1. Inhibidores de TK de EGFR en el tratamiento del Cáncer No Microcítico de Pulmón (CNMP) Luis Paz-Ares| Hospital Universitario Doce de Octubre & Instituto de Investigación i+12

2. EGFR mutated NSCLC is distinct disease

3. EGFR mutation-positive disease: a biologically distinct subtype of NSCLC PP Nucleus Adaptor Survival PIP 2 PI3K PIP 3 PTEN AKT Apoptosis regulators Proliferation Adaptor Transcription factors MAPK MEK RAF GTP -RAS GDP - RAS Sordella, et al. Science 2004 Preferential heterodimerisation with HER3 Increased signalling through the AKT and STAT anti-apoptotic pathways ‘Oncogene addiction’

4. Molecular alterations in lung cancer East Asia Adenocarcinoma, never smokers Johnson, et al. ASCO 2013 Sun, et al. J Clin Oncol 2010; Barlesi, et al. ASCO 2013 US Adenocarcinoma Europe All histology (n=52)(n=733)(n=9,911)

5. EGFR TKIs are biologically sound treatments

6. EGFR TKIs – “the magic bullet” The concept of a "magic bullet" drug comes from the experience of 19th century German chemists with selectively staining tissues for histological examination, and in particular, selectively staining bacteria (Ehrlich was an exceptionally gifted histological chemist, and invented the precursor technique to Gram staining bacteria). Ehrlich reasoned that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. Hence, a "magic bullet" would be created that killed only the organism targeted.magic bullet histologicalbacteriachemistGram stainingdiseaseorganism toxin “Wikipedia said” Paul Ehrlich Nobel Price of Medicine or Physiology 1908

7. Cytotoxic vs Cytostatic Effects of EGFR TKIs (Erlotinib) in NSCLC l Cytotoxic effects (apoptosis) primarily seen in EGFR Mt+ cancers (objective response) l Cytostatic effects (growth arrest) predominate in EGFR wild-type cancers (RECIST SD; disease control rate) Gandara DR,et al. Clin Lung Cancer. 2009;10:148-150. Gandara DR,et al. J Thoracic Oncol. 2010;5:1933-1938. Jänne PA,et al. Clin Cancer Res. 2006;12:4416s-4420s. A549H1666H3255 0 5 10 20 25 30 Percent Apoptosis 15 Control Gefitinib

8. Erlotinib in EGFR mutation+ NSCLC: Spanish Lung Cancer Group (SLCG) Median TTP = 14 months Rosell, et al. NEJM 2009 1.0 0.8 0.6 0.4 0.2 0 Probability 01020304050 Time (months) Median OS = 27 months 1.0 0.8 0.6 0.4 0.2 0 Probability 01020304050 Time (months) Patients (%) 100 75 50 25 0 SD PR CR PD DCR 90% Best response RR 71%

9. EGFR mutation is a good predictive biomarker

10. Anti EGFR Agents in NSCLC l Cetuximab: –RR: 3/66 = 4.5% l EGFR TKIs: Hanna et al J Clin Oncol 2006, Thatcher et al. Lancet 2006, Shepherd et al. NEJM 2005

11. Riely, et al. Clin Cancer Res 2006 Mutations identified in EGFR gene Exons 1–16 Exons 18–24 Exons 25–28 EGFR transcript Exon 17 Confer sensitivity/resistance to EGFR TKIs Unclear effect on sensitivity to EGFR TKIs 18 19 20 21 Deletions L858R G719A/S L861X P694X V700D E709X G735S V738F V742A T751I S752Y D761N A763V N765A S768I T783A L792P L798F G810S N826S L838V T847I I853T A859T E866K L833V H835L H850N V851X G863DA 864T L730F P733L E746K L688P V689M I715S L718P S720X D761Y D770_N771 insNPG T790M

12. How can predictive markers guide clinical practice? Predictive marker Select patients who benefit the most Exclude patients who are not likely to benefit High PPV High NPV

13. How can predictive markers guide clinical practice? Predictive marker Select patients who benefit the most EGFR Mutation Exclude patients who are not likely to benefit High PPV High NPV

14. EGFR TKIs are more efficacious than chemo - PFS - RR - OS ?

15. IPASS Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # 1:1 randomisation *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped  15 years ago and smoked  10 pack years; # limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Patients Chemonaïve Age ≥18 years Adenocarcinoma histology Never or light ex- smokers* Life expectancy ≥12 weeks PS 0-2 Measurable stage IIIB / IV disease Primary Progression-free survival (non- inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression Endpoints Mok et al NEJM 361:947 2009

