1. Thoracic Oncology Division, IEO, Milan, Italy
Filippo de Marinis
Thoracic Oncology Division, IEO, Milan, Italy

2. Driver, TT= 3.5 ys Driver, NO TT= 2.4 ys NO driver= 2.1 ys
M Kris et al, JAMA 2014

3. H Beltran et al, JAMA Oncol 2015

4. SL Wood et al, Cancer Treat Reviews 2015

5. ONCOGENIC DRIVERS IN LUNG ADENOCARCINOMA
Incidence Difference between China And Usa

6. M Juchum et al, Drug Resistance Updates 2015

7. A Russo et al , Oncotarget 2015

9. Benefit of 1st-line EGFR TKIs: 9 randomized phase III studies
Study
Ref.
TKI
CTx
N #
PFS mos
HR 95% CI
OS mos
IPASS
Mok
NEJM 2009
gefitinib
Cb/Pac
261
9.5 vs. 6.3
0.48
0.36 – 0.64
21.6 vs. 21.9
First-signal
Han
JCO 2012
Cis/Gem 42
8.0 vs. 6.3
27.2 vs. 25.6
NEJ002
Maemondo NEJM 2010
194
10.8 vs. 5.4
30.5 vs. 23.6
WJTOG 3405
Mitsudomi Lancet 2010
Cis/Doc
172
9.2 vs. 6.3
30.9 vs NR
OPTIMAL
Zhou
Lancet Oncol 2011
erlotinib
164
13.1 vs. 4.6
Not mature
EURTAC
Rosell
Lancet Oncol 2012
P/Doc or Gem
174
10.4 vs 5.1
19.3 vs 19.5
ENSURE Wu
P WCLC 2013
P/ Gem
217
11.0 vs. 5.6
LUX-LUNG 3
Sequist
JCO 2014
afatinib
Cis/Pem
308
13.6 vs. 6.9
31.5 vs 28.3
LUX-LUNG 6
Lancet Oncol 2014
364
0.28
23.6 vs. 23.5

10. 9.5 mos
6.3 mos
T Mok et al, NEJM 2009

11. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study
PFS OS
J-Y Douillard et al. BJC, 2014

12. GEFITINIB IN EGFR MUT+
FIRST IT HAS CHANGED THE «PARADIGM» OF TREATMENT CHEMO-BASED, BEING LINKED THEREFORE TO THE INNOVATIVE DISCOVERY OF EGFR MUTATION

13. PFS NOT assessed by IRC
C Zhou et al, Lancet Oncology 2011

14. PFS assessed by IRC
Y Wu et al, P WCLC 2013

15. R Rosell..F de Marinis et al, Lancet Oncology 2012

16. F de Marinis…R Rosell et al, Future Oncology 2015

17. ERLOTINIB IN EGFR MUT+
THIS WAS THE FIRST TKI REGISTERED IN EU AND US WITH A PHASE III EUROPEAN (ITALY INCLUDED) TRIAL ON CAUCASIAN RACE

18. AFATINIB RESULTS IN LUX-LUNG 3 & 6 TRIALS
Sequist L et al, J Clin Oncol 2013, Wu Y et al, Lancet Oncol 2014

19. L Sequist et al, JCO 2013

20. Yang JC et al, Lancet Oncol 2015

21. Yang JC et al, Lancet Oncol 2015

22. AFATINIB in EGFR MUT+
THIS HAS BEEN THE FIRST TKI TO OBTAIN A PFS > 13 MS IN TWO RANDOMIZED TRIALS AND THE ONLY ONE SHOWING MORE EFFICACY vs CHEMO FOR EXON 19 IN A SUBGROUP ANALYSIS

23. CK Lee et al, JCO 2015

24. EGFR TKIs IN COMPARISON
DOES THE GOLD STANDARD EXIST ?

25. ER Haspinger et al, CROH 2015

26. B Haaland et al, JTO 2014

27. THE IMPACT OF FIRST-LINE TYROSINE KINASE INHIBITORS ON OVERALL SURVIVAL IN PATIENTS WITH A-NSCLC AND ACTIVATING EGFR MUTATIONS: META-ANALYSIS OF PHASE III TRIALS BY MUTATION TYPE (DEL19 OR L858R)
T Kato …F de Marinis et al, The Oncologist 2015 (in press)

28. EFFICACY vs TOLERABILITY
Toxicity

29. STATISTICALLY SIGNIFICANT = CLINICALLY SIGNIFICANT ?
IPASS
EURTAC
LUX-L3
GEFINITIB
ERLOTINIB
AFATINIB VS VS NO

30. JJ Yang et al, Lung Cancer 2013

31. A Matikas et al, Lung Cancer 2015

32. LOCAL THERAPY IN AR at MSKCC
18/184 pts/7+ yrs underwent local therapy for extracranial PD
CNS PD excluded
From time of local therapy:
Median TTP: 10 months
Median time to new systemic Rx: 22 months
Median OS: 41 months
Yu et al, ASCO 2012, Abst#7527

33. ALGHORITM for TREATMENT of EGFR MUT+ve TKI Resistance
NSCLC EGFR Mut+ve responder to TKI
Oligo-Progression
Systemic st Progression
Systemic PD
Systemic 2nd-line therapy
Local therapy continuation of TKI
3rd gen. TKI
Targeting the resistant gene
Irreversible/pan HER TKI
Chemo

