Crizotinib is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met) RTK, ROS1 (c-ros) and recepteur d’Origine nantais (RON) RTKs. Crizotinib demonstrated concentration-dependent inhibition of the kinase activity of ALK, ROS1 and c-Met in biochemical assays and inhibited phosphorylation and modulated kinase-dependent phenotypes in cell-based assays. Crizotinib demonstrated potent and selective growth inhibitory activity and induced apoptosis in tumor cell lines exhibiting ALK fusion events (including EML4-ALK and NPM-ALK), ROS1 fusion events or exhibiting amplification of the ALK or MET gene locus. Crizotinib demonstrated antitumor efficacy, including marked cytoreductive antitumor activity, in mice bearing tumor xenografts that expressed ALK fusion proteins. The antitumor efficacy of crizotinib was dose-dependent and correlated to pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumors in vivo
The safety and efficacy of crizotinib in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 7 times human clinical exposure based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
Clinical Studies: Randomized Phase 3 Study 1007:
The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in a multicenter, multinational, randomized, open-label phase 3 study (study 1007). The primary objective of this study was to demonstrate that crizotinib 250 mg orally twice daily was superior to standard-of-care chemotherapy (pemetrexed 500 mg/m2
or docetaxel 75 mg/m2
) IV every 21 days in prolonging progression-free survival (PFS) in patients with ALK-positive advanced NSCLC who had received 1 prior chemotherapy regimen. Patients were required to have ALK-positive NSCLC as identified by FISH prior to randomization. Patients randomized to chemotherapy could cross over to receive crizotinib in study 1005 upon RECIST-defined disease progression confirmed by independent radiology review (IRR). The primary efficacy endpoint was PFS with disease progression events determined by IRR. Secondary endpoints included objective response rate (ORR) as determined by IRR, duration of response (DR), overall survival (OS) and patient-reported outcomes (PRO).
The full analysis population for study 1007 included 347 patients with ALK-positive advanced NSCLC. One hundred seventy-three (173) patients were randomized to the crizotinib arm (172 patients received crizotinib) and 174 patients were randomized to the chemotherapy arm [99 (58%) patients received pemetrexed and 72 (42%) patients received docetaxel]. Randomization was stratified by ECOG performance status (0-1, 2), brain metastases (present, absent) and prior EGFR tyrosine kinase inhibitor treatment (yes, no). The median duration of study treatment was 31 weeks in the crizotinib arm as compared to 12 weeks in the chemotherapy arm.
Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression, as assessed by IRR, at the discretion of the investigator if the patient was still experiencing clinical benefit. Fifty eight of 84 (69%) crizotinib-treated patients and 17 of 119 (14%) chemotherapy-treated patients continued treatment for at least 3 weeks after objective disease progression.
Key demographic and baseline characteristics for patients in this study were comparable between the crizotinib and chemotherapy arms as shown in Table 1 (see Table 1).
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Crizotinib significantly prolonged PFS compared to chemotherapy as assessed by IRR. The median PFS was 7.7 months for patients randomized to crizotinib and 3 months for patients randomized to chemotherapy. The hazard ratio was 0.487 with a p-value of <0.0001 (1-sided, based on stratified log-rank test). The median PFS for patients treated with crizotinib was 7.7 months and 4.2 months for patients treated with pemetrexed. The hazard ratio was 0.589 with a p-value of 0.0004 (1-sided, based on stratified log-rank test). The median PFS for patients treated with crizotinib was 7.7 months and 2.6 months for patients treated with docetaxel. The hazard ratio was 0.298 with a p-value of <0.0001 (1-sided stratified log-rank test).
Crizotinib also significantly improved IRR-assessed ORR as compared to chemotherapy with a p-value of <0.0001 (2-sided stratified test). The ORR for patients randomized to crizotinib was 65% (95% CI: 58%, 72%) and for patients randomized to chemotherapy was 20% (95% CI: 14%, 26%). The ORR for patients treated with crizotinib was 66% (95% CI: 58%, 73%) and 29% (95% CI: 21%, 39%) for patients treated with pemetrexed, with a p-value of <0.0001 (2-sided stratification test). The ORR for patients treated with crizotinib was 66% (95% CI: 58%, 73%) and 7% (95% CI: 2%, 16%) for patients treated with docetaxel, with a p-value of <0.0001 (2-sided stratified test).
Median DR was 32.1 weeks (95% CI: 26.4 weeks, 42.3 weeks) in the crizotinib arm and 24.4 weeks (95% CI: 15 weeks, 36 weeks) in the chemotherapy arm.
Overall survival data were not mature at the time of analysis.
Efficacy data from randomized phase 3 study 1007 are summarized in Table 2 and the Kaplan-Meier curve for PFS is shown in Figure 1. (See Table 2 and Figure 1.)
