EXPLORE THE BODY OF EVIDENCE GILOTRIF: For the first step in the treatment of mNSCLC with Del 19 and L858R EGFR mutations mNSCLC=metastatic non-small cell lung cancer; FDA=US Food and Drug Administration. INDICATIONS AND USAGE GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. Please see Important Safety Information starting on page 2. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. FOR THE 1ST-LINE TREATMENT OF EGFR M+ mNSCLC VS CHEMOTHERAPY GILOTRIF: Only agent with proven overall survival in patients with Del 19 mutations1-3 Median OS in LUX-Lung 3 Del 19 mutations populationa,b 100 Overall survival (%) 80 GILOTRIF (40 mg orally once daily; n=112) Pemetrexed/cisplatin (500 mg/m2 / 75 mg/m2 every 3 weeks, up to 6 cycles; n=57) 33.3 HR: 0.55 (95% CI, 0.36-0.79) months 60 45% reduction in risk of death 40 21.1 months 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time of overall survival (months) In a prespecified subgroup analysis of patients with Del 19 mutations for the secondary endpoint of OS. Measured by an independent central radiology review. a b OS=overall survival; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival. Primary endpoint: Median PFS for Del 19 mutations (n=170)1,4,5 13.7 MONTHS GILOTRIF Pemetrexed/ cisplatin 5.6 MONTHS 0 2 4 6 8 Time (months) 10 12 14 16 HR: 0.28 (95% CI, 0.18-0.44) SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Diarrhea •GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal. •For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose. •Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 2 FOR THE 1ST-LINE TREATMENT OF mNSCLC WITH L858R EGFR MUTATIONS GILOTRIF: Approved treatment option for patients with L858R1,2 Median OS in LUX-Lung 3 L858R mutation populationa,b 100 40.3 months Overall survival (%) 80 60 40 GILOTRIF (40 mg orally once daily; n=91) Pemetrexed/cisplatin (500 mg/m2 / 75 mg/m2 every 3 weeks, up to 6 cycles; n=47) 20 27.6 13.6 months months HR:1.30 (95% CI, 0.80-2.11) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time of overall survival (months) In a prespecified subgroup analysis of patients with L858R mutations for the secondary endpoint of OS. Measured by an independent central radiology review. a b Primary endpoint: Median PFS for L858R (exon 21) mutations (n=138)1,4,5 10.8 MONTHS GILOTRIF Pemetrexed/ cisplatin 8.1 MONTHS 0 2 4 6 8 Time (months) 10 12 14 16 HR: 0.73 (95% CI, 0.46-1.17) SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Bullous and Exfoliative Skin Disorders •GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF. •Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 3 GILOTRIF: Established safety profile Adverse reactions reported in LUX-Lung 3 in ≥10% of GILOTRIF-treated patients1 Adverse reaction GILOTRIF (n=229) Pemetrexed/cisplatin (n=111) All grades, % Grade 3a, % All grades, % Grade 3a, % Gastrointestinal disorders Diarrhea Stomatitisb Cheilitis 96 71 12 15 9 0 23 15 1 2 1 0 Skin and subcutaneous tissue disorders Rash/acneiform dermatitisc Pruritus Dry skin 90 21 31 16 0 0 11 1 2 0 0 0 Infections Paronychiad Cystitis 58 13 11 1 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis Rhinorrhea 17 11 0 0 2 6 1 0 Investigations Weight decreased 17 1 14 1 General disorders and administration site conditions Pyrexia 12 0 6 0 Eye disorders Conjunctivitis 11 0 3 0 Other clinically important adverse reactions observed in patients treated with GILOTRIF include: decreased appetite (29%), nausea (25%), and vomiting (23%).1 None of the adverse reactions in this table except stomatitis (1 patient on GILOTRIF [0.4%]) were grade 4 in severity. Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration. c Includes acne, acne pustular, dermatitis, acneiform dermatitis, dermatosis, drug eruption, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin disorder, skin erosion, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer. d Includes paronychia, nail infection, nail bed infection. a b SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Bullous and Exfoliative Skin Disorders (continued) •Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 4 GILOTRIF: The most common adverse reactions can usually be managed through supportive care, dose modifications, and discontinuations1,6-8 •The onset of diarrhea and skin reactions often occurs within the first 14 days of treatment –83% of