34. ASPIRATION TRIAL RESULTS
K Park et al, P ESMO 2014

35. Q Chen et al, Oncotarget 2015

36. Chairmen
F. de Marinis
C. Gridelli
Panelists
F. Cappuzzo
F. Ciardiello
F. Hirsch
T. Mok
R. Rosell
D. Spigel
J. Yang

38. T Mok et al, P ASCO 2013

39. DIRECT COMPARISON: LUX Lung 7 Randomized explorative phase IIb Study
Mutations de l’EGFR
Sample size
Increased to 319
Complete accrual on
Aug

40. M Takeda et al, Lung Cancer 2015

41. W Liang et al, PLOS One 2014

42. IS TOXICITY A REAL DRIVER FOR PATIENTS SELECTION?
Efficacy
Toxicity NO

43. N-H TOXICITY ACROSS THE TKIs REGISTRATION TRIALS
Symptom
LUX-LUNG 6 1
LUX-LUNG 3 2
EURTAC 3
IPASS 4
Afatinib n = 239 (%)
Afatinib n = 229 (%)
Erlotinib n= 84 (%)
Gefitinib n= 132* (%)
All Gr
Gr ≥3
Gr≥ 3
Diarrhoea
88.3
5.4
95.2
14.4
57.0
5.0
46.6
3.8
Rash/acne
80.8
14.6
89.1
16.2
80.0
13.0
66.2
3.1
Stomatitis/
mucositis
51.9
72.1
8.3 NR
17.0
0.2
Paronychia
32.6 -
56.8
11.4
13.5
0.3
1Y Wu et al, P ASCO 2013; 2Yang et al, P ASCO 2012;
3Rosell et al, Lancet Oncol 2012; 4Mok et al, NEJM 2009;
* Toxicity is referred to total 607 pts

44. M Takeda et al, Lung Cancer 2015

45. JC Yang et al, JCO 2013

46. incidences and trends of toxicities with different TKIs
A Passaro…F de Marinis et al. CLC, 2014

47. F de Marinis …R Rosell et al, Future Oncology 2015

49. ALGORITHM: DOSE MODIFICATION DUE TO TREATMENT-RELATED DERMATOLOGIC AEs
Proactive management
Grade 1 or tolerable grade 2 skin reaction
Grade ≥3 or intolerable grade 2
Refer to dermatologist or continue dermatologic treatment
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
Initiate dermatologic treatment
CONTINUE TKI AT CURRENT DOSE
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
According to CTCAE Version 3.0
Lacouture et al. Expert Rev Anticancer Ther. 2013

50. F de Marinis …R Rosell et al, Future Oncology 2015

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

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

53. ! TOXICITY BECOME A DRIVER WHEN… Efficacy
… efficacy don’t confirm the Oncologist expectations

54. Takezawa et al, Cancer Discovery 2012

55. A Matikas et al, Clin Lung Cancer 2015

56. EGFR mut associated with EGFR TKI sensitivity
Stage IIIB/IV NSCLC
EGFR mut associated with EGFR TKI sensitivity
Not PD ≥6 months after EGFR TKI
PD while on EGFR TKI or within 30 days of ceasing EGFR TKI¶
ECOG PS 0–2
Expand MTD: afatinib + cetuximab
(n=100 ± T790M+)
Afatinib cetuximab (escalating dose cohorts)
YY Janjigian et al, P ESMO 2012

57. DIFFERENT SEQUENCE HYPOTHESIS…
First-line
Second-line
Gefitinib
AZD9291
Erlotinib
AZD9291
Afatinib
AZD9291 ? ?
T790M

58. COMBO ?

59. T Seto et al, Lancet, 2014

60. PFS by EGFR mutation type
T Seto et al, Lancet, 2014

61. ETOP 2-11 BELIEF: An open-label multicenter phase II trial
Screening and Registration Phase
Treatment and Evaluation Phase
Procedures at Progression
Eligible and EGFR ex 19 del or L858R mutations
Translational research study subprojects
150 mg erlotinib daily and 15 mg/kg bevacizumab every 3 weeks until progression or unacceptable toxicity
Substudy 1: T790M present (n=35)
Substudy 2: T790M absent (n=67)
Tumor gene expression array
Plasma EGFR mutation monitoring
Recommendation for rebiopsy
Tumor rebiopsy, gene expression array and mutation analysis
EVERYWHERE, we use a color code for easy reading:
ALL pts is black, T790M positive is RED, T790M negative is BLUE (in the plots too)
ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September 2015

62. ETOP 2-11 BELIEF: Erlotinib and bevacizumab in EGFR mutated non-small cell lung cancer
ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September 2015

63. BEVERLY Study design R Control arm Erlotinib 150 mg orally once daily
Experimental arm
Bevacizumab 15 mg/kg iv every 21 days
NSCLC
Non-squamous Activating EGFR mutation Stadio IIIB o IV
PS 0-2 R
1:1
Treatment in both arms will be given until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision to stop
Strata:
PS (0-1 vs 2)
Type of mutation (exon19 del vs 21 L858R mut vs others)
Primary endpoints: investigator-assessed and blinded, indipendent centrally-reviewed PFS
Sample size: 200 pts
Centres involved: about 60
Principal Investigator: C Gridelli