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Time to deterioration (TTD) was pre-specified as the first occurrence of a ≥10-point increase in scores from baseline in symptoms of pain (EORTC QLQ-LC13 pain in chest), cough (EORTC QLQ-LC13 cough) or dyspnea (EORTC QLQ-LC13 dyspnea). The median TTD in patient-reported pain in chest, dyspnea or cough as a composite endpoint was 5.6 months (95% CI: 3.4 months, 11 months) in the crizotinib arm compared to 1.4 months (95% CI: 1 month, 1.8 months) in the chemotherapy arm. Treatment with crizotinib was associated with a significantly longer TTD in the symptoms of pain in chest, dyspnea or cough compared to chemotherapy (hazard ratio 0.535; 95% CI: 0.404, 0.709; Hochberg adjusted log-rank p<0.0001).
The change from baseline scores was found to be significantly different between the 2 treatment arms, with a significantly greater improvement observed in global quality of life in the crizotinib arm compared to the chemotherapy arm (overall difference in change from baseline scores 9.84; p<0.0001).
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Single-Arm Studies in ALK-Positive Advanced NSCLC:
The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in 2 multicenter, multinational, single-arm studies (studies 1001 and 1005). Patients enrolled into these studies had received prior systemic therapy, with the exception of 16 patients in study 1001 and 3 patients in study 1005 who had no prior systemic treatment for locally advanced or metastatic disease. The primary efficacy endpoint in both studies was ORR according to RECIST. Secondary endpoints included time to tumor response (TTR), DR, PFS and OS. Patients received crizotinib 250 mg orally twice daily. Demographic and disease characteristics for studies 1001 and 1005 are provided in Table 3 (see Table 3).
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In study 1001, patients with advanced NSCLC were required to have ALK-positive tumors prior to entering the clinical trial. ALK-positive NSCLC was identified using a number of local clinical trial assays.
One hundred nineteen (119) patients with ALK-positive advanced NSCLC were enrolled into study 1001 at the time of data cutoff. The median duration of treatment was 32 weeks. There were 2 complete responses and 69 partial responses for an ORR of 61%. The median DR was 48.1 weeks. Fifty-five percent (55%) of objective tumor responses were achieved during the first 8 weeks of treatment.
In study 1005, patients with advanced NSCLC were required to have ALK-positive tumors prior to entering the clinical trial. For most patients, ALK-positive NSCLC was identified by FISH.
Nine hundred thirty-four (934) patients with ALK-positive advanced NSCLC were treated with crizotinib in study 1005 at the time of data cutoff. The median duration of treatment for these patients was 23 weeks. Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression at the discretion of the investigator if the benefit/risk assessment justified continuation of treatment. Seventy-seven of 106 patients (73%) continued crizotinib treatment for at least 3 weeks after objective disease progression.
Seven hundred sixty-five (765) patients with ALK-positive advanced NSCLC from study 1005 were both evaluable for response and identified by the same FISH assay used in randomized phase 3 study 1007. There were 8 complete responses and 357 partial responses for an ORR of 48%. The median DR was 47.3 weeks. Eighty-three percent (83%) of objective tumor responses were achieved within the first 12 weeks of treatment.
Efficacy data from studies 1001 and 1005 are provided in Table 4. (See Table 4.)
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Following oral single dose administration in the fasted state, crizotinib is absorbed with median time to achieve peak concentrations of 4-6 hrs. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable with a median accumulation ratio of 4.8. The absolute bioavailability of crizotinib was determined to be 43% (range: 32-66%) following the administration of a single 250-mg oral dose.
A high-fat meal reduced crizotinib AUCinf
by approximately 14% when a 250-mg single dose was given to healthy volunteers. Crizotinib can be administered with or without food (see Dosage & Administration).
The geometric mean volume of distribution (Vss
) of crizotinib was 1772 L following IV 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.
Metabolism: In vitro
studies demonstrated that CYP3A4/5 were the major enzymes involved in the metabolic clearance of crizotinib. 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-
studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP2B6 and CYP3A.
Following single doses of crizotinib, the apparent plasma terminal half-life (t½
) of crizotinib was 42 hrs 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/hr) after 250 mg twice daily than that after a single 250-mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
Drug Interactions: Co-administration of Crizotinib and CYP3A Substrates:
Crizotinib has been identified as an inhibitor of CYP3A both in vitro
and in vivo
. Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUC was 3.7-fold (90% CI: 2.63-5.07) those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A (see Interactions).
Co-administration of Crizotinib and CYP3A Inhibitors:
Co-administration of a single 150-mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf
values that were approximately 3.2- and 1.4-fold, respectively, those seen when crizotinib was administered alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been established (see Interactions).
Co-administration of Crizotinib and CYP3A Inducers:
Co-administration of a single 250-mg crizotinib dose with rifampin (600 mg once daily), a strong CYP3A inducer, resulted in 82% and 69% decreases in crizotinib AUCinf
, respectively, compared to when crizotinib was given alone. However, the effect of CYP3A inducers on steady-state crizotinib exposure has not been established (see Interactions).
