Survival improvement in NSCLC translating scientific evidences into clinical practice Roma 16 Febbraio 2016 Gruppo di Lavoro 1 TKIs: FIRST LINE

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1 Survival improvement in NSCLC: translating scientific evidences into clinical practice Roma, Febbraio 2016 Gruppo di Lavoro 1 TKIs: FIRST LINE

2 EGFR-TKIs in Lung Cancer AFATINIB ERLOTINIB GEFITINIB Riassunto delle caratteristiche di prodotto - AIFA 2

3 versus gefitinib as first-line treatment for patients with advanced nonsmall cell lung cancer harboring activating EGFR mutations: LUX-Lung 7 Keunchil Park, Eng-Huat Tan, Li Zhang, Vera Hirsh, Kenneth O Byrne, Michael Boyer, James Chih-Hsin Yang, Tony Mok, Miyoung Kim, Dan Massey, Victoria Zazulina, Luis Paz-Ares è indicato nel trattamento di pazienti adulti naïve agli inibitori tirosinchinasici del recettore del fattore di crescita dell epidermide (EGFR-TKI) con carcinoma polmonare non a piccole cellule (NSCLC) localmente avanzato o metastatico con mutazione(i) attivante(i) l EGFR.

4 LL7 - BACKGROUND A. and other EGFR-targeting agents, erlotinib and gefitinib, are approved first-line treatments for EGFRm+ NSCLC 1 B. irreversibly inhibits signaling of EGFR, HER2-HER4 (2nd generation TKI), whereas gefitinib and erlotinib reversibly inhibit EGFR (1st generation TKIs) 2-4 C. LUX-Lung 7 is the first prospective global randomized trial evaluating two EGFR-directed therapies in patients with EGFRm+ NSCLC 1. Sebastian M, et al. Eur Respir Rev 2014;23: Costanzo R, et al. Expert Rev Anticancer Ther 2013;13: Li D, et al. Oncogene 2008;27: Solca F, et al. J Pharmacol Exp Ther 2012;343:

5 LL7 - STUDY DESIGN Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumor tissue * No prior treatment for advanced/ metastatic disease ECOG PS 0/1 1:1 40 mg once daily Stratified by Mutation type (Del19/L858R) Brain metastases (present/absent) 250 mg once daily Primary endpoints: PFS (independent) TTF OS Secondary endpoints: ORR Time to response Duration of response Duration of disease control Tumor shrinkage HRQoL Safety Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter Main study objective: to estimate the hazard ratio (HR) for PFS, TTF, and OS* on afatinib, relative to gefitinib * Central or local test Dose modification to 50, 30, 20 mg permitted in line with prescribing information Park K, et al. Presented at ASCO Asia

6 LL7 - STUDY RECRUITMENT: 64 sites,13 countries Canada France, Germany, Ireland, Norway, Spain, Sweden, United Kingdom Australia China Republic of Korea Singapore Taiwan Recruitment: December 2011-August 2013 Median follow-up for PFS: 27.3 months Park K, et al. Presented at ASCO Asia

7 LL7 - PATIENTS DISPOSITION Screened n=571 Randomized n=319 Treated with afatinib n=160 Stopped treatment n=140 (87.5%) On treatment n=20 (12.5%) TTF event Treated with gefitinib n=159 Stopped treatment n=149 (93.7%) On treatment n=10 (6.3%) PFS event By investigator: 131 (81.9%) By independent: 124 (77.5%) As of 21 August 2015 PFS event By investigator: 135 (84.9%) By independent: 122 (76.7%) Park K, et al. Presented at ASCO Asia

8 LL7 - BASELINE CHARACTERISTICS (n=160) (n=159) Median age, years (range) 63 (30-86) 63 (32-89) Gender, % Female/Male 57/43 67/33 Race, % Asian Non-Asian Brain metastases *, % Smoking status, % Never smoked Light ex-smoker Current/other ex-smoker Baseline ECOG, % NSCLC stage, % IIIB IV EGFR mutation, % Del19 L858R Park K, et al. Presented at ASCO Asia

9 LL7 - PFS by INDEPENDENT REVIEW Estimated PFS probability No. of patients p= % p= (n=160) (n=159) Median PFS (months) HR (95% CI) 0.73 ( ) p value % 15% 8% Time (months) Park K, et al. Presented at ASCO Asia

