1. Il trattamento di prima linea nel paziente con mutazione EGFR Vanesa Gregorc Thoracic Oncology and Melanoma area coordinator IRCCS Ospedale San Raffaele Milano

2. Who should be tested for EGFR mutations? Non-squamous NSCLC NSCLC NOS Adenosquamous NSCLC Squamous cell carcinoma if – Low smoking exposure – Young age

3. Smoking exposure and EGFR mutations Pham et al, JCO 2006 Pack-year%EGFR+ 0-15 >=160-10 30-51

4. At half of LCMC sites, multiplexed testing for all mutations is now routine practice in their pathology departments (ASCO 2011) - 16 US cancer centers - Test 10 driver mutations in 1000 lung adenocarcinomas Lung Cancer Consortium Mutation

5. EGFR mutations Sequist et al, JCO 2007

6. Test EGFR su DNA circolante Douillard et al, Br J Cancer 2013

7. Quale EGFR-TKI in EGFR mutati? Indicazioni AIFA Gefitinib Indicato in qualunque linea in EGFR mutati Erlotinib Indicato in I linea negli EGFR mutati; II-III linea indipendentemente da EGFR Afatinib Indicato in I linea negli EGFR mutati

8. 1st line: EGFR-TKIs vs CT AuthorStudyN (EGFR mut. +) EGFR-TKIMedian PFS* (months) PFS* HR MokIPASS261Gefitinib9.8 vs. 6.40.48 LeeFirst-SIGNAL42Gefitinib8.4 vs. 6.70.54 MitsudomiWJTOG 3405177Gefitinib9.2 vs. 6.30.49 MaemondoNEJGSG002228Gefitinib10.8 vs. 5.40.30 ZhouOPTIMAL154Erlotinib13.1 vs. 4.6 0.16 RosellEURTAC175Erlotinib9.7 vs. 5.20.37 YangLUX-Lung 3345Afatinib11.1 vs. 6.90.58 Wu LUX-Lung 6 364Afatinib11.0 vs 5.60.28 ShiCONVINCE296IcotinibNA *Primary endpoint

9. MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo PFS with TKIs better for del19 than L858R Lee et al. JCO 2015 Del19 HR: 0.24L858R HR: 0.48 p for interaction < 0.001

10. PFS

11. Lancet Oncology, Feb 2015

14. Del19Common Mutations LUX-Lung 3: OS in Common Mutations and Del19 in Asian and Whole Population Time (months) 203197 188181171162143 133 12110810190 584932 9 10 10498 928681 7163 5552474035 262010 5 10 149148 141135126121106 9891817767 474129 9 10 7570 6661575145 4240373127201710 5 10 Afatinib Cis/Pem No. of patients Afatinib Cis/Pem Time (months) Estimated OS probability 03691215182124273033363942454851 1.0 0.8 0.6 0.4 0.2 0 112108 10510296 9383807262 5851343021 610 5755 504643 3733272522 20161061 100 8281 787570 6859565245 4337272418 610 4140 373331 2622201817 1511751 100 Afatinib Pem/Cis No. of patients Afatinib Cis/Pem Afatinib (All) Afatinib (Asian) Cis/Pem (All) Cis/Pem (Asian) Time (months) Estimated OS probability 1.0 0.8 0.6 0.4 0.2 0 03691215182124273033363942454851 Afatinib (All) Afatinib (Asian) Cis/Pem (All) Cis/Pem (Asian) PFS in overall population LUX-Lung 3 (All) LUX-Lung 3 (Asian population) Afatinib n=112 Cis/Pem n=57 Afatinib n=82 Cis/Pem n=41 Median, months 33.321.133.322.9 HR (95%CI) P value 0.54 (0.36–0.79), P=0.0015 0.57 (0.36–0.90) P=0.0153 PFS in overall population LUX-Lung 3 (All) LUX-Lung 3 (Asian population) Afatinib n=203 Cis/Pem n=104 Afatinib n=149 Cis/Pem n=75 Median, months 31.628.231.729.1 HR (95%CI) P value 0.78 (0.58–1.06) P=0.1090 0.82 (0.57–1.17) P=0.2771 Sequist et al. CMSTO 2014. Oral presentation. Abstract 3341.

