1. EGFR Mutation: Clinical Evidence and Resistance to TKIs
Tony SK Mok, MD Professor, Department of Clinical Oncology The Chinese University of Hong Kong Hong Kong, China

2. Disclosure Slide
Consultant
AstraZeneca Pharmaceuticals LP, Merck Serono, Roche Laboratories Inc, Taiho Pharmaceutical Co Ltd
Speakers Bureau
AstraZeneca Pharmaceuticals LP, Lilly USA LLC, Roche Laboratories Inc

3. Clinical Evidence

4. Early Clinical Experience

5. Prospective Studies of Unselected Patients Treated with EGFR TKIs
Study
Patient #
Agent RR
PFS or OS
IDEAL 11
210
Gefitinib
250 mg
500 mg
18.4% 19.0%
PFS 2.7 months 2.8 months
IDEAL 22
221
12.0% 9.0%
OS 7.0 months 6.9 months
BR-213
488
Erlotinib
8.9%
PFS 2.2 months
ISEL4
1,129
8.2%
OS 5.6 months
1 J Clin Oncol 21: , 2003; 2 JAMA 290: , 2003; 3 N Engl J Med 353: , 2005; 4 Lancet 366: , 2005

6. Prospective Studies of Patients with EGFR Mutations Treated with EGFR TKIs
Author
# screened
EGFR mutations
Agent RR
TTP
Inoue1 99 16
Gefitinib
75%
9.7 mos
Paz-Ares2
1,047
127
Erlotinib
82%
13.3 mos
Tamura3
118 32 ND
Sutani4
100 38
78%
9.4 mos
Morikawa5
123 46
62%
Sequist6 98 31
55%
11.4 mos
1 Inoue A et al. J Clin Oncol 2006;24(21):3340-6; 2 Paz-Ares L et al. J Clin Oncol 2006;24(185 Suppl): Abstract 7020; 3 Tamura K et al. Br J Cancer 2008;98:907-14; 4 Sutani A et al. Br J Cancer 2006;95:1483-9; 5 Morikawa N et al. J Clin Oncol 2006;24(185 Suppl):Abstract 7077; 6 Sequist LV et al. J Clin Oncol 2008;26(15):

7. (AUC 5 or 6)/ paclitaxel (200 mg/m2) 3 weekly†
IPASS
Endpoints
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
Patients
Chemonaïve
Age ≥18 years
Adenocarcinoma histology
Never or light ex-smokers*
Life expectancy ≥12 weeks
PS 0-2
Measurable Stage IIIB/IV disease
Gefitinib (250 mg/day)
1:1 randomisation
Carboplatin
(AUC 5 or 6)/ paclitaxel (200 mg/m2) 3 weekly†
* 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
Mok TS et al. N Engl J Med 2009;361(10):947-57; Mok TS et al. Proc ESMO 2008;Abstract LBA2. 7 7

8. IPASS: Biomarker Study
EGFRF protein
overexpression by IHC
EGFRF gene
polysomy by FISH
EGFRF mutation
by PCR sequencing
365 samples (30%)
406 samples (33%)
437 samples (36%)
266 positive (73%)
249 positive (61%)
261 positive (60%)
Mok TS et al. N Engl J Med 2009;361(10): 8 8

9. Overall Population: Progression-Free Survival
Carboplatin/ paclitaxel
Gefitinib
Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free
5.7 61% 48% 25%
5.8 74% 48% 7%
609
212 76 24 5
608
118 22 3 1
363
412 4 8 12 16 20
Months
0.0
0.2
0.4
0.6
0.8
1.0
Probability of PFS
At risk :
Carboplatin/ paclitaxel
Gefitinib N
Events
609
453 (74.4%)
608
497 (81.7%)
HR (95% CI) = (0.651, 0.845) p <
Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS
Primary Cox analysis with covariates
HR <1 implies a lower risk of progression on gefitinib
Mok TS et al. Proc ESMO 2008;Abstract LBA2. 9 9