patients experienced diarrhea5 –64% of patients experienced rash/acne5 Serious adverse reactions1 •In LUX-Lung 3, 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 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%) Discontinuations •In LUX-Lung 3, discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14%1 •The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%)1 SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Interstitial Lung Disease •Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients. •Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 5 The most common adverse reactions—diarrhea, rash, stomatitis, and paronychia—can usually be managed through supportive care, dose modifications (including treatment interruptions), and discontinuations Supportive care Diarrhea Rash/Acne •Ensure adequate hydration8 •Use antidiarrheal agents (eg, loperamide) as appropriate1 •Make antidiarrheal agents readily available to patients so that treatment can be initiated at first signs of diarrhea and continued until loose bowel movements cease for 12 hours1 •Advise patients to wear protective clothing and/or use sunscreen to minimize exposure to sun8 •Intervene early with emollients, and topical steroids and/or antibiotics, as appropriate8 •Consider additional therapeutic intervention for patients with severe or prolonged skin reactions8 Stomatitis Paronychia •Provide palliation through bland saline rinses, topical lidocaine anesthetics, mucosal coating agents, and analgesics; the choice being driven by patient preference6 •Consider treating paronychia with silver nitrate or ferric subsulfate solution, with soaks for symptomatic relief. If infection is suspected, culture sites and treat with appropriate oral antibiotics7 SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hepatic Toxicity •Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal. •Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Treatment should be discontinued in patients who develop severe hepatic impairment while taking GILOTRIF. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 6 GILOTRIF: Dose modification1,4 Initiate therapy at the recommended 40-mg dose* Evaluate patients for adverse reactions within 2 weeks and periodically thereafter Pause Resume treatment for ≥ grade 3 adverse reactions or ≥ grade 2 •diarrhea (prolonged)a,b •cutaneous reactions (prolonged or intolerable)a,c •renal impairment treatment at 10 mg less per day when adverse reaction fully resolves, returns to baseline, or improves to grade 1 *In patients with severe renal impairment, the recommended dose of GILOTRIF is 30 mg orally once daily. National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0. Grade ≥2 diarrhea persisting ≥48 hours while taking antidiarrheal medication. c Grade 2 cutaneous reactions >7 days. a b Permanently discontinue GILOTRIF for1: Life-threatening bullous, blistering, or exfoliative skin lesions; confirmed ILD; severe drug-induced hepatic impairment; persistent ulcerative keratitis; symptomatic left ventricular dysfunction; and severe or intolerable adverse reaction occurring at a dose of 20 mg per day. SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Keratitis •Keratitis has been reported in patients taking GILOTRIF. •Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 7 Supportive care, including dose modification, is an important consideration when managing patients LUX-Lung 3: Over half of patients reduced dose1,5 43 % MAINTAINED 40-MG STARTING DOSE 38 % REDUCED TO 30 MG 19 % FURTHER REDUCED TO 20 MG The majority of first dose reductions in LUX-Lung 3 occurred within the first 2 months of GILOTRIF treatment5 •LUX-Lung 3 included patients who remained on therapy at the recommended 40-mg once-daily dose, and patients who started at the recommended dose, but subsequently required dose reductions9 SELECTED IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity •GILOTRIF can cause fetal harm when administered to a pregnant woman. 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, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 8 GILOTRIF: Selected grade 3 adverse reactions before and after dose modification Grade 3 adverse reactions with dose modification1,10 25 Reported in ≥10% of all patients After dose modification 20 Percent of patients *Includes 1 patient with a grade 4 event. 