16. Progression-free survival in EGFR mutation positive and negative patients EGFR mutation positiveEGFR mutation negative Treatment by subgroup interaction test, p<0.0001 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%) Gefitinib (n=132) Carboplatin / paclitaxel (n=129) ITT population Cox analysis with covariates HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C / P, 70 (82.4%) 132 71 311130 129377210 108 103 04812162024 Gefitinib C / P 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival At risk : 91 4 2100 85141000 21 58 04812162024 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) Months Mok et al NEJM 361:947 2009

17. EURTAC Trial: Erlotinib v Chemo Rosell et al., Lancet Oncol 2012

18. Primary endpoint: PFS LL3 & 6 superimposed

19. PFS in EGFR activating MUT+ (common) NSCLC Across Clinical Trials ErlotinibGefitinib Median PFS (months) 16 14 12 10 8 6 4 2 0 SLCGEURTACOPTIMALIPASSFirst- SIGNAL WJTOG 3405 NEJSG 002 WJTOG3405: stage IIIB/IV pts (median PFS in overall population = 9.2 mos) LUX lung 3 Rosell, et al. NEJM 2009; Janne, et al. ASCO 2010; Zhou, et al. ESMO 2010; Mok, et al. NEJM 2009Lee, et al. WCLC 2010; Mitsudomi, et al. Lancet Oncol 2010; Maemondo, et al. NEJM 2010 ; Yang et al ASCO 2012 LL2LL2 LL2LL2L LL6LL6L LL6LL6

20. IPASS: 2010 OS by EGFR mutation status (ITT) EGFR Mutation + 0000 Patients at risk: Gefitinib C / P 132 129 126 123 103 95 70 68 24 26 11 15 121 112 88 80 58 55 46 48 38 40 6767 3030 Time from randomisation (months) Probability of survival EGFR Mutation - 5204812162044242832364048 1.0 0.8 0.6 0.4 0.2 0.0 0000 5151 91 85 69 76 52 57 40 44 29 33 26 25 1111 19 16 11 8383 0101 Time from randomisation (months) 5204812162044242832364048 1.0 0.8 0.6 0.4 0.2 0.0 Probability of survival Gefitinib (n=132) Carboplatin/paclitaxel (n=129) HR (95% CI) 1.00 (0.76, 1.33); p=0.990 No. events G 104 (79%) C / P 95 (74%) Median OS G 21.6 months C / P 21.9 months Gefitinib (n=91) Carboplatin/paclitaxel (n=85) HR (95% CI) 1.18 (0.86, 1.63); p=0.309 No. events G 82 (90%) C / P 74 (87%) Median OS G 11.2 months C / P 12.7 months Treatment by subgroup interaction test p=0.480 Cox analysis with covariates; A hazard ratio < 1 implies a lower risk of death on gefitinib No formal adjustment made for multiple testing Mok, et al. London 2011

21. OS Differences? Maemondo et al., NEJM 2010

22. Two subgroups of LUX Lung 3 and 6 OS analysis 1.0 0.8 0.6 0.4 0.2 0 Estimated OS probability 03691215182124273033363942454851 Time (months) 1.0 0.8 0.6 0.4 0.2 0 Estimated OS probability Time (months) 03691215182124273033363942454851 23623022321720219217316014513111790503822610 1191131039587726355514338271491100 Afatinib Chemo No of patients 1831811671541411281119180706451272011300 93868278756961555040322520149410 Afatinib Chemo No of patients Del19 Afatinib n=236 Chemo n=119 Median, months 31.720.7 HR (95%CI), p-value 0.59 (0.45–0.77), p=0.0001 L858R Afatinib n=183 Chemo n=93 Median, months 22.126.9 HR (95%CI), p-value 1.25 (0.92–1.71), p=0.1600 Exon 19 Exon 21

23. LUX-Lung 3LUX-Lung 6 Afatinib (n=203) Pem/Cis (n=104) Afatinib (n=216) Gem/Cis (n=108) Discontinued treatment, n (%)184 (100)104 (100)194 (100)108 (100) Subsequent systemic therapy, n (%)*144 (78)88 (85)123 (63)70 (65) Chemotherapy, n (%)131 (71)49 (47)114 (59)29 (27) EGFR TKI therapy, n (%) Erlotinib Gefitinib Afatinib AZD9291 Dacomitinib Icotinib EGFR TKI combinations 81 (44) 61 (33) 28 (15) 2 (1) – 5 (3) 78 (75) 46 (42) 44 (42) 7 (7) 1 (1) – 9 (9) 50 (26) 21 (11) 19 (10) – 11 (6) 5 (3) 61 (56) 22 (20) 39 (36) – 3 (3) Other, n (%)5 (3)2 (2)3 (2)4 (4) Radiotherapy, n (%)32 (17)21 (20)4 (2)0 (0) Treatment beyond 1st line in patients with common mutations Presented by: James Chih-Hsin Yang *Collection of data on subsequent therapies still ongoing. More TKI exposure during the course of illness may be associated with longer survival 131/212 pt had exposure to TKI 419/419 pt had exposure to first line TKI plus 131/419 had further TKI 419/419 pt had exposure to first line TKI plus 131/419 had further TKI