10. Objective Response Rate in EGFR Mutation Positive and Negative Patients
Gefitinib
Carboplatin/paclitaxel
EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p =
EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p =
71.2%
Overall response rate (%)
47.3%
23.5%
1.1%
(n = 132)
(n = 129)
(n = 91)
(n = 85)
Odds ratio >1 implies greater chance of response on gefitinib
Mok TS et al. Proc ESMO 2008;Abstract LBA2. 10 10

11. IPASS: EGFR Mutation and Progression-Free Survival
EGFR mutation positive
EGFR mutation negative
Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129)
Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85)
1.0
1.0
HR (95% CI) = 0.48 (0.36, 0.64) p < 0.001
No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%)
HR (95% CI) = 2.85 (2.05, 3.98) p < 0.001
No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%)
0.8
0.8
0.6
0.6
Probability of progression-free survival
Probability of progression-free survival
0.4
0.4
0.2
0.2
0.0
0.0 4 8 12 16 20 24 4 8 12 16 20 24
Months
Months
At risk:
Gefitinib
132
108 71 31 11 3 91 21 4 2 1
C/P
129
103 37 7 2 1 85 58 14 1
Treatment by subgroup interaction test, p <
ITT population Cox analysis with covariates
Mok TS et al. N Engl J Med 2009;361(10):947-57; Copyright © 2009 Massachusetts Medical Society. 11 11

12. IPASS: 2010 OS by EGFR Mutation Status (ITT)
Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129)
HR (95% CI) (0.76, 1.33); p = 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) (0.86, 1.63); p = No. events G 82 (90%) C/P 74 (87%) Median OS G 11.2 months C/P 12.7 months
1.0
1.0
0.8
0.8
0.6
0.6
Probability of survival
Probability of survival
0.4
0.4
0.2
0.2
0.0
0.0 4 8 12 16 20 24 28 32 36 40 44 48 52 4 8 12 16 20 24 28 32 36 40 44 48 52
Time from randomisation (months)
Time from randomisation (months)
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 6 7 3 5 1 91 85 69 76 52 57 40 44 29 33 26 25 19 16 11 8 3
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 12 12

13. IPASS: 2010 Comparison of Post-Discontinuation Treatments
Mutation unknown (N = 780)
Mutation + (N = 261)
Mutation - (N = 176)
Gefitinib 20 patients ongoing*
22%
23%
36%
68% (55% C/P)
78%
73% (57% C/P)
54% (46% C/P)
Received no further systemic treatment
Received further treatment
Received platinum-based chemotherapy at some time†
Received an EGFR TKI at some time†
Received other chemotherapy
78%
77%
64%
26%
14%
19%
15%
14%
10%
C/P
29%
29%
43%
51% (39% G, 8% E, 6% other)‡
64% (47% G, 23% E, 7% other)‡
47% (40% G, 11% E, 5% other)‡
71%
71%
57%
21% 8% 8%
* % exclude the 20 patients in the gefitinib arm with ongoing randomised treatment (3 M+, 1 M-, 16 M unknown); † Patients may have also received other chemotherapy and/or EGFR TKI during the study; Radiotherapy, surgery, medical procedures and other treatments excluded; ‡ Categories are not mutually exclusive 13 13

14. Crossover Explains the Similar Survival
Treatment sequence in patients with EGFR mutation
Over 20 to 24 months
Gefitinib
Chemo
2nd/3rd-line therapy
Death
Chemo
Gefitinib
2nd/3rd-line therapy
Death x
2nd/3rd-line therapy
Chemo
Death
12 months

