LUX-Lung 7: Head-to-Head Comparison of Afatinib vs Gefitinib in Chemotherapy-Naive Patients With Advanced EGFR-Mutant NSCLC Slideset on: Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non- small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577-589. NSCLC, non-small-cell lung cancer. This activity is supported by educational grants from Genentech, Lilly, and Novartis Pharmaceutical Corporation.

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Background: TKIs in Advanced EGFR-Mutant NSCLC First-line therapeutic options for pts diagnosed with advanced EGFR-mutant NSCLC include TKIs targeting EGFR[1,2] Randomized, head-to-head comparative trials lacking for TKIs Afatinib: second-generation, broad-spectrum TKI that irreversibly blocks signaling from ErbB family receptors[1-4] Gefitinib: first-generation TKI that reversibly inhibits EGFR signaling[1,2] Randomized, exploratory phase IIb LUX-Lung 7 trial compared afatinib vs gefitinib in chemotherapy-naive pts with advanced EGFR-mutant NSCLC[1] NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Park K, et al. Lancet Oncol. 2016;17:577-589. 2. Steuer CE, et al. Mol Aspects Med. 2015;45:67-73. 3. Li D, et al. Oncogene. 2008;27:4702-4711. 4. Solca F, et al. J Pharmacol Exp Ther. 2012;343:342-350. Slide credit: clinicaloptions.com

LUX-Lung 7: Phase IIb Study Schema Stratified by EGFR mutation (exon 19 deletion vs L858R) and brain metastases at baseline (yes vs no) Afatinib*† 40 mg PO QD (n = 160) Treatment-naive pts with stage IIIB or IV lung adenocarcinoma, exon 19 deletion or L858R EGFR mutations, ECOG PS 0-1, adequate organ function (N = 319) Treatment continued until PD or unacceptable toxicity Gefitinib†‡ 250 mg PO QD (n = 159) DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PS, performance status; QoL, quality of life; TEAE, treatment-emergent adverse events; TTF, time to treatment failure. *Dose escalation allowed to 50 mg in absence of TEAEs. †≤ 14 day treatment interruptions allowed. ‡Dose modifications allowed. Coprimary endpoints: PFS, TTF, OS Secondary endpoints: ORR, time to response, DoR, duration of disease control, tumor shrinkage, QoL Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

Median PFS, Mos (95% CI) 11.0 (10.6-12.9) 10.9 (9.1-11.5) LUX-Lung 7: PFS PFS significantly longer with afatinib vs gefitinib Afatinib benefit observed for most subgroups except light exsmokers (smoked < 15 pack-yrs, stopped > 1 yr prior to diagnosis) 100 Median PFS, Mos (95% CI) 11.0 (10.6-12.9) 10.9 (9.1-11.5) 12-Mo PFS*, % (95% CI) 47.4 (39.2-55.2) 41.3 (33.0-49.5) 24-Mo PFS*, % (95% CI) 17.6 (11.7-24.6) 7.6 (3.5-13.8) 80 Afatinib (n = 160) Gefitinib (n = 159) 60 HR: 0.73 (95% CI: 0.57-0.95; P = .017) 40 20 6 12 18 24 30 36 42 Mos *Estimated using exploratory Kaplan-Meier analyses. Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

LUX-Lung 7: PFS by Subgroup Median PFS, Mos (95% CI) HR (95% CI) P Value Events/Pts, n Afatinib Gefitinib EGFR mutation Leu858Arg Del19 Brain metastases Absent Present Baseline ECOG PS 1 Sex Men Women Age, yrs < 65 ≥ 65 Ethnic origin Non-Asian Asian Smoking history Never smoked Light ex-smoker* Other current or ex-smokers Total 102/133 144/186 204/268 42/51 63/98 183/221 99/122 147/197 131/177 115/142 105/137 141/182 161/212 35/40 50/67 246/319 10.9 (8.1-12.9) 12.7 (10.6-14.7) 12.7 (10.9-13.3) 7.2 (3.7-17.0) 11.0 (10.6-17.4) 11.0 (9.0-13.2) 10.9 (7.3-12.9) 12.8 (10.8-14.7) 11.0 (9.2-17.0) 11.0 (9.2-12.9) 12.7 (10.8-14.7) 11.0 (9.1-12.9) 9.2 (7.2-10.9) 17.0 (10.7-20.1) 11.0 (10.6-12.9) 10.8 (7.2-12.8) 11.0 (9.1-12.7) 10.9 (9.1-12.7) 7.4 (5.4-12.8) 12.8 (10.8-14.7) 10.5 (8.0-11.0) 10.8 (7.3-12.8) 10.9 (9.0-12.2) 9.2 (7.3-11.0) 11.4 (10.8-12.9) 10.6 (7.4-12.7) 11.0 (9.1-12.8) 10.9 (7.2-13.3) 9.1 (3.5-12.7) 10.9 (9.1-11.5) 0.71 (0.48-1.06) 0.76 (0.55-1.06) 0.74 (0.56-0.98) 0.76 (0.41-1.44) 0.89 (0.54-1.47) 0.71 (0.52-0.95) 0.88 (0.59-1.31) 0.65 (0.47-0.91) 0.68 (0.48-0.97) 0.85 (0.59-1.22) 0.72 (0.49-1.06) 0.76 (0.54-1.06) 0.80 (0.58-1.10) 1.09 (0.56-2.14) 0.48 (0.27-0.85) 0.73 (0.57-0.95) .809 .93 .43 .39 .309 .88 .083 ECOG, Eastern Cooperative Oncology Group; PS, performance status. 1/16 1/4 1 4 16 Slide credit: clinicaloptions.com Favors afatinib Favors gefitinib

