Professor Martin Schuler MD West German Cancer Center Essen, Germany Right patient, right treatment: Insights in EGFR mutation-positive NSCLC Professor Martin Schuler MD West German Cancer Center Essen, Germany

Question: What is your current standard-of-care in the first-line treatment of patients with Del19 NSCLC? Afatinib* Chemotherapy Erlotinib Gefitinib Other *Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada, under the brand name GIOTRIF® and in the USA under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.

Question: What is your current standard-of-care in the first-line treatment of patients with L858R NSCLC? Afatinib Chemotherapy Erlotinib Gefitinib Other

Afatinib: An irreversible ErbB family blocker Molecular potency and selectivity IC50 (nM) EGFR 0.5 HER2 14 ErbB4 1 HGFR >10,000 VEGFR2 >100,000 Li D, et al. Oncogene 2008;27:4702–11; Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50; Yang J, et al. Lancet Oncol 2012;13:539–48

First-generation EGFR TKIs: Clinical benefits in EGFR mutation-positive NSCLC, although no OS benefits Trial EGFR TKI EGFR mutation ORR (%) PFS (months) OS (months) IPASS1,2,3 Gefitinib 261* 71 vs 47 p<0.001 9.5 vs 6.3 HR 0.48 (0.36–0.64) 21.6 vs 21.9 HR 1.00 (0.76–1.33) NEJGSG-0024,5 224 74 vs 31 p<0.001 10.8 vs 5.4 HR 0.32 (0.24–0.44) 27.7 vs 26.6 HR 0.89 (0.63–1.24) WJTOG34056,7 172 62 vs 32 p<0.0001 9.2 vs 6.3 HR 0.49 (0.34–0.71) 34.8 vs 37.3 HR 1.25 (0.88–1.78) OPTIMAL8,9 Erlotinib 154 83 vs 36 p<0.0001 13.1 vs 4.6 HR 0.16 (0.10–0.26) 22.8 vs 27.2 HR 1.19 (0.83–1.71) EURTAC10 173 65 vs 16 10.4 vs 5.2 HR 0.34 (0.23–0.49) 22.9 vs 19.5 HR 0.93 (0.64–1.35) ENSURE11 217 63 vs 34 11.0 vs 5.5 HR 0.34 (0.22–0.51) 26.3 vs 25.5 HR 0.91 (0.63–1.31) Rosell et al. Lancet Oncol 2012;13:239 Khozin et al. Oncologists 2014;19:774 Wu et al. Ann Oncol 2015;pii:mdv270 (epub ahead of print); ENSURE *Out of a total of 1217 patients. 1. Mok T, et al. N Engl J Med 2009;361:947–57; 2. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 3.Yang J, et al. Eur J Cancer 2011;47:S633–4; 4. Maemondo M, et al. New Engl J Med 2010;362:2380–8; 5. Inoue A, et al. Ann Oncol 2013;24:54–59; 6. Mitsudomi T, et al. Lancet Oncol 2010;11:121–28; 7. Yoshioka, H et al. ASCO 2014. Poster 8117; 8. Zhou C, et al. Lancet Oncol 2011;12:735–42; 9. Zhou C, et al. Ann Oncol 2015;26:1877–83; 10. Khozin S, et al. Oncologist 2014;19:774–9; 11. Wu Y, et al. Ann Oncol 2015;pii:mdv270 [Epub ahead of print]

First-generation EGFR TKIs: Efficacy by mutational status (Del 19 vs L858R) Trial EGFR TKI EGFR mutation ORR (%) PFS (months) OS (HR, 95% CI) Del 19 L858R IPASS1,2 Gefitinib 261* 84.8 60.9 11.0 9.2 0.79 (0.54–1.15) 1.44 (0.90–2.30) NEJGSG-0023,4 224 82.8 67.3 11.5 10.8 0.83 (0.52–1.34) 0.82 (0.49–1.38) OPTIMAL5,6 Erlotinib 154 - 15.3 12.5 1.52 (0.91–2.52) 0.92 (0.55–1.54) EURTAC7,8 173 8.4 0.94 (0.57–1.54) 0.99 (0.56–1.76) ENSURE9 217 11.1 8.3 0.79 (0.48–1.30) 1.05 (0.60–1.84) *Out of a total of 1217 patients; -, not available or reported. 1. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 2.Yang J, et al. Eur J Cancer 2011;47:S633–4; 3. Maemondo M, et al. New Engl J Med 2010;362:2380–8; 4. Inoue A, et al. ASCO 2011. Poster 7519; 5. Wu Y, et al. Ann Oncol 2010;21:LBA14; 6. Zhou C, et al. Ann Oncol 2015;26:1877–83; 7. Rosell R, et al. Lancet Oncol 2012;13:239–46; 8. Khozin S, et al. Oncologist 2014;19:774–9; 9. Wu Y, et al. Ann Oncol 2015;pii:mdv270 [Epub ahead of print]

