XALKORI®

1.1 ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer

XALKORI is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see Dosage and Administration (2.1)].

1.2 Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma

XALKORI is indicated for the 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.

1.3 Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor

XALKORI is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.

2.1 Patient Selection

Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see Clinical Studies (14.1, 14.2, 14.3)].

Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at http://www.fda.gov/companiondiagnostics.

2.2 Recommended Testing During Treatment with XALKORI

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Monitor liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases [see Warnings and Precautions (5.1)].

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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 [see Adverse Reactions (6.1)].

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For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter [see Warnings and Precautions (5.5)].

2.3 Recommended Dosage

The recommended dosage of XALKORI is provided in Table 1.

Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC

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The recommended dosage for adult patients with ALK- or ROS1-positive metastatic NSCLC is XALKORI capsules 250 mg orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.

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For adults who cannot swallow capsules, the recommended dosage of XALKORI pellets is 250 mg (2 x 50 mg + 1 x 150 mg) orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.

Recommended Dosage for Pediatric and Young Adult Patients with ALK-Positive ALCL

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The recommended dosage for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic ALK-positive ALCL is based on body surface area (BSA) and is provided in Table 2.

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Administer XALKORI capsules or pellets orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.

Table 2 provides the dosage based on body surface area (BSA) for XALKORI capsules or pellets.

Recommended Dosage for Pediatric and Adult Patients with ALK-Positive IMT

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The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT is provided in Table 1.

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The recommended dosage for pediatric patients 1 year of age and older with unresectable, recurrent, or refractory ALK-positive IMT is based on BSA and is provided in Table 3.

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Administer XALKORI capsules or pellets orally twice daily, with or without food, until disease progression or unacceptable toxicity occurs.

Table 3 provides the dosage based on BSA for XALKORI capsules or pellets.

2.4 Administration

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Administer XALKORI capsules or pellets orally, twice daily, with or without food.

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If a dose of XALKORI capsules or pellets is missed, make up that dose unless the next dose is due within 6 hours.

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If vomiting occurs after taking a dose of XALKORI capsules or pellets, do not take an additional dose. Take the next dose at the regular scheduled time.

XALKORI Capsules

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Swallow XALKORI capsules whole, with or without food twice daily.

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Do not chew, crush or split XALKORI capsules.

XALKORI Pellets

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XALKORI pellets are supplied encapsulated in shells.

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Do not chew or crush XALKORI pellets.

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Do not swallow XALKORI pellets encapsulated in the shell.

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XALKORI pellets can be administered by 2 options:

1.

Open shell(s) containing XALKORI pellets and empty the contents directly into the patient’s mouth.

2.

Open shell(s) containing XALKORI pellets and empty the contents into a consumer-supplied oral dosing aid (e.g., spoon, medicine cup). Administer XALKORI pellets via the dosing aid directly into the patient’s mouth.

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Immediately after administration, give a sufficient amount of water to ensure that all medication is swallowed.

2.5 Concomitant Treatments for Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities.

Consider intravenous or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically indicated [see Warnings and Precautions (5.6)].

2.6 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.

The recommended dosage modifications for adverse reactions for pediatric patients with ALCL or IMT and young adults with ALCL are based on body surface area and are provided in Table 5.

Recommended Dosage Modifications for Hematologic Adverse Reactions for Adult Patients with NSCLC or IMT

The recommended dosage modifications for hematologic adverse reactions for adult patients with NSCLC or IMT are provided in Table 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.

Recommended Dosage Modifications for Hematologic Adverse Reactions in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

The recommended dosage modifications for hematologic adverse reactions in pediatric and young adult patients with ALCL or pediatric patients with IMT are provided in Table 7.

Recommended Dosage Modifications for Non-Hematologic Adverse Reactions

The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.