10 LL7 - PFS in PROSPECTIVELY DEFINED SUBGROUPS Factors N PFS HR (95% CI) Total ( ) EGFR mutation L858R ( ) Del ( ) Brain metastases Absent Present ( ) 0.76 ( ) Baseline ECOG score ( ) 0.71 ( ) Gender Male ( ) Female ( ) Age <65 years ( ) 65 years ( ) Race Non-Asian ( ) Asian ( ) Smoking history Never smoked ( ) Light ex-smoker ( ) Current or other ex-smokers ( ) 1/4 1 Favors afatinib 4 Favors gefitinib Park K, et al. Presented at ASCO Asia

11 LL7 - TIME TO TREATMENT FAILURE Probability of being on-treatment (n=160) (n=159) Median TTF (months) HR (95% CI) 0.73 ( ) p value No. of patients Time (months) Park K, et al. Presented at ASCO Asia

12 LL7 - OBJECTIVE RESPONSE and DURATION of RESPONSE (independent review) 80 p= ORR (%) % 56% (n=112) (n=89) Median DoR (months) % CI ( ) ( ) 20 0 n=112/160 n=89/159 Park K, et al. Presented at ASCO Asia

13 LL7 - EFFICACY in PATIENTS with Del19 MUTATION Estimated PFS probability Median PFS (months) HR (95% CI) 0.76 ( ) p value Maximum decrease from baseline (%) % increase (n=0) 0 <20% increase (n=3) >0 <30% decrease (n=15) 30 <50% decrease (n=29) 50% decrease (n=41) 70 (80%) with 30% reduction Time (months) No. of patients (n=93) (n=93) ORR 73% 66% Maximum decrease from baseline (%) % increase (n=0) 0 <20% increase (n=2) >0 <30% decrease (n=18) 30 <50% decrease (n=27) 50% decrease (n=41) 68 (77%) with 30% reduction Park K, et al. Presented at ASCO Asia

14 LL7 - EFFICACY in PATIENTS with L858R MUTATION Estimated PFS probability Median PFS (months) HR (95% CI) 0.71 ( ) p value Maximum decrease from baseline (%) % increase (n=1) 0 <20% increase (n=3) >0 <30% decrease (n=12) 30 <50% decrease (n=21) 50% decrease (n=24) 45 (74%) with 30% reduction Time (months) No. of patients (n=67) (n=66) ORR 66% 42% 0 0 Maximum decrease from baseline (%) % increase (n=4) 0 <20% increase (n=4) >0 <30% decrease (n=23) 30 <50% decrease (n=19) 50% decrease (n=13) 32 (51%) with 30% reduction Park K, et al. Presented at ASCO Asia

15 LL7 - OVERALL SUMMARY of AEs Events, % (n=160) (n=159) Any AE Drug-related AEs AEs leading to dose reduction * * Drug-related AEs leading to discontinuation Serious AEs Drug-related serious AEs Drug-related fatal AE * No dose reductions foreseen for gefitinib according to prescribing information Including four patients with drug-related ILD (no drug-related ILD on afatinib) One patient died of hepatic failure Park K, et al. Presented at ASCO Asia

16 LL7 - DRUG-RELATED AEs (>10%) (n=160) (n=159) AE category, % All Grade 3 All Grade 3 Diarrhea Rash/Acne * Stomatitis * Paronychia * Dry skin Pruritus Fatigue * Decreased appetite Nausea Alopecia Vomiting ALT increased AST increased * Grouped terms of AEs Park K, et al. Presented at ASCO Asia

17 LL7 - DRUG-RELATED AEs LEADING to DISCONTINUATION in >1 PATIENT 5,0% 5.0 4,0% 4.0 Patients (%) 3,0% 3.0 2,0% (3.1%) 2 (1.3%) 2 (1.3%) 5 (3.1%) 3 (1.9%) 4 (2.5%) 1,0% 1.0 0,0% 0.0 0% 0% 0% Diarrhoea Fatigue+ Toxic skin Diarrhea Fatigue * Toxic skin eruption 0% 0% 0% A G A G A G A G A G A G ALT increase ALT increase AST AST increase ILD ILD Park K, et al. Presented at ASCO Asia

