Necitumumab

1 INDICATIONS AND USAGE PORTRAZZA™ is an epidermal growth factor receptor (EGFR) antagonist indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer. ( 1.1 ) Limitation of Use: PORTRAZZA is not indicated for treatment of non-squamous non-small cell lung cancer. ( 1.2 , 5.6 , 14.2 ) 1.1 Squamous Non-Small Cell Lung Cancer (NSCLC) PORTRAZZA™ is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer. 1.2 Limitation of Use PORTRAZZA is not indicated for treatment of non-squamous non-small cell lung cancer [see Warnings and Precautions ( 5.6 ) and Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION Recommended dose of PORTRAZZA is 800 mg (absolute dose) as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle. ( 2.1 ) 2.1 Recommended Dose and Schedule The recommended dose of PORTRAZZA is 800 mg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion. Continue PORTRAZZA until disease progression or unacceptable toxicity. 2.2 Premedication For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent PORTRAZZA infusions [see Dosage and Administration ( 2.3 )] . For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each PORTRAZZA infusion [see Dosage and Administration ( 2.3 )] . 2.3 Dose Modifications Infusion-Related Reactions (IRR) Reduce the infusion rate of PORTRAZZA by 50% for Grade 1 IRR [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.5 )] . Stop the infusion for Grade 2 IRR until signs and symptoms have resolved to Grade 0 or 1; resume PORTRAZZA at 50% reduced rate for all subsequent infusions [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.5 )] . Permanently discontinue PORTRAZZA for Grade 3 or 4 IRR [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.5 )] . Dermatologic Toxicity Withhold PORTRAZZA for Grade 3 rash or acneiform rash until symptoms resolve to Grade ≤2, then resume PORTRAZZA at reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles. Permanently discontinue PORTRAZZA if: - Grade 3 rash or acneiform rash do not resolve to Grade ≤2 within 6 weeks, - Reactions worsen or become intolerable at a dose of 400 mg - Patient experiences Grade 3 skin induration/fibrosis [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )] or - Grade 4 dermatologic toxicity [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )] . 2.4 Preparation for Administration Inspect vial contents for particulate matter and discoloration prior to dilution [see Description ( 11 )] . Discard the vial if particulate matter or discoloration is identified. Store vials in a refrigerator at 2° to 8°C (36˚ to 46˚F) until time of use. Keep the vial in the outer carton in order to protect from light [see How Supplied/Storage and Handling ( 16.2 )] . Dilute the required volume of PORTRAZZA with 0.9% Sodium Chloride Injection, USP in an intravenous infusion container to a final volume of 250 mL. Do not use solutions containing dextrose. Gently invert the container to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medication. Store diluted infusion solution for no more than 24 hours at 2° to 8°C (36° to 46°F), or no more than 4 hours at room temperature (up to 25°C [77°F]). Discard vial with any unused portion of PORTRAZZA. 2.5 Administration Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discoloration is identified, discard the solution. Administer diluted PORTRAZZA infusion via infusion pump over 60 minutes through a separate infusion line. Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion.

