Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.

Recommended Dosage Reductions

Recommended Dosage Modifications for Patients with NSCLC

Recommended dosage modifications for hematologic and non-hematologic adverse reactions for patients with NSCLC are provided in Tables 3 and 4.

Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.

Recommended Dosage Modifications for Patients with ALCL

Recommended dosage modifications for hematologic and non-hematologic adverse reactions for patients with ALCL are provided in Tables 5 and 6.

Monitor complete blood counts including differential 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 occur.

ALK- or ROS1-positive metastatic NSCLC

The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 3 times ULN] is 200 mg orally twice daily.

The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin greater than 3 times ULN) is 250 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Systemic ALK-positive ALCL

The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 3 times ULN] is the first dose reduction based on BSA as shown in Table 2 [see Dosage and Administration (2.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin greater than 3 times ULN) is the second dose reduction based on BSA as shown in Table 2 [see Dosage and Administration (2.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

ALK- or ROS1-positive metastatic NSCLC

The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr) less than 30 mL/min, calculated using the modified Cockcroft-Gault equation] not requiring dialysis is 250 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Systemic ALK-positive ALCL

The recommended dosage of XALKORI in patients with severe renal impairment (CLcr) less than 30 mL/min, calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric patients not requiring dialysis is the second dose reduction based on BSA as shown in Table 2 [see Dosage and Administration (2.5), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

ALK- or ROS1-positive metastatic NSCLC

Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 250 mg orally once daily [see Drug Interactions (7.1)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

Systemic ALK-positive ALCL

Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to the second dose reduction based on BSA as shown in Table 2 [see Dosage and Administration (2.5), Drug Interactions (7.1)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

ALK- or ROS1-Positive Metastatic NSCLC

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014)

The data in Table 7 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) 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. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 34% of patients treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.

Dose reductions due to adverse reactions were required in 6% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).

Tables 7 and 8 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007)

The data in Table 9 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) 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. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.

The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.

Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.4%).

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001)

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2], which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm3 (750/mm3 if bone marrow was involved), platelet count ≥75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m2, and QTc ≤480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors.

Patients with ALCL received XALKORI 165 mg/m2 or 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. 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% of patients treated for at least 12 months.

Serious adverse reactions occurred in 35% of patients treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%).

Dose interruptions and dose reductions occurred in 77% and 19% of patients, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.

The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 11.

Clinically relevant adverse reactions in <20% of patients treated with XALKORI included:

• Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%)
• Vascular Disorders: Hypotension (19%)
• Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%)
• Nervous System Disorders: Peripheral neuropathy (12%)
• Gastrointestinal disorders: Esophagitis (8%)
• Blood and lymphatic disorders: Febrile neutropenia (3.8%)
• Musculoskeletal disorders: Muscular weakness (8%)
• Renal Disorder: Acute renal injury (8%)

Strong or Moderate CYP3A Inhibitors

Concomitant use of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of XALKORI. Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the XALKORI dosage [see Dosage and Administration (2.8)]. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Use caution with concomitant use of moderate CYP3A inhibitors.

Strong CYP3A Inducers

Concomitant use of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers.

CYP3A Substrates

Concomitant use of crizotinib increases plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of these substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

Risk Summary

Based on findings from animal studies and its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of XALKORI during pregnancy. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity (see Data). Advise pregnant women of the potential risk to fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There is no information regarding the presence of crizotinib or its metabolites in human milk, or the effects on the breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI [see Use in Specific Population (8.1)].

Contraception

XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Infertility

Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Juvenile Animal Toxicity Data

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 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Cardiac Electrophysiology

In an ECG substudy conducted in 52 patients with ALK-positive NSCLC, 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) following administration of XALKORI 250 mg orally twice daily. An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see Warnings and Precautions (5.3)].

Absorption

A single crizotinib dose was absorbed with median time to achieve peak concentration of 4 to 6 hours, and the mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%).

Distribution

The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following a single intravenous dose. Protein binding of crizotinib is 91% and is independent of drug concentration in vitro. Crizotinib is a substrate for P-glycoprotein (P-gp) in vitro. The blood-to-plasma concentration ratio is approximately 1.

Elimination

The mean apparent plasma terminal half-life of crizotinib was 42 hours following single doses of crizotinib in patients. 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).

Specific Populations

No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, or ethnicity (Asian, non-Asian). For patients <18 years of age, body weight has a significant effect on the pharmacokinetics of crizotinib, with lower crizotinib exposures observed in patients with higher body weight.

Drug Interaction Studies

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014; NCT01154140)

The efficacy 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, 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/m2 with cisplatin 75 mg/m2 or 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. At the time of the final analysis of overall survival, 84% of patients randomized to the chemotherapy arm subsequently received XALKORI.

Study 1 demonstrated a statistically significant improvement in PFS in patients treated with XALKORI. There was no statistically significant difference in OS between patients treated with XALKORI and patients treated with chemotherapy. Table 12 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.

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

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007; NCT00932893)

The efficacy 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-naïve; 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.

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. At the time of the final analysis of overall survival, 89% of patients randomized to the chemotherapy arm subsequently received XALKORI.

Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 13 and Figure 2 summarize the efficacy results.

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

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001; NCT00585195)

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, 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 14.