15. Kato T et al., ISPOR 2015; PCN40 HR for OS in del19

17. HR for OS in L858R 75% 53% 52% Adapted from West, ASCO 2014 Crossover from CT to TKI 95% 76%

18. Kato T et al., ISPOR 2015; PCN40 HR for OS in L858R

19. Outcome in caso di mutazioni non comuni Yang et al, WCLC 2013

20. Survey (n = 562, 10 countries): first-line choice in EGFR mutated Spicer et al, ELCC 2015

21. OPEN Questions: EGFR-TKI and OBD vs MTD, side effects, dosage, drug interaction, drug reductions

22. Skin Rash : Gefitinib: 49-85% Erlotinib: 73-79% Afatinib: 80-89% Stomatitis : Erlonib: 13% Gefitinib: 9-40% Afatinib: 50-72% Paronichia : Erlonib: 4% Gefitinib: 13-32% Afatinib: 32-56% Anorexia : Afatinib: 10-20% Gefitinib: 14-44% Erlotinib: 31% Fatigue : Afatinib: 10-17% Gefitinib: 10-39% Erlotinib: 5-57% Modified from Landi L, Expert Opin Pharmacother 2014 Diarrhoea : Erlonib: 25-57% Gefitinib: 34-54% Afatinib: 88-95% Vomiting : Erlonib: 1% Afatinib: 9-17% Gefitinib: 12-19% Transaminitis : Erlotinib: 6% Afatinib: 11% Gefitinib: 40-60%

23. Afatinib Plasma Levels in Patients Who Dose Reduced and Those Who Remained on Afatinib 40 mg Dose reduction was more likely in patients with higher plasma concentrations Geometric mean plasma concentrations – 24.4 ng/mL after dose reduction to 30 mg ≥4 days previously (n=38) – 23.7 ng/mL in patients who remained on 40 mg (n=126) 23 : patients who remained on 40 mg until C3V1 (n=126);, patients who dose 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]) 140 120 100 80 60 40 20 0 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 Datapoints outside percentiles Yang et al. ASCO 2015 #8073

24. PFS in Patients Who Had or Had Not Dose Reductions Within the First 6 Months Median PFS was similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily 24 No. at risk <40 mg in first 6 months ≥40 mg for first 6 months 105 124 87 93 75 76 58 62 41 36 26 24 15 16 6 4 2 1 0 0 Time (months) 1.0 0.6 0.4 0.2 0 Estimated PFS probability 0369121518212427 0.8 CI, confidence interval; HR, hazard ratio Yang et al. ASCO 2015 #8073 PFS in overall population <40 mg in first 6 months (n=105) ≥40 mg for first 6 months (n=124) Median PFS (mo)11.311.0 HR (95% CI) P-value 1.25 (0.91–1.72) 0.175 <40 mg in first 6 months ≥40 mg in first 6 months

25. Pharmacokinetic parameters for EGFR TKI ParameterReversible EGFR - TKIIrreversible EGFR - TKI GefitinibErlotinibAfatinibDacomitinib Usual starting dose (mg/day) 250150 (100)40 (50/30/20)45 T max (h) 3-742-5 ≈ 6 Vol distr. (L) 170023228702600 Protein binding (%) ≈ 90 ≈ 95 97-98 t ½ (h) 48 -72363772 Metabolism Extensive MinimalExtensive Renal excretion 4%9%< 5%3% Accumulation 1.5 to ≈ 4 fold1.5 to ≈ 5.4fold2 to 3 fold ≈ 6 fold Gastric PH effect Reduces absReduce absNot knownReduces abs Food effect Not relevantAUC 34-66%AUC 39%Not relevant Drug interaction CYP P-gp transp Potent CYP 2D6 sub Afatinib 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. Adapted from S. Peters et al. Cancer Treatments review 40(2014) 917-926

26. OPEN Questions: Direct comparisons?

27. Patients with –Advanced lung adenocarcinoma –Documented common EGFR mutations (del19 or L858R) –First line (no prior treatment) N = 264 Afatinib 40 mg Randomization Gefitinib 250 mg Primary endpoint: PFS and disease control rate at 12 months ClinicalTrials.gov. NCT01466660. LUX Lung 7: phase IIb trial of afatinib vs gefitinib

28. Patients with –Advanced NSCLC –Documented common EGFR mutations (del19 or L858R ± T790M) –First line (no prior treatment) N = 440 Dacomitinib 45 mg Randomization Gefitinib 250 mg Primary endpoint: PFS ClinicalTrials.gov. NCT01774721 ARCHER 1050: phase III trial of dacomitinib vs gefitinib

29. OPEN Questions: EGFR-TKIS clinical strategy?

30. Del19/L858R: first line TKI and post progression treatment Gefitinib, erlotinibAZD9291, Rociletinib Afatinib PFS (months) 9-11 8-9 10-13 ? T790M+ (60%) ?