18 LL7 - SUMMARY and CONCLUSIONS 1. significantly improved PFS of patients with EGFRm+ NSCLC relative to gefitinib. Results are consistent across subgroups 2. treatment was associated with a significant improvement in response rate and TTF 3. The improvement in efficacy was observed in both Del19 and L858R populations 4. OS data are immature (current HR: 0.87, 95%CI: ) 5. AEs in both groups were consistent with previous experience, and were manageable leading to equally low rates of treatment discontinuation 6. LUX-Lung 7 confirms the benefit of irreversible ErbB blockade with afatinib over reversible EGFR inhibition with gefitinib in treatment of EGFRm+ NSCLC Park K, et al. Presented at ASCO Asia

19 LUX-Lung 3 trial: OS in Del19 subgroup Estimated OS probability Pem/Cis n=112 n=57 Median (months) HR (95% CI) 0.54 ( ) p-value No of patients Time (months) Pem/Cis Yang JC, et al. Lancet Oncol. 2015;16:

20 LUX-Lung 6 trial: OS in Del19 subgroup Estimated OS probability Gem/Cis n=124 n=62 Median (months) HR (95% CI) 0.64 ( ) p-value Time (months) No of patients Gem/Cis Yang JC, et al. Lancet Oncol. 2015;16:

21 Phase III Trials in EGFR Mutation-Positive NSCLC: PFS nella Del 19 GEFITINIB ERLOTINIB AFATINIB * Cisplatin/Pemetrexed Modified from: Sebastian M, et al. Eur Respir Rev 2014;23: Mok T, et al. N Engl J Med 2009;361:947-57; Mitsudomi T, et al. Lancet Oncol 2010;11:121-8; estimation from Kaplan-Meier curves in Fukuoka M. et al. J Clin Oncol 2011;29: ; Wu YL, et al. J Thorac Oncol 2013;8:602. Sequist LV, et al. J Clin Oncol 2013;31: EU CHMP Variation Assessment Report, Giotrif, July Rosell R, et al. Lancet Oncol 2012;13: EU CHMP Variation Assessment Report, Tarceva, July

22 LUX-Lung 3: OS in Mut. Leu858Arg subgroup Pem/Cis n=91 n=47 Median (months) Estimated OS probability HR (95% CI) 1.30 ( ) p-value 0.29 No of patients Pem/Cis Time (months) Yang JC, et al. Lancet Oncol 2015;

23 Phase III Trials in EGFR Mutation-Positive NSCLC: PFS nella Mutazione L858R Erlotinib Modified from: Sebastian M, et al. Eur Respir Rev 2014;23: Mok T, et al. N Engl J Med 2009;361:947-57; Mitsudomi T, et al. Lancet Oncol 2010;11:121-8; estimation from Kaplan-Meier curves in Fukuoka M. et al. J Clin Oncol 2011;29: ; Wu YL, et al. J Thorac Oncol 2013;8:602. Sequist LV, et al. J Clin Oncol 2013;31: EU CHMP Variation Assessment Report, Giotrif, July Rosell R, et al. Lancet Oncol 2012;13: EU CHMP Variation Assessment Report, Tarceva, July

24 Phase III Trials in EGFR Mutation-Positive NSCLC: PFS per delezione degli studi clinici controllati Modified by Sebastian M, et al. Eur Respir Rev 2014;23:

25 LUX-Lung 3, Lux-Lung 6, Lux-Lung 7, EURTAC, IPASS: Most Frequently Reported AE (Regardless of Cause) % of Patients LUX-Lung 3 1 (n=229) LUX-Lung 6 2 (n=239) LUX-Lung 7 3 (n=160) EURTAC 4 Erlotinib (n=84) IPASS 5 (n=607) All Grade 3 All Grade 3 All Grade 3 All Grade 3 All Grade 3 Diarrhea Rash/acne a Stomatitis/mucositis a NR NR Paronychia NR NR Dry skin NR NR Decreased appetite Pruritus a NR NR Nausea NR NR Fatigue a Vomiting NR NR Alopecia a Group term in at least 1 of the trials included in the table - NR=not reported. 1. Sequist LV, et al. J Clin Oncol 2013;31: Wu YL, et al. Lancet Oncol 2014;15: Park K, et al. Presented at ESMO Asia 2015 Congress, LBA2-4. Rosell R, et al. Lancet Oncol 2012;13: Mok T, et al. N Engl J Med 2009;361:

26 LUX-Lung 3, Lux-Lung 6, Lux-Lung 7, EURTAC, IPASS: Most Frequently Reported AE (Regardless of Cause) % of Patients LUX-Lung 3 1 (n=229) LUX-Lung 6 2 (n=239) LUX-Lung 7 3 (n=160) EURTAC 4 Erlotinib (n=84) IPASS 5 (n=607) NR Any grade Dose reduction due to AE Discontinuation due to AE 7.9 (related) 5.9 (related) (related) 16.1 (modification) 6.9 Treatment-related AEs Fatal serious AE 1.7 (related) 0.4 (related) 0 1 (related) 3.8 ILD-like a Group term in at least 1 of the trials included in the table - NR=not reported. 1. Sequist LV, et al. J Clin Oncol 2013;31: Wu YL, et al. Lancet Oncol 2014;15: Park K, et al. Presented at ESMO Asia 2015 Congress, LBA2-4. Rosell R, et al. Lancet Oncol 2012;13: Mok T, et al. N Engl J Med 2009;361:

27 LL3: Influenza dell aggiustamento del dosaggio sulla sicurezza e l efficacia di afatinib - 1 L esposizione mediana al trattamento nei pazienti che hanno avuto una riduzione della dose di afatinib è stata di 48,5 giorni al dosaggio di 40 mg (n=122), 140 giorni al dosaggio di 30 mg (n=120) e 276,5 giorni al dosaggio di 20 mg (n=40). Esposizione mediana al trattamento nei pazienti ai quali è stato ridotto il dosaggio di afatinib Yang J, et al. J Clin Oncol 33, 2015 (suppl; abstr 8073)

28 LL3: Influenza dell aggiustamento del dosaggio sulla sicurezza e l efficacia di afatinib - 2 Nonostante un esposizione al trattamento più lunga con i dosaggi inferiori, la riduzione della dose in base alla tollerabilità ha portato ad una diminuzione dell incidenza e della severità degli eventi avversi treatment-related. Eventi avversi di maggiore importanza nei pazienti che hanno richiesto una modifica del dosaggio di afatinib in base alla tollerabilità Yang J, et al. J Clin Oncol 33, 2015 (suppl; abstr 8073)

29 LL3: Influenza dell aggiustamento del dosaggio sulla sicurezza e l efficacia di afatinib - 3 La riduzione del dosaggio è stata più probabile nei pazienti con concentrazione plasmatica di afatinib più alta. Livelli plasmatici di afatinib nei pazienti nei quali il dosaggio è stato ridotto a 30 mg 4 giorni prima e in quelli che hanno continuato a ricevere 40 mg Yang J, et al. J Clin Oncol 33, 2015 (suppl; abstr 8073)

30 LL3: Influenza dell aggiustamento del dosaggio sulla sicurezza e l efficacia di afatinib - 4 PFS nei pazienti che hanno richiesto una riduzione del dosaggio di afatinib nei primi 6 mesi e quelli che hanno continuato a ricevere 40 mg/die Yang J, et al. J Clin Oncol 33, 2015 (suppl; abstr 8073)

31 CONCLUSIONI GRUPPO di LAVORO: Impatto dello STUDIO LUX-Lung 7 sulla pratica clinica Il dato interessante non è tanto quello relativo alla PFS (11.0 vs 10.9 mesi), ma il dato di HR (0.73) ed il fatto che le curve si separano tardi appare efficace e con profilo di sicurezza accettabile anche negli anziani può essere utilizzato anche nei pazienti PS=2 se il deterioramento del performance status è dovuto alla malattia Nella strategia di approccio multidisciplinare importante indirizzare il prima possibile i pazienti a consulenza con dietologo e dermatologo La riduzione del dosaggio di da 40 a 30 mg die al fine di ridurre l incidenza di AE in pazienti anziani o small size non sembra modificare i dati di efficacia 31