July 28, 2016
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Xalkori

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Xalkori




CLINICAL PHARMACOLOGY

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 echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

Pharmacodynamics

Cardiac electrophysiology

In an ECG substudy conducted in 52 patients with ALK-positive NSCLC who received crizotinib 250 mg twice daily, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms). An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

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 [observed minimum concentration (Cmin) 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 AUC from time zero to infinity (AUCinf) and maximum observed plasma concentration (Cmax) by approximately 14%. XALKORI can be administered with or without food [see DOSAGE AND ADMINISTRATION].

Distribution

The geometric mean volume of distribution (Vss) of crizotinib was 1772 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.

Elimination

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 after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.

Metabolism

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.

Specific Populations

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 times ULN or greater than 5 times ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 times ULN were also excluded [see Use In Specific Populations]. The population pharmacokinetic analysis using the data from approximately 1200 patients with cancer who received XALKORI 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 the 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. 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 Cmax 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.

Body weight and gender: No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis.

Drug Interactions

Effect of Other Drugs on Crizotinib

Strong 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].

Strong CYP3A inducers: Coadministration of crizotinib (250 mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib steady-state AUCtau and Cmax by 84% and 79%, respectively, compared to crizotinib alone [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 Cmax).

Effect of Crizotinib on Other Drugs

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 crizotinib-mediated 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.

UGT substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for uridine diphosphate glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur.

Substrates of transporters: Crizotinib inhibited P-gp in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.

Crizotinib inhibited the hepatic uptake transporter, organic cation transporter (OCT) 1, and renal uptake transporter, OCT2, in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.

Crizotinib did not inhibit the human hepatic uptake transport proteins, organic anion transporting polypeptides (OATP) B1 or OATP1B3, or the renal uptake transport proteins organic anion transporter (OAT) 1 or OAT3 in vitro at clinically relevant concentrations.

Other transporters: Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations.

Clinical Studies

ALK-Positive Metastatic NSCLC

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1

The efficacy and safety of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, duration of response (DOR), and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment.

Patients were randomized to receive XALKORI (n=172) or chemotherapy (n=171). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0-1, 2), race (Asian, non-Asian), and brain metastases (present, absent). Patients in the XALKORI arm received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m²with cisplatin 75 mg/m²or carboplatin AUC of 5 or 6 mg·min/mL by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI.

The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients' tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. Of those randomized to chemotherapy, 70% received XALKORI after IRR documented progression.

Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. The OS analysis conducted at the time of the PFS analysis did not suggest a difference in survival between arms. Table 7 and Figure 1 summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment.

Table 7: Previously Untreated ALK-Positive Metastatic NSCLC - Efficacy Results

  XALKORI
(N=172)
Chemotherapy
(N=171)
Progression-Free Survival (Based on IRR)
  Number of Events (%) 100 (58%) 137 (80%)
     Progressive Disease 89 (52%) 132 (77%)
     Death 11 (6%) 5 (3%)
  Median, Months (95% CI) 10.9 (8.3, 13.9) 7.0 (6.8, 8.2)
  HR (95% CI)a 0.45 (0.35, 0.60)
  p-valueb < 0.001
Overall Survivalc
  Number of Events (%) 44 (26%) 46 (27%)
  Median, Months (95% CI) NR NR
  HR (95% CI)a 0.82 (0.5Z h 1.26)
  p-valueb 0.36
Tumor Responses (Based on IRR)
  Objective Response Rate % (95% CI) 74% (67, 81) 45% (37, 53)
     CR n (%) 3 (1.7%) 2 (1.2%)
     PR, n (%) 125 (73%) 75 (44%)
  p-valued < 0.001
Duration of Response
  Median, Monthse (95% CI) 11.3 (8.1, 13.8) 5.3 (4.1, 5.8)
HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; NR=not reached; CR=complete response; PR=partial response.
a Based on the Cox proportional hazards stratified analysis.
b Based on the stratified log-rank test.
c OS analysis was not adjusted for the potentially confounding effects of cross over.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Estimated using the Kaplan Meier method.

Figure 1: Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 1

Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR - Illustration

Previously Treated ALK-Positive Metastatic NSCLC - Study 2

The efficacy and safety of XALKORI as monotherapy for the treatment of 347 patients with ALK-positive metastatic NSCLC, previously treated with 1 platinum-based chemotherapy regimen, were demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). The major efficacy outcome was PFS according to RECIST version 1.1 as assessed by IRR. Additional efficacy outcomes included ORR as assessed by IRR, DOR, and 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 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past smokers, and 63% never smokers. The disease characteristics of the overall study population were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.

Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 8 and Figure 2 summarize the efficacy results.

Table 8: Previously Treated ALK-Positive Metastatic NSCLC - Efficacy Results

  XALKORI
(N=173)
Chemotherapy
(N=174)
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)
  p-valuec < 0.001
Overall Survivald
  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)
  p-valuec 0.92
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%)
  p-valuee < 0.001
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; IRR=independent radiology review; NR=not reached; CR=complete response; PR=partial response.
a For pemetrexed, the median PFS was 4.2 months. For docetaxel, the median PFS was 2.6 months.
b Based on the Cox proportional hazards stratified analysis.
c Based on the stratified log-rank test.
d Interim OS analysis conducted at 40% of total events required for final analysis.
e Based on the stratified Cochran-Mantel-Haenszel test.

Figure 2: Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 2

Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR - Illustration

ROS1-Positive Metastatic NSCLC

The efficacy and safety of XALKORI was investigated in a multicenter, single-arm study (Study 3), in which patients with ROS1-positive metastatic NSCLC received XALKORI 250 mg orally twice daily. Patients were required to have histologically-confirmed advanced NSCLC with a ROS1 rearrangement, age 18 years or older, ECOG performance status of 0, 1, or 2, adequate organ function, and measurable disease. The efficacy outcome measures were ORR and DOR according to RECIST version 1.0 as assessed by IRR and investigator, with imaging performed every 8 weeks for the first 60 weeks.

Baseline demographic and disease characteristics were female (56%), median age of 53 years, baseline ECOG performance status of 0 or 1 (98%), White (54%), Asian (42%), past smokers (22%), never smokers (78%), metastatic disease (92%), adenocarcinoma (96%), no prior systemic therapy for metastatic disease (14%), and prior platinum-based chemotherapy for metastatic disease (80%). The ROS1 status of NSCLC tissue samples was determined by laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial assays. For assessment by FISH, ROS1 positivity required that ≥ 15% of a minimum of 50 evaluated nuclei contained a ROS1 gene rearrangement.

Efficacy results are summarized in Table 9.

Table 9: ROS1-Positive Metastatic NSCLC - Efficacy Results*

Efficacy Parameters IRR
(N=50)
Investigator-Assessed
(N=50)
Objective Response Rate (95% CI) 66% (51, 79) 72% (58, 84)
  Complete Response, n 1 5
  Partial Response, n 32 31
Duration of Response
  Median, Months (95% CI) 18.3 (12.7, NR) NR (14.5, NR)
IRR=independent radiology review; CI=confidence interval; NR=not reached.
*As assessed by RECIST version 1.0.

Last reviewed on RxList: 5/9/2016
This monograph has been modified to include the generic and brand name in many instances.

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