Preplanned OS analysis of LUX-Lung 3: Mutation subgroups Del19 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 Estimated OS probability 30 33 36 39 42 45 48 51 Afatinib Cis/Pem No. at risk: Afatinib 112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 Cis/Gem 57 55 50 46 43 37 33 27 25 22 20 16 10 Time of overall survival (months) Del19 L858R Afatinib (n=112) Cis/Pem (n=57) Afatinib (n=91) Cis/Pem (n=47) Median, months 33.3 21.1 27.6 40.3 HR (95% CI) p value 0.54 (0.36–0.79) p=0.0015 1.30* (0.80–2.11) p=0.29 *HR 1.02 (0.62–1.69) when adjusted for baseline imbalances. Yang J, et al. Lancet Oncol 2015;16:141–51

Preplanned OS analysis of LUX-Lung 6: Mutation subgroups Del19 1.0 Afatinib Cis/Gem 0.8 0.6 Estimated OS probability 0.4 0.2 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 No. at risk: Afatinib 124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 Cis/Gem 62 58 53 49 44 35 30 28 26 21 18 11 4 3 Time of overall survival (months) Del19 L858R Afatinib (n=124) Cis/Gem (n=62) Afatinib (n=92) Cis/Gem (n=46) Median, months 31.4 18.4 19.6 24.3 HR (95% CI) p value 0.64 (0.44–0.94) p=0.023 1.22 (0.81–1.83) p=0.34 Yang J, et al. Lancet Oncol 2015;16:141–51

Key practical considerations in the management of EGFR mutation positive NSCLC

What would you do? Newly diagnosed advanced or metastatic NSCLC (adeno) not suitable for surgical resection 1) Start chemotherapy immediately? 2) Perform biomarker analysis and treat based on analysis results?

What would you do? Newly diagnosed advanced or metastatic NSCLC (adeno) not suitable for surgical resection 1) Start chemotherapy immediately? 2) Perform biomarker analysis and treat based on analysis results? Therascreen EGFR PCR test turnaround time:1 4.9 business days (95% CI 4.5–5.5 days) Actual time from the test request to the result: 17.8 days (95% CI 16.4–19.4 days) 1. https://www.nice.org.uk/guidance/dg9/chapter/5-Outcomes(Accessed 20 August 2015)

Quality-of-life/symptom improvement Convenience Other Question: What is the key factor determining your therapy choice in first-line EGFR mutation-positive NSCLC? Efficacy Safety Quality-of-life/symptom improvement Convenience Other

Afatinib plasma levels: Patients with and without dose reduction Dose reduction was more likely in patients with higher plasma concentrations 140 120 100 80 60 40 20 Trough plasma concentrations (ng/mL) C3V1 (Day 43) 40 mg (n=126) 30 mg (n=38) C2V1 (Day 22) 40 mg (n=122) 40 mg (n=10) Individual data with median and 25th/75th percentiles 10th/90th percentiles Data points outside percentiles After dose reduction to 30 mg ≥4 days previously (n=38) Patients who remained on 40 mg (n=126) Geometric mean plasma concentrations 24.4 ng/mL 23.7 ng/mL Patients who remained on 40 mg until C3V1 (n=126) Patients whose dose was reduced to 30 mg before C3V1 (n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1. The rest had either no PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling). Yang J, et al. J Clin Oncol 2015;(Suppl.). Abstract 8073

Tolerability-guided dose modification and PFS Median PFS similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily Time (months) 1.0 0.6 0.4 0.2 Estimated PFS probability 3 6 9 12 15 18 21 24 27 0.8 <40 mg in first 6 months ≥40 mg in first 6 months No. at risk <40 mg in first 6 months 105 87 75 58 41 26 15 6 2 ≥40 mg for first 6 months 124 93 76 62 36 24 16 4 1 <40 mg in first 6 months (n=105) ≥40 mg for first 6 months (n=124) Median PFS, months 11.3 11.0 HR (95% CI); p value 1.25 (0.91–1.72); 0.175 CI, confidence interval; HR, hazard ratio. Yang J, et al. J Clin Oncol 2015;(Suppl.). Abstract 8073

Summary and conclusion First-generation EGFR TKIs have provided significant clinical benefits to patients with EGFR mutation-positive NSCLC. However, no OS advantage has been formally demonstrated so far First-line afatinib significantly improved OS vs chemotherapy in EGFR Del19 patients in two randomised trials LUX-Lung 3: median 33.3 vs 21.1 months, HR 0.54, p=0.0015 LUX-Lung 6: median 31.4 vs 18.4 months, HR 0.64, p=0.023 No significant difference in OS of patients with L858R mutations treated with afatinib, individually, or in exploratory combined analysis However, benefit in PFS, ORR and PRO have been demonstrated in LUX-Lung 3 and 6 Afatinib also showed robust activity in patients with most frequent uncommon EGFR mutations including those with point mutations or duplications in exons 18–21 (ORR 71.1%, PFS 10.7 months, OS 19.4 months) Certain practical considerations may be important in maximising benefit in first-line treatment of patients with EGFR mutation+ NSCLC and should be kept in mind when managing these patients

Questions and discussion