6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: Cardiopulmonary Arrest [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Hypomagnesemia [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Venous and Arterial Thromboembolic Events [see Warnings and Precautions ( 5.3 )] . Dermatologic Toxicities [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.4 )] . Infusion-Related Reactions [see Dosage and Administration ( 2.2 , 2.3 ) and Warnings and Precautions ( 5.5 )] . Non-Squamous NSCLC - Increased Toxicity and Increased Mortality [see Warnings and Precautions ( 5.6 ) and Clinical Studies ( 14.2 )] . The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of ≥30% and ≥2% higher than gemcitabine and cisplatin alone arm were rash and hypomagnesemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) 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 practice. The safety of PORTRAZZA was evaluated in two randomized, open-label trials comparing PORTRAZZA plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and PORTRAZZA plus pemetrexed and cisplatin to pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2). Since the data in Study 2 demonstrated similar incidence of adverse reactions over control as observed in Study 1, the safety data from Study 1 alone is described below. For patients who received at least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to 84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had metastatic disease in 2 or more sites. Patients received PORTRAZZA 800 mg intravenously on days 1 and 8 of each 21 day cycle in combination with up to six cycles of gemcitabine (1250 mg/m 2 on days 1 and 8) and cisplatin (75 mg/m 2 on day 1). Patients received PORTRAZZA until progressive disease or unacceptable toxicity. Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the PORTRAZZA plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of PORTRAZZA until disease progression or unacceptable toxicity. The median duration of exposure to PORTRAZZA in 538 patients who received at least 1 dose of treatment in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182 patients exposed for at least 6 months and 41 patients exposed for greater than 1 year. Patients were monitored for safety until 30 days after treatment discontinuation and resolution of treatment-emergent adverse events. The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of ≥15% and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting (29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe (Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in PORTRAZZA-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%). Table 1 contains selected adverse drug reactions observed in Study 1 at an incidence of ≥5% in the PORTRAZZA arm and at ≥2% higher incidence than the control arm. Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% All Grades or a ≥2% Grade 3-4 Difference Between Arms in Patients Receiving PORTRAZZA in Study 1 a Pulmonary embolism is also included in the composite term venous thromboembolic events under system organ class vascular disorders. b VTE is a composite term which includes: pulmonary embolism, deep vein thrombosis, thrombosis, mesenteric veins thrombosis, pulmonary artery thrombosis, pulmonary venous thrombosis, venous thrombosis limb, axillary vein thrombosis, thrombophlebitis, thrombosis in device, vena cava thrombosis, venous thrombosis, subclavian vein thrombosis, superior vena cava syndrome, and thrombophlebitis superficial. c Conjunctivitis is a composite term that includes conjunctivitis, eye irritation, vision blurred, conjunctivitis bacterial, dry eye, visual acuity reduced, blepharitis, allergic blepharitis, conjunctiva hemorrhage, eye infection, eye pain, lacrimation increased, ocular hyperemia, Sjogren's syndrome, visual impairment, and eye pruritus. Adverse Reactions (MedDRA) System Organ Class PORTRAZZA PLUS GEMCITABINE AND CISPLATIN N=538 (%) GEMCITABINE AND CISPLATIN N=541 (%) All Grades (Frequency %) Grade 3-4 (Frequency %) All Grades (Frequency %) Grade 3-4 (Frequency %) Skin and Subcutaneous Tissue Disorders Rash 44 4 6 0.2 Dermatitis Acneiform 15 1 0.6 0 Acne 9 0.4 0.6 0 Pruritus 7 0.2 0.9 0.2 Dry Skin 7 0 1 0 Skin fissures 5 0.4 0 0 Gastrointestinal Disorders Vomiting 29 3 25 0.9 Diarrhea 16 2 11 1 Stomatitis 11 1 6 0.6 Investigations Weight decreased 13 0.7 6 0.6 Respiratory, Thoracic and Mediastinal Disorders Hemoptysis 10 1 5 0.9 Pulmonary embolism a 5 4 2 2 Nervous System Disorders Headache 11 0 6 0.4 Vascular Disorders Venous Thromboembolic Events (VTE) b 9 5 5 3 Infections and Infestations Paronychia 7 0.4 0.2 0 Eye Disorders Conjunctivitis c 7 0.4 2 0 Clinically relevant adverse reactions (all grades) reported in ≥1% and <5% of patients treated with PORTRAZZA were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRR (1.5%). In Study 1, 12% of the patients on the PORTRAZZA arm discontinued study treatment due to an adverse reaction. The most common PORTRAZZA related toxicity leading to PORTRAZZA discontinuation was skin rash (1%). Table 2 contains selected electrolyte abnormalities observed in Study 1 according to laboratory assessment at an incidence of >10% in the PORTRAZZA arm and at >2% higher incidence than the control arm. The median time to onset of hypomagnesemia was 6 weeks (25 th percentile 4 weeks; 75 th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received PORTRAZZA. In Study 1, 32% of the patients in the PORTRAZZA arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement. Table 2: Electrolyte Abnormalities according to Laboratory Assessment at Incidence Rate >10% and a >2% Difference between Arms in Patients Receiving PORTRAZZA in Study 1 a a Only patients with baseline and at least one post-baseline result are included. LABORATORY PARAMETER PORTRAZZA PLUS GEMCITABINE AND CISPLATIN N=538 GEMCITABINE AND CISPLATIN N=541 N a All Grades (Frequency %) Grade 3 or 4 (Frequency %) N a All Grades (Frequency %) Grade 3 or 4 (Frequency %) Hypomagnesemia 461 83 20 457 70 7 Hypokalemia 505 28 5 505 18 3 Hypocalcemia 502 45 6 499 30 2 Hypocalcemia (albumin corrected) 477 36 4 480 23 2 Hypophosphatemia 462 31 8 454 23 6 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to PORTRAZZA. No relationship was found between the presence of ADA and incidence of infusion-related reactions. The impact of ADA on efficacy (overall survival) could not be assessed due to the limited number of patients with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower in patients with ADA post-treatment than in patients without detectable ADA [see Clinical Pharmacology ( 12.3 )] . The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to PORTRAZZA with the incidences of antibodies to other products may be misleading.

12.3 Pharmacokinetics Based on population pharmacokinetic (popPK) analysis of serum concentration data from patients in clinical studies with PORTRAZZA, necitumumab exhibits dose-dependent kinetics. Following the administration of PORTRAZZA 800 mg on Days 1 and 8 of each 21 day cycle, the estimated mean total systemic clearance (CL tot ) at steady state is 14.1 mL/h (CV=39%), the steady state volume of distribution (V ss ) is 7.0 L (CV=31%) and the elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days. Specific Populations Effect of Age, Body Weight, Sex and Race: Based on the popPK analysis with data obtained in 807 patients, age (range 19-84 years), sex (75% males), and race (85% Whites) have no effect on the systemic exposure of necitumumab. Body weight is identified as a covariate in the popPK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is necessary. Renal Impairment Patients with Renal Impairment — PopPK analysis did not identify a correlation between necitumumab exposure and renal function as assessed by estimated creatinine clearance ranging from 11-250 mL/min. Hepatic Impairment Patients with Hepatic Impairment — PopPK analysis did not identify a correlation between the exposure of necitumumab and hepatic function as assessed by alanine aminotransferase (ranging from 2-615 U/L), aspartate transaminase (ranging from 1.2-619 U/L) and total bilirubin (ranging from 0.1-106 μmol/L). Drug Interactions Effect of Necitumumab on Gemcitabine and Cisplatin In 12 patients with advanced solid tumors who received gemcitabine and cisplatin in combination with PORTRAZZA, the geometric mean dose-normalized AUC of gemcitabine was increased by 22% and C max increased by 63% compared to administration of gemcitabine and cisplatin alone while exposure to cisplatin was unchanged. Effect of Gemcitabine and Cisplatin on Necitumumab Concomitant administration of gemcitabine and cisplatin had no effect on the exposure of necitumumab. Immunogenicity In Study 1, the CL tot of necitumumab was 26% higher and C ss,ave was 34% lower in patients who tested positive for anti-necitumumab antibodies (ADA) post-treatment than patients who tested negative for ADA post-treatment.