1. Gli Inibitori di I e II generazione sono tutti uguali? Roberta Buosi Camogli, 30 aprile 2016

3. ERBB Family ErbB1, ErbB2, ErbB3, ErbB4 Ubiquitarriamente espressi su tutti i tessuti epiteliali e anche nel SNC

4. MECCANISMO D’AZIONE

6. Formula chimica GefitinibErlotinib Afatinib

7. AFFINITA’ DI LEGAME the overall characteristics of these kinase inhibitors remain the same: a heterocyclic core scaffold makes many of the same contacts as the purine ring of ATP. Side chains on the scaffold allow for the generation of inhibitors that target a diverse set of kinases. Among the many reported heterocyclic cores, the 4-anilinoquinazoline plays a particularly important role in demonstrating the potential for selectivity. All three clinically approved TKIs for EGFR based on the 4-anilinoquinazoline scaffold. b) Gefitinib c) AEE 788 d) ATP

8. Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342. Afatinib si lega con legame covalente e blocca in modo irreversibile tutti gli omo ed eterodimeri formati dai 4 recettori ErbB. Meccanismo d’azione di afatinib

9. Efficacia?

10. Benefit of 1 st- line EGFR TKIs: 9 randomized phase III studies

11. Phase III Trials in EGFR Mutation–Positive NSCLC: PFS negli studi clinici controllati Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. NR * Cisplatin/Pemetrexed * *

12. PFS mediana nei trials di fase III nel NSCLC EGFRmut+ Exon 19 Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. Mok T, et al. N Engl J Med 2009;361:947–957; Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; Estimation from Kaplan–Meier Curves in Fukuoka M. et al. J Clin Oncol 2011; 29: 2866–2874. Sequist et al. J Clin Oncol. 2013;31:3327. Wu et al. Lancet Oncol. 2014;15:213. Rosell R, et al. Lancet Oncol 2012;13:239–246; EU CHMP Variation Assessment Report, Tarceva, July 21 2011. Phase III Trials in EGFR Mutation–Positive NSCLC: Exon 19

13. Fukuoka et al, J Clin Oncol 2011 Exon 19 L858R

14. Lux–Lung 3 Del 190,54 (0,36 – 0,79) Lux-Lung 6 Del 190,64 (0,44 – 0,94) IPASS Del 190,79 (0,54 – 1,15) NS NEJ002 Del 190,83 (0,52 – 1,34) NS EURTAC Del 190,94 (0,57 – 1,54) NS ENSURE Del 19NA Studio OS HR (95% CI) 1.Sequist et al. J Clin Oncol 2013;31:3327; 2. Wu et al. Lancet Oncol 2014;15.2013; 3. Mok et al. N Engl J Med. 2009;361:947; 4. Fukuoka et al. J Clin Oncol. 2011;29:2866; 5. Yang et al. Eur J of Cancer. 2011 (suppl1;S633); 6. Maemondo et al. N Engl J Med. 2010;362:2380; 7. Inoue et al. Ann Oncol. 2013;24:54; 8. Rossel et al. Lancet Onco.. 2012;13:239; 9.TARCEVA® (erlotinib) prescribing information, 2013; 10. Wu et al. J Thorac Oncol. 2013;8:suppl 2 (P1.11-021). Del19: Quali evidenze? OS nei trials di Fase III nel NSCLC EGFRmut+ Del19 012 NS = dato non statisticamente significativo AFATINIB GEFITINIB ERLOTINIB

15. Yang JC et al, Lancet Oncol 2015

16. PFS mediana nei trials di Fase III nel NSCLC EGFRmut+ Exon 21 Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. Mok T, et al. N Engl J Med 2009;361:947–957; Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; Estimation from Kaplan–Meier Curves in Fukuoka M. et al. J Clin Oncol 2011; 29: 2866–2874. Sequist et al. J Clin Oncol. 2013;31:3327. Wu et al. Lancet Oncol. 2014;15:213. Rosell R, et al. Lancet Oncol 2012;13:239–246; EU CHMP Variation Assessment Report, Tarceva, July 21 2011. Phase III Trials in EGFR Mutation–Positive NSCLC: Exon 21

17. Confronto Indiretto

18. Progression Free Survival Haspinger E, CROH 2014

19. DELEZIONE 19 Haspinger E, CROH 2014

20. I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, WLCC 2013 Gefitinib verso erlotinib

21. I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, CROH 2014 Gefitinib verso Afatinib

22. I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, CROH 2014 Erlotinib vs Afatinib

24. …no statistically significant differences between afatinib and erlotinib or gefitinib in terms of PFS, some numerical differences were observed, particularly in patients with common EGFR mutations. All comparisons for PFS versus currently available reversible TKIs (erlotinib and gefitinib) showed a trend favouring afatinib.