15 10 5 0 Diarrhea Rash/Acne Stomatitis* Paronychia Treatment-related grade 3 adverse reactions •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%)1 In a post hoc analysis, PFS results were consistent among patients who required dose reductions within the first 6 months and those who remained on GILOTRIF 40 mg9 SELECTED IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS Adverse Reactions observed in clinical trials were as follows: First-line treatment of EGFR mutation-positive, metastatic non-small cell lung cancer (NSCLC) •In GILOTRIF-treated patients (n=229) the most common adverse reactions (≥20% all grades & vs pemetrexed/ cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/acneiform dermatitis (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), and pruritus (21% vs 1%). Other clinically important adverse reactions observed in patients treated with GILOTRIF include: decreased appetite (29%), nausea (25%), and vomiting (23%). •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 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). •More GILOTRIF-treated patients (2.2%) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%). Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 9 IN ADVANCED SQUAMOUS CELL CARCINOMA OF THE LUNG GILOTRIF: Significantly improved survival vs erlotinib1 Median OS: 7.9 months with GILOTRIF vs 6.8 months with erlotinib1 Overall survival (key secondary endpoint) GILOTRIF (n=398) Erlotinib (n=397) 100 7.9 13.6 months months Overall survival (%) 80 HR: 0.81 (95% CI, 0.69-0.95) 60 40 19% reduction in risk of death vs erlotinib 6.8 months 20 0 0 3 6 9 12 15 18 21 24 27 30 Time (months) GILOTRIF: Significantly improved PFS vs erlotinib •Median PFS: 2.4 months with afatinib vs 1.9 months with erlotinib (HR: 0.82; 95% CI, 0.68-0.99)1 •PFS benefit was consistent across clinically relevant subgroups11 LUX-Lung 8: •Randomized, multicenter, open-label, active-controlled study evaluating GILOTRIF in patients with metastatic squamous NSCLC with disease progression following ≥ 4 cycles of platinum-based chemotherapy •Patients were randomized (1:1) to receive GILOTRIF 40 mg or erlotinib 150 mg orally once daily until progression •Primary endpoint was PFS; secondary endpoints were OS, and objective response rate SELECTED IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS Adverse Reactions observed in clinical trials were as follows: Previously Treated Metastatic Squamous NSCLC •In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%). •Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%). Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 10 A similar proportion of patients had serious adverse reactions in each group11 •44% of patients in each treatment arm experienced serious adverse reactions11 Adverse reactions reported in LUX-Lung 8 in ≥10% of GILOTRIF-treated patients1 GILOTRIF (n=392) Erlotinib (n=395) Adverse reaction All grades, % Grade 3-4, % All grades, % Grade 3-4, % Gastrointestinal disorders Diarrhea Stomatitisa Nausea Vomiting 75 30 21 13 11 4 2 1 41 11 16 10 3 1 1 1 Skin and subcutaneous tissue disorders Rash/acneiform dermatitisb Pruritus 70 10 7 0 70 13 11 0 Infections Paronychiac 11 1 5 0 25 3 26 2 Metabolism and nutrition disorders Decreased appetite Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration. a Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer. b Includes paronychia, nail infection, nail bed infection. c Treatment-related discontinuation due to any adverse reactions was similar in both arms (20% vs 17% for GILOTRIF vs erlotinib)11 Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 20%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (4.1%) and rash/acne (2.6%).1 Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 11 GILOTRIF: 40-mg, once-daily dosing1 Patient selection •Select patients for the 1st-line treatment of mNSCLC with GILOTRIF based on the presence of Del 19 or L858R mutations in tumor specimens •Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics Recommended dose1 •The recommended dose is 40 mg orally once daily •In patients with severe renal impairment, the recommended dose of GILOTRIF is 30 mg orally once daily* *Estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2. How to take1 •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 Treatment duration1 •Treatment should be continued until disease progression or until no longer tolerated by the patient Multiple strengths1 •Multiple tablet strengths are available for dose adjustment GILOTRIF 40-mg tablet GILOTRIF 30-mg tablet GILOTRIF 20-mg tablet Not actual size. Not actual size. Not actual size. Please see information on dose modifications for drug-related adverse reactions on pages 6-9. SELECTED IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS Postmarketing Experience Pancreatitis has been reported during post-marketing use of GILOTRIF. The frequency and causal relationship of pancreatitis to GILOTRIF has not been established. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 12 Drug-drug interactions •GILOTRIF does not have a known impact on CYP450 enzymes1 •Cytochrome P450 liver enzymes (CYPs) metabolize ~90% of all medications12 •In vitro data indicated that drug-drug interactions with GILOTRIF due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely1 •GILOTRIF is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes1 •Interactions with proton pump inhibitors are unlikely, as GILOTRIF is not metabolized via CYP450 enzymes, and solubility of GILOTRIF is not affected by pH1,13 Effect of P-glycoprotein (P-gp) inhibitors and inducers1 •P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) can increase exposure to afatinib •P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) can decrease exposure to afatinib For patients who require therapy with a P-gp inhibitor or inducer1 •P-gp inhibitors –Reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated •P-gp inducers –Increase GILOTRIF daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer SELECTED IMPORTANT SAFETY INFORMATION DRUG INTERACTIONS Effect of P-glycoprotein (P-gp) Inhibitors and Inducers •Concomitant use 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. •Concomitant use 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. Please see additional Important Safety Information continued on following pages. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 13 Majority of patients in LUX-Lung 3 had Del 19 or L858R EGFR mutations1,14 Overall study population by mutation subtype1 49% Del 19 (exon 19) 11% Uncommon 40% L858R (exon 21) LUX-Lung 3: Largest global trial in EGFR M+ mNSCLC to date3 •Randomized, multicenter, open-label trial that assessed the safety and efficacy of GILOTRIF 40 mg orally once daily (n=230) vs up to 6 cycles of pemetrexed/cisplatin (n=115) as 1st-line therapy in patients with EGFR M+ mNSCLC1 •Primary endpoint was PFS; key secondary endpoint was OS4 Efficacy information in uncommon mutations (n=37)1 •There were 26 GILOTRIF-treated patients in the “other” (uncommon) EGFR mutations subgroup, which consisted of 9 unique mutation patterns1 •Median PFS: 2.8 months with GILOTRIF vs 9.9 months with pemetrexed/cisplatin (HR: 1.89; 95% CI, 0.84-4.28)1,15 •Median OS: 15.9 months with GILOTRIF vs 40.8 months with pemetrexed/cisplatin (HR: 2.35; 95% CI, 0.96-6.11)1,5 SELECTED IMPORTANT SAFETY INFORMATION USE IN SPECIFIC POPULATIONS Lactation •Because of the potential for serious adverse reactions in nursing infants from GILOTRIF, lactating women should not breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose. Females and Males of Reproductive Potential •GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible. Renal Impairment •Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis. Hepatic Impairment •GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated. GF PROF ISI July 2016 Please see additional Important Safety Information starting on page 2. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 14 TM ® ® For patients prescribed GILOTRIF, Solutions Plus® offers patient support from the start Enroll your patients in Solutions Plus® by calling 1-877-814-3915 from 8am-8pm ET To help with treatment initiation and continued adherence, all patients taking GILOTRIF will receive a Patient Support Kit Making patient support our priority by providing a broad range of access and clinical support solutions for patients who are prescribed GILOTRIF ` Access and Reimbursement Solutions for patients Clinical Support Solutions for patients •Coverage & reimbursement—assistance with benefit verification, prior authorizations, GILOTRIF Bridge*, denials, and appeals •Patient Support Kit—patient resources to help with treatment