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Mechanism of Action
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). 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, ROS1, 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.
The QT interval prolongation potential of crizotinib was assessed in all patients who received XALKORI 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of crizotinib on QT intervals. Sixteen of 1167 patients (1.4%) were found to have QTcF (corrected QT by the Fridericia method) greater than or equal to 500 msec and 51 of 1136 patients (4.4%) had an increase from baseline QTcF greater than or equal to 60 msec by automated machine-read evaluation of ECG. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent increase in QTcF [see WARNINGS AND PRECAUTIONS].
Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady-state systemic exposure (C min and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily.
The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose.
A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. XALKORI can be administered with or without food [see DOSAGE AND ADMINISTRATION].
The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
Crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.
Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients.
Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
CYP3A inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUCinf and Cmax values by approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated [see DRUG INTERACTIONS].
CYP3A inducers: Coadministration of a single 250 mg oral dose of crizotinib with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated [see DRUG INTERACTIONS].
Gastric pH elevating medications: In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and no change in C max ).
CYP3A substrates: Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A [see DRUG INTERACTIONS].
Other CYP substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinibmediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur.
Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6.
An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur.
Substrates of transporters: Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered substrates of P-gp.
In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3 at therapeutic concentrations. Therefore, clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the hepatic uptake of substrates for these transporters are unlikely to occur.
Hepatic Impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, XALKORI has not been studied in patients with hepatic impairment. Clinical studies excluded patients with ALT or AST greater than 2.5 x ULN or greater than 5 x ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 x ULN were also excluded [see Use in Specific Populations]. The population pharmacokinetic analysis using the data from Studies 1, 2 and 3 suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to 124 U/L) did not have a clinically relevant effect on the exposure of crizotinib.
Renal impairment: The pharmacokinetics of crizotinib were evaluated using a population pharmacokinetic analysis in patients with mild (CLcr 60-89 mL/min, N=433) and moderate (CLcr 30-59 mL/min, N=137) renal impairment enrolled in Studies 1, 2, and 3. Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib.
A study was conducted in 7 patients with severe renal impairment (CLcr < 30 mL/min) who did not require dialysis and 8 patients with normal renal function (CLcr ≥ 90 mL/min). All patients received a single 250 mg oral dose of XALKORI. The mean AUCinf for crizotinib increased by 79% and the mean C max increased by 34% in patients with severe renal impairment compared to those with normal renal function. Similar changes in AUCinf and Cmax were observed for the active metabolite of crizotinib [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Ethnicity: No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients (N=691).
Age: Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
Body weight and gender: No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
ALK-Positive Metastatic NSCLC-Study 1
The efficacy and safety of XALKORI as monotherapy for the treatment of 347 patients with metastatic ALK-positive NSCLC, previously treated with one platinum-based chemotherapy regimen, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). The major efficacy outcome was progression-free survival (PFS) as assessed by independent radiology review (IRR). Additional efficacy outcomes included objective response rate (ORR) as assessed by IRR and overall survival (OS).
Patients were randomized to receive XALKORI 250 mg orally twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of pemetrexed 500 mg/m² (if pemetrexed na´ve; n=99) or docetaxel 75 mg/m² (n=72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Randomization was stratified by ECOG performance status (0-1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. A total of 112 (64%) patients randomized to the chemotherapy arm subsequently received XALKORI after disease progression.
The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 (39%) or 1 (52%), 52% White and 45% Asian, 4% current smokers, 33% past-smokers, and 63% never smokers. The disease characteristics were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.
Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 5 and Figure 1 summarize the efficacy results.
Table 5: ALK-Positive Metastatic NSCLC -Efficacy
|Progression-free Survival (Based on IRR)|
|Number of Events (%)||100 (58%)||127 (73%)|
|Progressive Disease||84 (49%)||119 (68%)|
|Death||16 (9%)||8 (5%)|
|Median, Months (95% CI)||7.7 (6.0, 8.8)||3.0a (2.6, 4.3)|
|HR (95% CI)b||0.49 (0.37,0.64)|
|Number of Events (%)||49 (28%)||47 (27%)|
|Median, Months (95% CI)||20.3 (18.1,NR)||22.8 (18.6,NR)|
|HR (95% CI)b||1.02 (0.68,1.54)|
|Tumor Responses (Based on IRR)|
|Objective Response Rate % (95% CI)||65% (58, 72)||20% (14, 26)|
|CR, n (%)||1 (0.6%)||0|
|PR, n (%)||112 (65%)||34 (20%)|
|Duration of Response|
|Median, Months (95% CI)||7.4 (6.1, 9.7)||5.6 (3.4, 8.3)|
|HR = Hazard Ratio; CI =
confidence interval; NR= not reached; CR = complete response; PR = partial
aFor pemetrexed, the median PFS was 4.2 months. For docetaxel, the median PFS was 2.6 months .
bBased on the Cox proportional hazards stratified analysis
cBased on the stratified Log-rank test
dInterim OS analysis conducted at 40% of total events required for final analysis
eBased on the stratified Cochran-Mantel-Haenszel test
Figure 1: Kaplan-Meier
Curves of Progression-Free Survival as Assessed by IRR in Study 1
Single-Arm Studies In ALK-Positive Metastatic NSCLC-Studies 2 And 3
The safety and anti-tumor activity of single-agent XALKORI in the treatment of metastatic ALK-positive NSCLC was demonstrated in two multinational, single-arm studies (Studies 2 and 3). The major outcome in both studies was investigator-assessed ORR according to RECIST. Patients in both studies received 250 mg of XALKORI orally twice daily.
In Study 2 (n=934) the demographic characteristics were 57% female, median age of 52 years, baseline ECOG performance status of 0/1 (82%) or 2/3 (18%), 52% White and 44% Asian, 4% current smokers, 30% past-smokers, and 66% never smokers. The disease characteristics were 92% metastatic; 94% of the cancers were classified as adenocarcinoma histology.
Of the 934 ALK-positive metastatic NSCLC patients who received XALKORI in Study 2, 765 were ALK-positive as identified by Vysis ALK Break-Apart FISH Probe Kit and evaluable for response; demographic characteristics were similar to that of the overall population for this study. The median duration of treatment was 5.5 months. Based on investigator assessments, there were 8 complete and 357 partial responses for an ORR of 48% (95% CI: 44, 51) and the median DR was 11.0 months.
In Study 3 (n=119) the demographic characteristics were 50% female, median age of 51 years, baseline ECOG performance status of 0 (35%) or 1 (53%), 62% White and 29% Asian, less than 1% were current smokers, 27% past-smokers, and 72% never smokers. The disease characteristics were 96% metastatic, 98% of the cancers were classified as adenocarcinoma histology, and 13% had no prior systemic therapy for metastatic disease.
In Study 3, 119 patients with metastatic ALK-positive NSCLC were treated with XALKORI with a median duration of treatment of 32 weeks. Based on investigator assessments, the ORR was 61% (95% CI: 52%, 70%) and the median DR was 11.1 months.
Last reviewed on RxList: 12/5/2013
This monograph has been modified to include the generic and brand name in many instances.
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