25. The Lancet Oncology, 2014 CONFRONTO DIRETTO 134 centres in 23 countries, 878 patients 439 dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib locally advanced or metastatic non-small-cell lung cancer, ECOG 0–2, dacomitinib (45 mg/day) or erlotinib (150 mg/day) Randomisation was stratified by histology (adenocarcinoma vs non- adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian subcontinent), performance status (0–1 vs 2), and smoking status. Median PFS 2·6 months in dacomitinib group and erlotinib group

26. Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/21 Ramalingam SS et al. WCLC 2015 121 EGFR Mutant Patients Retrospectively analysed from ARCHER 1028 (Ramalingam S JCO 2012) and ARCHER 1009 (Ramalingam S Lancet Oncol 2014) PFSOS Dacomitinib (N=66)Erlotinib (N=55)Dacomitinib (N=66)Erlotinib (N=55) Events(%)51 (77.3%)44 (80.0%)39 (59.1%)32 (58.2%) Median (95% CI) in Mons10.9 (7.4-17.4)9.6 (7.4-11.3)26.6 (20.1-29.0)24.1 (17.9-39.4) Un-stratified HR (95% CI)0.815 (0.542-1.224)0.958 (0.596-1.538) P-value (1-sided)0.1600.431 PFS OS

27. Eventi avversi Daconitinib Gr 3/4 Erlotinib Gr 3/4 rash7%3% diarrea 11 % 2% stomatiti3% < 1% AES 12% 9%

28. DIRECT COMPARISON: LUX Lung 7 Randomized explorative phase IIb Study Complete accrual on Aug 16 2013 Complete accrual on Aug 16 2013 Sample size Increased to 319 Sample size Increased to 319

29. LL7: END-POINTS DI EFFICACIA - PFS

30. LL7: END-POINTS DI EFFICACIA - TTF

31. RISPOSTA SU POPOLAZIONE GLOBALE

34. Our analysis reported that exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome S786I and S786I þ L858R mutations were thought to be sensitizing in the afatinib study different effect with different TKIs rare frequencies, it is practically impossible to enroll enough patients to power a clinical trial Barbara Klughammer, J Thor Oncol, 2016

35. PROFILO DI TOSSICITA’

36. W Liang et al, PLOS One 2014

37. * Toxicity is referred to total 607 pts 1 Y Wu et al, P ASCO 2013; 2 Yang et al, P ASCO 2012; 3 Rosell et al, Lancet Oncol 2012; 4 Mok et al, NEJM 2009;

38. M Takeda et al, Lung Cancer 2015

39. ALGORITHM: DOSE MODIFICATION DUE TO TREATMENT-RELATED DERMATOLOGIC AEs According to CTCAE Version 3.0 Proactive management Use alcohol-free skin products Minimise exposure to the sun Use protective clothing/hat Use sunscreen with a high protection factor and UVA/UVB protection Avoid any perfume or perfume- based skin products Grade 1 or tolerable grade 2 skin reaction Grade ≥3 or intolerable grade 2 Initiate dermatologic treatment CONTINUE TKI AT CURRENT DOSE Refer to dermatologist or continue dermatologic treatment Lacouture et al. Expert Rev Anticancer Ther. 2013 INTERRUPT UNTIL GRADE 0/1 1. Resume treatment with dose reduction by 10-mg decrements 2. If patient cannot tolerate 20 mg/day, permanent discontinuation should be considered

40. J Yang… F de Marinis et al, ASCO 2015

42. Conclusioni Esistono diverse sfumature … dipende da quale lato le si osserva -1° linea in EGFR + i TKI sono meglio della CT Diversi in : meccanismo d’azione Profilo di tossicità ciò che è statisticamente significativo non sempre ha significato clinico Efficacia sovrapponibile …