2.7 Dosage Modifications for Moderate and Severe Hepatic Impairment

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 shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7), 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 shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Dosage and Administration (2.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.8 Dosage Modification for Severe Renal Impairment

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 for adult patients and the Schwartz equation for pediatric patients] not requiring dialysis is the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.9 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1)]. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

5.1 Hepatotoxicity

Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI for NSCLC across clinical trials [see Adverse Reactions (6.1)]. Concurrent elevations in ALT or AST ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in <1% of patients treated with XALKORI. Increased ALT or AST >5 times the ULN occurred in 11% and 6% of patients, respectively. One percent (1.0%) of patients required permanent discontinuation due to elevated transaminases. Increased transaminases generally occurred within the first 2 months of treatment.

In Study ADVL0912, of 121 patients ages 1 to ≤21 years treated with XALKORI for relapsed or refractory tumors including ALCL and IMT, 71% and 79% had increases of AST and ALT, respectively, with increased ALT or AST >5 times the ULN in 6% each. Of the 26 patients with ALCL treated with XALKORI, 65% and 81% had increases of AST and ALT, respectively, with increases >5 times the ULN in 4% each. Of the 14 pediatric patients with IMT treated with XALKORI, 71% had increases of AST and 71% had increases of ALT.

In Study A8081013, of the 7 adult patients with IMT treated with XALKORI, 57% and 43% had increases of AST and ALT, respectively.

Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage and Administration (2.6)].

5.2 Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC (n=1719), 2.9% of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and 0.5% had fatal ILD [see Adverse Reactions (6.1)]. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI.

In Study ADVL0912, among 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including ALCL and IMT, ILD occurred in 0.8% of patients.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.6)].

5.3 QT Interval Prolongation

QTc prolongation can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC, 2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and 5% of 1582 patients had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs.

In Study ADVL0912, QTc prolongation was reported as an adverse reaction in 4.1% of patients, including 8% of patients with ALCL and 7% of pediatric patients with IMT.

Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.6), Clinical Pharmacology (12.2)].

5.4 Bradycardia

Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials in patients with NSCLC, bradycardia occurred in 13% of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients [see Adverse Reactions (6.1)].

In Study ADVL0912, among 121 patients ages 1 to ≤21 years treated with XALKORI, bradycardia was reported in 14%, including Grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL treated with XALKORI, bradycardia (all Grade 1) was reported in 19%. Of the 14 pediatric patients with IMT treated with XALKORI, bradycardia was reported in 14% of patients, including Grade 3 bradycardia in 7% of patients.

Avoid using XALKORI in combination with other medications known to cause bradycardia (e.g., beta-blockers, nondihydropyridine-calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as recommended [see Dosage and Administration (2.6)].

5.5 Severe Visual Loss

Across all clinical trials in patients with NSCLC, the incidence of Grade 4 visual field defect with visual loss was 0.2% of 1719 patients [see Adverse Reactions (6.1)]. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss.

In Study ADVL0912, visual disorders occurred in 46% of 121 patients with XALKORI, including 65% of 26 patients with ALCL and 50% of 14 patients with IMT. Of the 56 patients who experienced visual disorders, one pediatric patient with IMT experienced Grade 3 myopic optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.

Assessment of visual symptoms for all patients is recommended monthly during treatment. Report new visual symptoms to an eye specialist.

For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter. The ophthalmological evaluation should consist of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate [see Dosage and Administration (2.6), Adverse Reactions (6.1)].

Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified [see Dosage and Administration (2.6)]. There is insufficient information to characterize the risks of resumption of XALKORI in patients who develop visual symptoms or visual loss. A decision to resume XALKORI should consider the potential benefits versus risks to the patient.

5.6 Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

XALKORI can cause severe gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT [see Adverse Reactions (6.1)]. In patients with ALCL (n=26), gastrointestinal toxicity occurred in 100% of patients; Grade 3 gastrointestinal toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis. In pediatric patients with IMT (n=14), vomiting occurred in 93%, nausea occurred in 86%, and diarrhea occurred in 64% of patients.

Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT. Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. If patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold XALKORI until resolved, and then resume at the next lower dose level. Consider supportive care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated [see Dosage and Administration (2.6)].

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days following the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013).

6.2 Postmarketing Experience

The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Investigations: Increased blood creatine phosphokinase

7.1 Effect of Other Drugs on XALKORI

7.2 Effect of XALKORI on Other Drugs

7.3 Drugs That Prolong the QT Interval

XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)].

7.4 Drugs That Cause Bradycardia

XALKORI can cause bradycardia. Avoid concomitant use of XALKORI with drugs that cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) [see Warnings and Precautions (5.4)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of XALKORI have been established in pediatric patients 1 year of age and older with relapsed or refractory, systemic ALK-positive ALCL or with unresectable, recurrent, or refractory ALK-positive IMT [see Adverse Reactions (6.1), Clinical Studies (14.2, 14.3)]. The safety and effectiveness have not been established in pediatric patients younger than 1 year of age with ALCL or with IMT, or in any pediatric patients with NSCLC.

In a study that evaluated XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%. The safety and effectiveness of XALKORI in combination with chemotherapy have not been established in patients with newly diagnosed ALCL.

8.5 Geriatric Use

Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.8% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Clinical studies of XALKORI in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin greater than 1.5 times ULN and less than or equal to 3 times ULN) or severe (any AST and total bilirubin greater than 3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3)]. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.7)]. No dose adjustment is recommended in patients with pre-existing mild hepatic impairment (AST > ULN and total bilirubin less than or equal to 1 times ULN or any AST and total bilirubin greater than 1 times ULN but less than or equal to1.5 times ULN).

8.7 Renal Impairment

Increased exposure to crizotinib occurred in patients with pre-existing 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, therefore reduce dosage of XALKORI in these patients [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min).

12.1 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.

In vitro, 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 the tumor at a dose of 100 mg/kg once daily.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Following XALKORI 250 mg capsules twice daily, steady-state was reached within 15 days with a median accumulation ratio of 4.8. Steady-state minimum concentration (Cmin.ss) and AUC increased in a greater than dose-proportional manner over the dose range of 200 mg to 300 mg twice daily (0.8 to 1.2 times the approved recommended dosage).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with crizotinib have not been conducted.

Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

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 greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the recommended human dose 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 (approximately 10 times the recommended human dose based on body surface area) for 3 days.

14.1 ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer

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 16 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 16. Previously Untreated ALK-Positive Metastatic NSCLC - Efficacy Results in Study 1

	XALKORI (N=172)	Chemotherapy (N=171)
HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; NR=not reached; CR=complete response; PR=partial response.
* Based on the Cox proportional hazards stratified analysis. † Based on the stratified log-rank test. ‡ Based on the stratified Cochran-Mantel-Haenszel test.
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)*	0.45 (0.35, 0.60)
p-value†	<0.001
Overall Survival
Number of Events (%)	71 (41%)	81 (47%)
Median, Months (95% CI)	NR (45.8, NR)	47.5 (32.2, NR)
HR (95% CI)*	0.76 (0.55, 1.05)
p-value†	0.098
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-value‡	<0.001
Duration of Response
Median, Months (95% CI)	11.3 (8.1, 13.8)	5.3 (4.1, 5.8)

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 17 and Figure 2 summarize the efficacy results.