initiation and adherence •Financial support—Co-pay Assistance Program, alternative funding support, and BI Cares Foundation •Distribution—single, dedicated specialty pharmacy partner (Accredo®) and select on-site pharmacies •GILOTRIF Pledge™—patient and participating payers refunded for first month of therapy if eligible† patients discontinue before first refill •Nurse support—real-time patient education assistance from oncology-trained nurses to complement care •Pharmacy support—Accredo pharmacists are available 24/7 to answer questions related to GILOTRIF‡ •GILOTRIF Dose Exchange™—facilitates transition to new dose, eliminates additional GILOTRIF co-pay in a given month for eligible patients§ *For commercially and publicly insured patients treated with GILOTRIF who may experience a payer delay >5 days for the FDA-approved indication, or when a patient changes insurance and a treatment gap is expected. † For commercially insured patients serviced through Accredo who are participating in the Nurse Support Program. ‡ For patients serviced through Accredo. § GILOTRIF Dose ExchangeTM covers up to 2 dose modifications for patients serviced through Accredo or GILOTRIF Dispensing Network who have 9 or more tablets to exchange. Please see Important Safety Information starting on page 2. Click here for full Prescribing Information, including Patient Information. THINK DEL 19. THINK GILOTRIF. 15 IN 1ST-LINE EGFR M+ mNSCLC Identify Del 19. Prescribe GILOTRIF 1st-line EGFR NCCN CATEGORY ARs T 40 1st-line OS and PFS in Del 19, and PFS in L858R1,16 NCCN Category 1 recommendation •Afatinib (GILOTRIF) has an NCCN Category 1 recommendation for 1st-line treatment of mNSCLC patients with Del 19 or L858R mutations16 An established safety profile based on data from more than 4200 patients in clinical trials1 40-mg, once-daily dosing1* Solutions Plus®: Access and clinical support solutions for patients •bisolutionsplus.com or call a Patient Care Advocate at 1-877-814-3915 from 8am-8pm ET •Dedicated GILOTRIF team at Accredo® 1-844-569-2837 from 8:30am-7pm ET SqCC Significantly improved OS and PFS vs erlotinib in advanced squamous cell carcinoma of the lung progressing after platinum-based chemotherapy1 *In patients with severe renal impairment, the recommended dose of GILOTRIF is 30 mg orally once daily. INDICATIONS AND USAGE GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. Please see Important Safety Information starting on page 2. Click here for full Prescribing Information, including Patient Information. References: 1. Gilotrif® (afatinib) tablets Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; April 2016. 2. Yang JC-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-151. 3. Lee CK, Wu YL, Ding PN, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol. 2015;33(17):1958-1965. 4. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. 5. Data on file. Boehringer Ingelheim. CTR. 6. Bensinger W, Schubert M, Ang KK, et al. NCCN Task Force Report: prevention and management of mucositis in cancer care. J Natl Compr Canc Netw. 2008;6(suppl 1):S1-S21. 7. Burtness B, Anadkat M, Basti S, et al. NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw. 2009;7(suppl 1):S5-S21. 8. Hirsh V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol. 2011;18(3):126-138. 9. Yang J C-H, Ahn M-J, Dickgreber NJ, et al. Influence of dose adjustment on afatinib safety and efficacy in patients with advanced EGFR mutation-positive NSCLC. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29–June 2, 2015; Chicago, IL. 10. Yang JC, Sequist LV, O’Byrne KJ, et al. Epidermal growth factor receptor (EGFR)-mediated adverse events in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) treated with afatinib. Poster presented at: ECCO17-ESMO38-ESTRO32 European Cancer Congress; September 27–October 1, 2013; Amsterdam, The Netherlands. 11. Soria J-C, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16:897-907. 12. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396. 13. Peters S, Zimmermann S, Adjei AA. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions. Cancer Treat Rev. 2014;40(8):917-926. 14. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169-181. 15. Data on file. Boehringer Ingelheim. Other mutations PFS table. 16. National Comprehensive Cancer Network. 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