adverse effect determined to be grade 3 or higher in severity comprised neutropenia, lymphopenia and thrombocytopenia.
Sixty-two percent of such patients experienced grade 4 neutropenia, while 35% reported grade 4 lymphopenia, and 19% experienced grade 4 thrombocytopenia.
Just under half of all study participants, or 46%, experienced visual disorders with crizotinib.
A phase 1/2 trial examined pediatric patients with solid tumors or ALCL who were relapsed/refractory to known curative treatments to evaluate the antitumor activity and safety profile of twice daily crizotinib.
Nine patients with ALK-translocated ALCL were enrolled, of whom 7 had a complete response and 1 had a partial response to therapy.2
ALCL is a form of non-Hodgkin lymphoma accounting for 10% to 15% of all childhood lymphomas, with roughly 90% of pediatric cases containing a chromosomal translocation that may include ALK.
It is effectively treated in the frontline with intensive chemotherapy regimens, such as CHOP, but prognosis is poor if the disease relapses following chemotherapy.