Co-administration of Crizotinib with Agents that Increase Gastric pH:
The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility. Administration of a single 250-mg crizotinib dose following treatment with esomeprazole 40 mg once daily for 5 days resulted in an approximately 10% decrease in crizotinib total exposure (AUCinf
) and no change in peak exposure (Cmax
); the extent of the change in total exposure was not clinically meaningful. Therefore, starting dose adjustment is not required when crizotinib is co-administered with agents that increase gastric pH (eg, proton-pump inhibitors, H2
-blockers or antacids).
Co-administration with Other CYP Substrates: In vitro
studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.
Crizotinib is an inhibitor of CYP2B6 in vitro
. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are predominantly metabolized by CYP2B6. In vitro
studies in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A.
Co-administration with UGT Substrates: In vitro
studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.
Co-administration with Drugs that are Substrates of Transporters:
Crizotinib is an inhibitor of P-gp in vitro
. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of P-gp.
Crizotinib is an inhibitor of OCT1 and OCT2 in vitro
. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of OCT1 or OCT2.
, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3, or the renal uptake transport proteins OAT1 or OAT3 at clinically relevant concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the hepatic or renal uptake of drugs that are substrates for these transporters.
Effect on Other Transport Proteins: In vitro
, crizotinib is not an inhibitor of BSEP at clinically relevant concentrations.
Pharmacokinetics in Special Patient Groups: Hepatic Insufficiency:
As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with ALT or AST >2.5 x ULN or, if due to underlying malignancy, >5 x ULN or with total bilirubin >1.5 x ULN (see Table 6 and Dosage & Administration). The population pharmacokinetic analysis using the data from these studies indicated that baseline total bilirubin or AST levels did not have a clinically meaningful effect on the pharmacokinetics of crizotinib.
Patients with mild (60≤ CrCl <90 mL/min) and moderate (30≤ CrCl <60 mL/min) renal impairment were enrolled in single-arm studies 1001 and 1005. The effect of renal function as measured by baseline CrCl on observed crizotinib steady state trough concentrations (Ctrough
) was evaluated. In study 1001, the adjusted geometric mean of plasma Ctrough
in mild (N=35) and moderate (N=8) renal impairment patients were 5.1% and 11% higher, respectively, than those in patients with normal renal function. In study 1005, the adjusted geometric mean Ctrough
of crizotinib in mild (N=191) and moderate (N=65) renal impairment groups were 9.1% and 15% higher, respectively, than those in patients with normal renal function. In addition, the population pharmacokinetic analysis from studies 1001, 1005 and 1007 indicated CrCl did not have a clinically meaningful effect on the pharmacokinetics of crizotinib. Due to the small size of the increases in crizotinib exposure (5-15%), no starting dose adjustment is recommended for patients with mild or moderate renal impairment. After a single 250-mg dose in subjects with severe renal impairment (CrCl <30 mL/min) not requiring peritoneal dialysis or hemodialysis, crizotinib AUC and Cmax
increased by 79% and 34%, respectively, compared to those with normal renal function. An adjustment of the dose of crizotinib is recommended when administering crizotinib to patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis (see Dosage & Administration and Precautions).
Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, age has no effect on crizotinib pharmacokinetics.
Body Weight and Gender:
Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, there was no clinically meaningful effect of body weight or gender on crizotinib pharmacokinetics.
Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, the predicted steady-state AUC (95% CI) was 23-37% higher in Asian patients (n=523) than in non-Asian patients (n=691).
The QT interval prolongation potential of crizotinib was assessed in all patients who received crizotinib 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) ≥500 msec, and 51 of 1136 patients (4.4%) had an increase from baseline QTcF ≥60 msec by automated machine-read evaluation of ECG. A central tendency analysis of the QTcF data demonstrated that the highest upper bound of the 2-sided 90% CI for QTcF was <15 msec at the protocol pre-specified time points. A pharmacokinetic/pharmacodynamic analysis suggested a relationship between crizotinib plasma concentration and QTc.
Toxicology: Preclinical Safety Data: Genotoxicity:
Crizotinib was not mutagenic in vitro
in the bacterial reverse mutation (Ames) assay. Crizotinib was aneugenic in an in vitro
micronucleus assay in Chinese hamster ovary cells and in an in vitro
human lymphocyte chromosome aberration assay. Small increases of structural chromosomal aberrations at cytotoxic concentrations were seen in human lymphocytes. In the rat bone marrow in vivo
, increases in micronuclei were only seen at doses significantly exceeding the expected human exposure. Increases in micronuclei were observed in rats at 250 mg/kg/day (approximately 7 times the AUC at the recommended human dose).
Carcinogenicity studies with crizotinib have not been performed.
No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (approximately 2-fold human clinical exposure based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day for 3 days.