Table 17. Previously Treated ALK-Positive Metastatic NSCLC - Efficacy Results in Study 2

	XALKORI (N=173)	Chemotherapy (N=174)
HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; CR=complete response; PR=partial response.
* For pemetrexed, the median PFS was 4.2 months. For docetaxel, the median PFS was 2.6 months. † Based on the Cox proportional hazards stratified analysis. ‡ Based on the stratified log-rank test. § Based on the stratified Cochran-Mantel-Haenszel test.
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)	3.0* (2.6, 4.3)
HR (95% CI)†	0.49 (0.37, 0.64)
p-value‡	<0.001
Overall Survival
Number of Events (%)	116 (67%)	126 (72%)
Median, Months (95% CI)	21.7 (18.9,30.5)	21.9 (16.8,26.0)
HR (95% CI)†	0.85 (0.66, 1.10)
p-value‡	0.229
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-value§	<0.001
Duration of Response
Median, Months (95% CI)	7.4 (6.1, 9.7)	5.6 (3.4, 8.3)

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

14.2 Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma

The efficacy of XALKORI was evaluated in Study ADVL0912 (NCT00939770), a multicenter, single arm, open-label study in patients 1 to ≤21 years of age that included 26 patients with relapsed or refractory, systemic ALK-positive ALCL after at least one systemic treatment. ALK-positive status (confirmation of an ALK fusion) was determined locally by immunohistochemistry or fluorescence in situ hybridization. The study excluded patients with primary cutaneous ALCL or central nervous system involvement by lymphoma.

Patients received XALKORI 280 mg/m2 (20 patients) or 165 mg/m2 (6 patients) orally twice daily until disease progression or unacceptable toxicity. Patients were permitted to discontinue XALKORI to undergo hematopoietic stem cell transplantation (HSCT).

Of the 26 patients evaluated, the median age was 11 years (range: 3 to 20); 69% were male, 54% were White, 19% Black, 8% Asian. Patient enrollment by age category was 4 patients from 3 to <6 years, 11 patients from 6 to <12 years, 7 patients from 12 to <18 years, and 4 patients from 18 to ≤21 years.

All patients had received multi-agent systemic therapy, 2 (8%) had received a prior HSCT and 4 (15%) had received at least 3 prior therapies.

Efficacy was based on objective response rate and duration of response, as assessed by an independent review committee (Table 19). The median time to first response was 3.9 weeks (range: 3.5 to 9.1 weeks).

14.3 Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor

Hepatotoxicity

Inform patients to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].

Interstitial Lung Disease (Pneumonitis)

Advise patients to immediately report any new or worsening pulmonary symptoms [see Warnings and Precautions (5.2)].

Bradycardia

Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of any heart or blood pressure medications [see Warnings and Precautions (5.4)].

Severe Visual Loss

Inform patients of the potential risk of severe visual loss and to immediately contact their healthcare provider if they develop severe visual loss. Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse reactions and may occur while driving or operating machinery. The onset of visual disorders most commonly occurs during the first week of treatment [see Warnings and Precautions (5.5), Adverse Reactions (6)].

Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

Inform patients with ALCL or pediatric patients with IMT of the risk of severe nausea, vomiting, diarrhea, and stomatitis. Advise patients to immediately inform their healthcare provider of problems with swallowing, vomiting, or diarrhea [see Warnings and Precautions (5.6)].

Drug Interactions

Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

Photosensitivity

Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen or protective clothing during treatment with XALKORI [see Adverse Reactions (6.1)].

Dosage and Administration

Advise patients to take XALKORI with or without food. If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. If a patient vomits after taking a dose of XALKORI, advise the patient not to take an extra dose, but to take the next dose at the regular time [see Dosage and Administration (2.4)].

Capsules:

Advise patients to swallow XALKORI capsules whole [see Dosage and Administration (2.4)].

Oral Pellets:

Inform patient or caregiver to open the encapsulated XALKORI oral pellets and administer the oral pellets directly in the patient’s mouth or with a consumer-supplied oral dosing aid, for example a spoon or medicine cup. Advise patient or caregiver that the oral pellets are not to be chewed and to give a sufficient amount of water after pellets are administered to ensure all oral pellets are swallowed [see Dosage and Administration (2.4)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days after the last dose [see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Lactation

Advise females not to breastfeed during treatment with XALKORI and for 45 days after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].