31. Del19/L858R: first line TKI and post progression treatment AZD9291, Rociletinib PFS (months) ? ? Randomized trials of 3 rd vs 1 st generation TKI in 1L are ongoing

32. OPEN Questions: T790M in TKI-naïve patients

33. EURTAC: PFS according to T790M and treatment Costa et al. Clinical Cancer Research 2014 9.7 months 6.0 months T790M detected in 65.2% of patient

34. T790M in TKI-naïve patients 20 T790M TKI-naïve patients (2% of EGFR-mutant tumors) –16/20 concurrent L858R –4/20 concurrent exon 19 deletion Yu et al. Ann Oncol 2014

35. PFS under TKIs inT790M+ patients Yu et al. Ann Oncol 2014

36. Afatinib Dacomitinib Gefitinib Erlotinib EGFRm T790M Wt 1x 10x 100x Relative IC50 Adapted from Oxnard Irreversible TKIs and T790M: small therapeutic window Ideal T790M inhibitor EGFRm T790M Wt

37. OPEN Questions: EGFR-TKIS resistance EGFR-Tkis & future?

38. A001 L858R A006 Ex 19 del A014 L858R A021 L858R A017 L858R A027 Ex 19 del A022 Ex 20 ins A028 L858R TP53 EGFR PTEN MAP3K19 TP53 EGFR ARID1B TP53 EGFR TP53 EGFR Private Shared Trunk 100 No of mutations 50 EGFR mutations are early events Tan, WLCC 2015

39. ETOP 2-11 BELIEF | 18 th ECCO – 40 th ESMO European Cancer Congress, September 2015 Infiammation+/-IMMS angiogenesis

40. Future perspectives Need for a deepened understanding of mechanisms of primary resistance to TKIs in EGFR mutated patients Mutation-based mechanisms: De novo T790M PIK3CA mutations (2%) PTEN loss (5%) Microenvironment mediated cancer progression: Angiogenesis: VEGFR, FGFR (nintedanib, ramucirumab) Paracrine signalling: HGF (ficlatuzumab) Immune escape: PD-1/PDL-1 (immunotherapy)

41. Erlotinib +/- ramucirumab

42. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC

43. PROSE study: VeriStrat proteomic algorithm as a prognostic and predictive test VeriStrat proteomic classifier is prognostic for OS and PFS OS: HR Poor vs Good 2.50 [95% CI 1.88–3.31]; p<0.0001 PFS: HR Poor vs Good 1.75 [95% CI 1.34–2.29]; p<0.0001 43 Good classification group had no significant OS difference between treatment arms: HR Erl vs CT 1.06 [95% CI 0.77–1.46], p=0.714. Poor classification group had significantly shorter OS on erlotinib than on chemotherapy: HR Erl vs CT 1.72 [95% CI 1.08–2.74], p=0.022. Gregorc et al. Lancet Oncol.2014 Jun;15(7):713-21

44. 44 Mok et al. Ann Oncol. 2012;23(Suppl 9):ix391:Abstract 1198P Mok et al. Ann Oncol, 25 (Suppl. 4) (2014), pp. 58–84 (Abstract 205P) Good Poor Phase II study of Ficlatuzumab+Gefitinib vs Gefitinib+placebo VeriStrat retrospective analysis

45. Erlotinib +/- Ficlatuzumab

46. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC FOCAL (NCT02318368) Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects with Previously Untreated Metastatic, EGFR-mutated NSCLC and BDX004 Positive Label

47. AZD9291 +/- MEDI4736

48. Ongoing studies RELAY (NCT02411448) Erlotinib in Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC CAURAL (NCT02454933) Phase III Study of AZD9291 in Combination with MEDI4736 (anti PD-L1 mAb)versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic EGFR T790M positive NSCLC who have received Prior EGFR TKIs FOCAL (NCT02318368) Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects with Previously Untreated Metastatic, EGFR-mutated NSCLC and BDX004 Positive Label

49. Afatinib Gefitinib/Erlotinib L858R Gefitinib/Erlotinib/Afatinib Or CT followed by EGFR-TKis Uncommon EGFRm Afatinib/Erlotinib/Gefitinib -Drug interaction -Patient compliance (ECOG PS, age, education..) -Liver function EGFR- mutant NSCLC Del 19

50. Database Center Net Database NSCLC Navigator Database Clinical Trial ongoing Forum di discussione Link a siti utili www.lucenetwork.it alessandro.urbani@programmaergo.com