Afatinib

12.1 Mechanism of Action Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2. Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

1 INDICATIONS AND USAGE GILOTRIF is a kinase inhibitor indicated for: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test ( 1.1 ) Limitations of Use : Safety and efficacy of GILOTRIF were not established in patients whose tumors have resistant EGFR mutations ( 1.1 ) Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy ( 1.2 ) 1.1 EGFR Mutation-Positive, Metastatic Non-Small Cell Lung Cancer GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test [see Dosage and Administration (2.1) , Clinical Pharmacology (12.1) , Clinical Studies (14.1) ]. Limitations of Use : The safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations [see Clinical Studies (14.1) ]. 1.2 Previously Treated, Metastatic Squamous NSCLC GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy .

2 DOSAGE AND ADMINISTRATION Recommended dosage : 40 mg orally once daily ( 2.2 ) Renal impairment : 30 mg orally once daily in patients with severe renal impairment ( 2.4 , 8.6 , 12.3 ) Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal ( 2.2 ) 2.1 Patient Selection for Non-Resistant EGFR Mutation-Positive Metastatic NSCLC Select patients for first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of non-resistant EGFR mutations in tumor specimens [see Clinical Pharmacology (12.1) , Clinical Studies (14.1) ]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage The recommended dosage of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take GILOTRIF at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. 2.3 Dosage Modifications for Adverse Reactions Withhold GILOTRIF for: Grade* 3 or higher adverse reactions Diarrhea of Grade 2 persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions (5.1) ] Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2) ] * National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 3.0 Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute GILOTRIF at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred. Permanently discontinue GILOTRIF for: Life-threatening bullous, blistering, or exfoliating skin lesions [see Warnings and Precautions (5.2) ] Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3) ] Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4) ] Gastrointestinal perforation [see Warnings and Precautions (5.5) ] Persistent ulcerative keratitis [see Warnings and Precautions (5.6) ] Symptomatic left ventricular dysfunction [see Adverse Reactions (6.1) ] Severe or intolerable adverse reaction occurring at a dose of 20 mg per day 2.4 Dosage Modification for Pre-Existing Severe Renal Impairment The recommended dosage of GILOTRIF in patients with pre-existing severe renal impairment (estimated glomerular filtration rate [eGFR*] 15 to 29 mL/min /1.73 m 2 ) is 30 mg orally once daily [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . * Use the Modification of Diet in Renal Disease [MDRD] formula to estimate eGFR. 2.5 Dosage Modifications for Drug Interactions P-glycoprotein Inhibitors Reduce GILOTRIF daily dose by 10 mg if not tolerated for patients who require therapy with a P-glycoprotein (P-gp) inhibitor. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] . P-glycoprotein Inducers Increase GILOTRIF daily dose by 10 mg as tolerated for patients who require chronic therapy with a P-gp inducer. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Diarrhea [see Warnings and Precautions (5.1) ] Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2) ] Interstitial Lung Disease [see Warnings and Precautions (5.3) ] Hepatic Toxicity [see Warnings and Precautions (5.4) ] Gastrointestinal Perforation [see Warnings and Precautions (5.5) ] Keratitis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥20%) were diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 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 data in the Warnings and Precautions section reflect exposure to GILOTRIF for clinically significant adverse reactions in 4257 patients enrolled in LUX-Lung 3 (n=229) and LUX-Lung 8 (n=392), and 3636 patients with cancer enrolled in 42 studies of GILOTRIF administered alone or in combination with other anti-neoplastic drugs at GILOTRIF doses ranging from 10-70 mg daily or at doses 10-160 mg in other regimens. The mean exposure was 5.5 months. The population included patients with various cancers, the most common of which were NSCLC, breast, colorectal, brain, and head and neck. The data described below reflect exposure to GILOTRIF as a single agent in LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. EGFR Mutation-Positive Metastatic NSCLC The safety of GILOTRIF was evaluated in 229 EGFR-tyrosine kinase inhibitor-naïve patients with EGFR mutation-positive, metastatic non-squamous NSCLC enrolled in a randomized (2:1), multicenter, open-label trial (LUX-Lung 3). Patients received either GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy or pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses. The median exposure was 11 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%). Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in LUX-Lung 3 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%). Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%). Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all <Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). Tables 1 and 2 summarize common adverse reactions and laboratory abnormalities in LUX-Lung 3. Table 1 Adverse Reactions Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 3* Adverse Reaction GILOTRIF n=229 Pemetrexed/Cisplatin n=111 All Grades (%) Grade 3 † (%) All Grades (%) Grade 3 † (%) *NCI CTCAE v 3.0 † None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity. 1 Includes stomatitis, aphtho

7 DRUG INTERACTIONS P-glycoprotein (P-gp) Inhibitors : Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce GILOTRIF by 10 mg per day if not tolerated. ( 2.5 , 7 ) P-gp Inducers : Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated. ( 2.5 , 7 ) Effect of P-glycoprotein (P-gp) Inhibitors and Inducers Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib [see Clinical Pharmacology (12.3) ]. Reduce GILOTRIF daily dose as recommended [see Dosage and Administration (2.5) ]. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) with GILOTRIF can decrease exposure to afatinib [see Clinical Pharmacology (12.3) ]. Increase GILOTRIF daily dose as recommended [see Dosage and Administration (2.5) ].