Crizotinib

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.

1 INDICATIONS AND USAGE XALKORI is a kinase inhibitor 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. ( 1.1 , 2.1 ) • 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. ( 1.2 , 2.3 ) o Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. • adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. ( 1.3 , 2.3 ) 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 . Limitations of Use : The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. 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 DOSAGE AND ADMINISTRATION • Metastatic NSCLC: The recommended dosage is 250 mg orally twice daily. ( 2.3 ) • Systemic ALCL: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. ( 2.3 ) • Unresectable IMT: o Adult: The recommended dosage is 250 mg orally twice daily. ( 2.3 ) o Pediatric: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area. ( 2.3 ) • See full prescribing information for dosage adjustments by indication for patients with moderate or severe hepatic impairment or severe renal impairment. ( 2.7 , 2.8 ) 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 • 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) ] . • 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) ] . • 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. Table 1. Recommended Dosage of XALKORI Indication Recommended Dosage of XALKORI ALK- or ROS1-Positive Metastatic NSCLC Adults : 250 mg orally twice daily Relapsed or Refractory, Systemic ALK-Positive ALCL Pediatric Patients and Young Adults : 280 mg/m 2 orally twice daily See Table 2 for Recommended Dosage based on body surface area for pediatric patients and young adults with ALCL for the capsules and oral pellets. Unresectable, Recurrent, or Refractory ALK-Positive IMT Adults : 250 mg orally twice daily Pediatric Patients : 280 mg/m 2 orally twice daily See Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets. Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC • 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. • 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 • 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. • 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. Table 2. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older and Young Adults With ALK-Positive ALCL Using Either XALKORI Capsules or Pellets Body Surface Area (BSA) Recommended XALKORI Dosage to Achieve 280 mg/m 2 Twice Daily Dose Strength Combinations of XALKORI Pellets to Administer No more than 4 oral pellet shells are to be used for a single dose. Dose Strength Combinations of XALKORI Capsules to Administer 0.38 to 0.46 m 2 120 mg twice daily 1 x 20 mg + 2 x 50 mg --- 0.47 to 0.51 m 2 140 mg twice daily 2 x 20 mg + 2 x 50 mg --- 0.52 to 0.61 m 2 150 mg twice daily 1 x 150 mg --- 0.62 to 0.80 m 2 200 mg twice daily 1 x 50 mg + 1 x 150 mg --- 0.81 to 0.97 m 2 250 mg twice daily 2 x 50 mg + 1 x 150 mg --- 0.98 to 1.16 m 2 300 mg twice daily 2 x 150 mg --- 1.17 to 1.33 m 2 350 mg twice daily 1 x 50 mg + 2 x 150 mg --- 1.34 to 1.51 m 2 400 mg twice daily 2 x 50 mg + 2 x 150 mg 2 x 200 mg 1.52 to 1.69 m 2 450 mg twice daily 3 x 150 mg 1 x 200 mg + 1 x 250 mg 1.7 m 2 or greater 500 mg twice daily 1 x 50 mg + 3 x 150 mg 2 x 250 mg Recommended Dosage for Pediatric and Adult Patients with ALK-Positive IMT • The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT is p

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) ] • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] • QT Interval Prolongation [see Warnings and Precautions (5.3) ] • Bradycardia [see Warnings and Precautions (5.4) ] • Severe Visual Loss [see Warnings and Precautions (5.5) ] • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥25%) in adult patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. ( 6.1 ) The most common adverse reactions (≥35%) in patients with ALCL are diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3–4 laboratory abnormalities (≥15%) are neutropenia, lymphopenia, and thrombocytopenia. ( 6.1 ) The most common adverse reactions (≥35%) in adult patients with IMT are vision disorders, nausea, and edema. ( 6.1 ) The most common adverse reactions (≥35%) in pediatric patients with IMT are vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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). 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 9 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/m 2 with cisplatin 75 mg/m 2 (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 XALKO

7 DRUG INTERACTIONS • Strong CYP3A Inhibitors: Avoid concomitant use. ( 2.9 , 7.1 ) • Strong CYP3A Inducers: Avoid concomitant use. ( 7.1 ) • CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious adverse reactions. ( 7.2 ) 7.1 Effect of Other Drugs on XALKORI 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 (2.9) ] . 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. 7.2 Effect of XALKORI on Other Drugs 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. 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) ] .