24. Dacomotinib as First Line Treatment in EGFR mut+ NSCLC Janne et al., Lancet Oncol 2014 PFSOS

25. Afatinib: Time to Symptom Deterioration & QoL

26. Can we improve efficacy of EGFR TKIs ?

27. Assessed for eligibility Withdrew before treatment started Thrombosis: 1 Pleural effusion: 1 Randomized (n = 154) Received EB and eligible for analysis (n = 75) Received E and eligible for analysis (n = 77) JO25567: Randomized phase II study on erlotinib + bevacizumab E monotherapy (n = 77) EB combination (n = 77) Seto et al., Lancet Oncol 2014

28. Erlotinib v Erlotinib + Bevacizumab: PFS Seto et al., Lancet Oncol 2014

29. EGFR TKIs are less toxic than chemo

30. EGFR TKIs have better safety profile Bbbb Maemondo et al., NEJM 2010

31. EGFR TKIs have better safety profile Rosell et al., Lancet Oncol 2012

32. Comparing toxicities

33. EGFR TKIs work even in poor PS patients

34. - Phase II trial - 30 patients, treatment naive - Poor PS and/or elderly EGFR TKIs work even in poor PS patients Inoue A et al. JCO 2009

35. EGFR TKIs work in later stages

36. EGFR TKIs work in later stages (but only if treatment is prescribed)

37. Median PFSHR (months)(95% CI) First14.09.7–18.3 Second13.09.7–16.3 Line of therapy Median OSHR (months)(95% CI) First28.022.7–33.0 Second27.019.9–34.1 Line of therapy Previous chemotherapy did not influence TKI efficacy 1.0 0.8 0.6 0.4 0.2 0 Probability of PFS 012243648 Time (months) Second-line First-line 1.0 0.8 0.6 0.4 0.2 0 Probability of OS Second-line First-line 012243648 Time (months) Rosell R, et al. N Eng J Med 2009;361:958–67

38. SATURN: PFS and OS with maintenance Erlotinib in EGFR MUT+ disease Time (weeks) 08162432404856647280 88 96 Probability of PFS Log-rank p<0.0001 HR=0.10 (0.04–0.25) Tarceva (n=22) Placebo (n=27) Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1) EGFR MUT+ 0369121518212427303336 1.0 0.8 0.6 0.4 0.2 0 Time (months) Log-rank p=0.6810 HR=0.83 (0.34–2.02) Tarceva (n=22)Median NR Placebo (n=27)Median 23.8 1.0 0.8 0.6 0.4 0.2 0 Significantly improved PFS in patients with EGFR MUT+ disease OS data not yet mature. Note that 67% of patients with EGFR MUT+ disease in the placebo arm received a second-line EGFR TKI Probability of OS

39. Who is better? Is there a difference anyway?

40. Meta-estimate based on the randomized studies Response rate PFS Haaland et al JTO 2014

41. LUX Lung 7: Randomized IIb Study Advanced NSCLC Adenocarcinoma EGFR mut+ First-line treatment PS 0-1 RANDOMIZERANDOMIZE Afatinib 40mg qd Gefitinib 250mg qd 1 1 N= 319 patients Primary endpoint: PFS 13.7 vs 10 months HR 0.73 Primary endpoint: PFS 13.7 vs 10 months HR 0.73 Complete accrual Aug 16 2013 Complete accrual Aug 16 2013

42. ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 RANDOMIZERANDOMIZE Dacomitinib 45mg qd Gefitinib 250mg qd 1 1 N= 440 patients Primary endpoint in PFS 14.8 vs 9.5 months Primary endpoint in PFS 14.8 vs 9.5 months Stratification -Race -Exon 19 v 21 >350 accrued

43. Graciaslpazaresr@seom.org

44. Del19L858R Afatinib (n=236) Chemo (n=119) Afatinib (n=183) Chemo (n=93) Median, months 31.720.722.126.9 HR (95% CI), P-value 0.59 (0.45-0.77), P=0.0001 1.25 (0.92-1.71), P=0.1600 LUX-Lung 3 and 6 Exploratory Combined OS Analysis: Del19 and L858R Subgroups Yang J et al. Lancet Oncol 2015