On January 14, 2021, crizotinib was approved for treatment of pediatric patients 1 year of age and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive.1,2 The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory systemic ALK-positive ALCL.
Supporting Efficacy Data
Approval was supported by findings in the phase I/II Study ADVL0912 (ClinicalTrials.gov identifier NCT00939770).2 The study included 26 patients aged 1 to 21 years with relapsed or refractory disease after at least one systemic treatment who received oral crizotinib at 280 mg/m2 (n = 20 patients) or 165 mg/m2 (n = 6) twice daily until disease progression or unacceptable toxicity. Patients were permitted to discontinue crizotinib to undergo hematopoietic stem cell transplantation.
Eligible patients were required to have an absolute neutrophil count ≥ 1,000/mm3 (750/mm3 if bone marrow involved), platelet count ≥ 75,000/mm3 (25,000/mm3 if bone marrow involved), creatinine clearance ≥ 70 mL/min/1.73 m2, and QTc ≤ 480 msec. Patients with alanine transaminase > 2.5 times the upper limit of normal (ULN), bilirubin > 1.5 ULN, and central nervous system tumors were excluded from the study.
Crizotinib has warnings/precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, severe visual loss, gastrointestinal toxicity in patients with ALCL, and embryofetal toxicity.
Among all 26 patients, median age was 11 years (range = 3–20 years), with 4 patients aged 3 to < 6, 11 aged 6 to < 12, 7 aged 12 to < 18, and 4 aged 18 to ≤ 21 years. Overall, 69% were male, 54% were White, 19% were Black, and 8% were Asian. All had received multiagent systemic therapy, two (8%) had been undergone prior hematopoietic cell transplant, and four (15%) had receoved at least three prior therapies.
Efficacy was based on objective response rate and duration of response as assessed by an independent review committee. Objective response was observed in 23 patients (88%, 95% confidence interval = 71%–96%), with complete remission in 21 (81%). Among responders, 39% maintained response for at least 6 months and 22% maintained response for at least 12 months.
How It Works
Crizotinib inhibits multiple receptor tyrosine kinases, including ALK, hepatocyte growth factor receptor (c-Met), ROS1, and recepteur d’origine nantais. 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 mice with tumor xenografts expressing echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
In in vitro studies, crizotinib induced apoptosis and inhibited proliferation and ALK-mediated signaling in ALCL-derived cell lines (containing NPM-ALK) at clinically achievable exposures. In vivo data obtained in an ALCL-derived mouse model showed complete regression of tumors at a dose of 100 mg/kg once daily.
How It Is Used
The recommended crizotinib dosage for systemic ALCL is 280 mg/m2 twice daily based on body surface area until disease progression or unacceptable toxicity. Prescribing information provides milligram doses to be administered according to body surface area. The agent should be administered to pediatric patients under adult supervision. Prescribing information provides details on starting dose reduction in patients with moderate or severe hepatic impairment and severe renal impairment.
Patients should receive standard antiemetic and antidiarrheal agents for gastrointestinal toxicities; antiemetics are recommended prior to and during treatment to prevent nausea and vomiting. Intravenous or oral hydration should be considered for patients at risk of dehydration, and electrolytes should be replaced as clinically indicated.
Product labeling provides instructions on dose reductions for adverse effects according to body surface area. Treatment should be permanently discontinued if more than two dose reductions are required. Product labeling provides instructions on dosage modification, including dose reduction and withholding and discontinuing treatment, and management of adverse reactions, including low absolute neutrophil count; low platelet count; anemia; hepatotoxicity; interstitial lung disease/pneumonitis; QT prolongation; bradycardia; ocular toxicity, including vision loss; and gastrointestinal toxicity.
Concomitant use of strong CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin) should be avoided; prescribing information provides instructions for crizotinib dose reduction and dose resumption if concomitant use cannot be avoided. Concomitant use of strong CYP3A inducers (eg, phenobarbital, phenytoin, rifampicin) and CYP3A substrates (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided.
Among the 26 patients receiving crizotinib in Study ADVL0912, the median duration of exposure was 5.4 months (range = 1.8–82.3 months), with 46% of patients treated for at least 6 months and 35% treated for at least 12 months.
The most common adverse events of any grade (≥ 35%), excluding laboratory abnormalities, were diarrhea (92%), vomiting (92%), nausea (77%), vision disorder (65%), headache (58%), musculoskeletal pain (58%), abdominal pain (50%), stomatitis (46%), fatigue (46%), decreased appetite (42%), pyrexia (38%), cough (35%), and pruritus (35%). Clinically relevant adverse events of any grade occurring in up to 20% of patients included bradycardia (19%), QT prolongation (8%), hypotension (19%), increased alkaline phosphatase (19%), and hypernatremia (19%). The most common grade 3 or 4 adverse events included diarrhea (12%), musculoskeletal pain (12%), and stomatitis (8%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (77%), lymphopenia (38%), and thrombocytopenia (19%). Grade 4 laboratory abnormalities (≥ 15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).
Serious adverse events occurred in 35% of patients, the most common being neutropenia (12%) and hypotension (8%). Adverse events led to dose interruption, dose reduction, and treatment discontinuation in 77%, 19%, and 8% of patients, respectively.
Crizotinib has warnings/precautions for hepatotoxicity, including fatal cases; interstitial lung disease/pneumonitis; QT interval prolongation; bradycardia; severe visual loss; gastrointestinal toxicity in patients with ALCL, including severe nausea, vomiting, diarrhea, and stomatitis; and embryofetal toxicity.
Patients should undergo periodic liver function testing. Treatment should be permanently discontinued for any grade interstitial lung disease/pneumonitis. ECG and electrolyte monitoring should be performed in patients with a history of or predisposition for QT prolongation or who are taking medications that prolong QT. Heart rate and blood pressure should be monitored regularly. Patients should have ophthalmologic evaluations at baseline and serially thereafter, together with a monthly assessment of visual acuity and visual symptoms. Patients should have complete blood cell counts, including differential monitored weekly for the first month of therapy and then at least monthly, with more frequent monitoring if grade 3 or 4 abnormalities, fever, or infection occurs. Patients should be advised not to breastfeed while receiving crizotinib.
1. U.S. Food and Drug Administration: FDA approves crizotinib for children and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large. Accessed January 27, 2021.
2. Xalkori (crizotinib) capsules prescribing information, Pfizer Inc, January 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf. Accessed January 27, 2021.