LUX-Lung 7: Time-to-Treatment Failure TTF significantly longer with afatinib vs gefitinib Afatinib benefit observed for most subgroups except light exsmokers and pts without brain metastases 100 Median TTF, Mos (95% CI) 13.7 (11.9-15.0) 11.5 (10.1-13.1) 80 Afatinib (n = 160) Gefitinib (n = 159) 60 HR: 0.73 (95% CI: 0.58-0.92; P = .0073) 40 TTF, time to treatment failure. 20 6 12 18 24 30 36 42 Mos Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

LUX-Lung 7: Other Efficacy Outcomes Insufficient events to determine OS at time of analysis (194/213 planned events) Secondary efficacy outcome ORR significantly higher with afatinib vs gefitinib Parameter Afatinib (n = 160) Gefitinib (n = 159) P Value ORR, % 70 56 .0083 Median DoR, mos 10.1 8.4 -- DCR, % 91 87 .24 Duration of DC, mos 12.7 11.1 Pts with ≥ 50% tumor shrinkage, % 44 36 DC, disease control; DCR, disease control rate; DoR, duration of response; ORR, objective response rate; OS, overall survival. Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

LUX-Lung 7: Outcomes by EGFR Mutation Type Similar efficacy patterns for afatinib vs gefitinib regardless of EGFR mutation type Parameter Afatinib (n = 160) Gefitinib (n = 159) P Value PFS by EGFR mutation, mos L858R Exon 19 deletion 10.9 12.7 10.8 11.0 .086 .107 ORR by EGFR mutation, % 66 73 42 -- Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

LUX-Lung 7: Most Common AEs Safety profiles as expected for afatinib vs gefitinib Most Common Treatment-Related AEs, n (%) Afatinib (n = 160) Gefitinib (n = 159) Any Grade Grade ≥ 3 Any 156 (98) 50 (31) 153 (96) 29 (18) Diarrhea 144 (90) 20 (13) 97 (61) 2 (1) Rash or acne 142 (89) 15 (9) 129 (81) 5 (3) Stomatitis 103 (64) 7 (4) 38 (24) Paronychia 89 (56) 3 (2) 27 (17) 1 (1) Dry skin 52 (33) 59 (37) Pruritus 37 (23) 36 (23) Fatigue 33 (21) 9 (6) 23 (14) Increased ALT/AST 16 (10) 39 (25) 14 (9) AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase. Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

Conclusions and Faculty Assessment Afatinib conferred a significant outcome benefit vs gefitinib for chemotherapy-naive pts with advanced EGFR-mutant NSCLC Median PFS: 11.0 vs 10.9 mos (P = .017); median TTF: 13.7 vs 11.5 mos (P = .0073); ORR: 70% vs 56% (P = .0083) Efficacy patterns similar for common EGFR mutation types Safety profiles as expected; both agents well tolerated Diarrhea, rash more common with afatinib; elevated liver enzymes, interstitial lung disease more common with gefitinib Grade ≥ 3 AEs increased with afatinib vs gefitinib: 31% vs 18% Afatinib may offer improved efficacy vs gefitinib as first- line treatment for pts with advanced EGFR-mutant NSCLC AE, adverse event; NSCLC, non-small-cell lung cancer; TTF, time to treatment failure. Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

Conclusions and Faculty Assessment Weaknesses of this study Immature data on OS precluded robust analysis Statistical significance not corrected for multiple comparisons Open-label design may have biased TTF in favor of newer afatinib treatment Future directions Explore combination approaches to overcome acquired resistance mutations following first-line treatment with EGFR TKIs TKI, tyrosine kinase inhibitor; TTF, time to treatment failure. Slide credit: clinicaloptions.com Park K, et al. Lancet Oncol. 2016;17:577-589.

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