15. Summary of First-Line EGFR TKI in Patients with EGFR Mutation
Author
Study
N (EGFR mut +) RR
Median PFS
Median OS
Mok et al
IPASS
266
71.2% vs 47.3%
9.8 vs 6.4 months
21.6 vs 21.9 months
Lee et al
First-SIGNAL 42
84.6% vs 37.5%
8.4 vs 6.7 months
30.6 vs 26.5 months
Mitsudomi et al
WJTOG 3405 86
62.1% vs 32.2%
9.2 vs 6.3 months
Pending
Maemondo et al
NEJGSG002
114
73.7% vs 30.7%
10.8 vs 5.4 months
30.5 vs 23.6 months
Zhou et al
OPTIMAL
154
83% vs
36%
13.1 vs 4.6 months NA
Rosell et al
EURTAC
135
58% vs 15%
9.7 vs 5.2 months
Mok et al. NEJM 2009; Lee et al. WCLC 2009; Mitsudomi et al. Lancet Oncology 2010; Maemondo. NEJM 2010

16. EGFR TKI Resistance

17. Clinical Definition: Jackman Criteria for EGFR TKI Resistance
Previously received treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib)
Either of the following:
A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q)
Objective clinical benefit from treatment with an EGFR TKI as defined by either:
Documented partial or complete response (RECIST or WHO), or
Significant and durable (≥6 months) clinical benefit (stable disease as defined by RECIST or WHO) after initiation of gefitinib or erlotinib
Systemic progression of disease (RECIST or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days
No intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy
Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors.
Jackman et al. JCO 2010; Mok JCO 2010

18. RECIST Criteria EGFR TKI Resistance by RECIST 5cm 1cm 1.3cm EGFR TKI
Stop
EGFR TKI?
5cm
1cm
1.3cm
EGFR TKI
EGFR TKI
EGFR TKI
Resistance
by RECIST

19. Cessation of EGFR TKI upon Progression
Changes in tumor on CT and FDG-PET
After stopping gefitinib or erlotinib
After restarting gefitinib or erlotinib
3 wks after adding everolimus
Median change in tumor diameter
Mean change in tumor diameter
Range in change in tumor diameter
+9%
-13% to +29%
-1% 1%
-14% to +23%
-8%
-9%
-34% to +15%
Median change in tumor volume
Mean change in tumor volume
Range in change in tumor volume
+50%
+61%
-4% to +260%
-4%
-27% to +15%
-11%
-10%
-40% to +26%
Median change in SUVmax
Mean change in SUVmax
Range in change in SUVmax
+18%
+23%
-17% to +87%
-45% to +62%
-18%
-39% to +82%
Riely et al. Clin Can Res 13:5150, 2007

20. 45 Females Treated with Gefitinib for Exon 19 Mutation Positive Disease Since 2005
Aug 2008
Oct 2008
Apr 2009
Aug 2009
Dec 2009
May 2010 20 20

21. What Happens at EGFR TKI Resistance in Patients with EGFR Mutation?
Primary resistance
(<10%)
Early
Late

22. What Happens at EGFR TKI Resistance in Patients with EGFR Mutation?
Primary resistance
(<10%)
Early
Late
What accounts for the difference in time to resistance?
Mechanism unknown
T790M: 50%
c-MET overexpression: 20%
Others: 30%

23. What Do We Know about T790M?
Acquired point mutation resulting in threonine-to-methioine amino acid change at positive 790
Kobayashi S et al. N Engl J Med 2005;352;(8): Copyright © 2005 Massachusetts Medical Society.

24. Incidence of De-Novo T790M
Study
Technique
# cases/# EGFRm
Inukai, CR 2006
Sequencing
Enriched PCR
1/98 (1%)
4/98 (4%)
Sequist, JCO 2008
2/34 (6%)
IPASS, NEJM 2009
SARMS
7/261 (3%)
Maheswaran, NEJM 2009
10/36 (28%)
Rossell ASCO 2010
Taqman + PNA probe
45/129 (35%)
Hata, JTO, 2010
PNA-LNA clamp
3/318 (1%)

25. Difference in PFS Is Partly Attributed to the Pre-existing T790M Mutation
SLCG: 129 erlotinib treated patients with activated EGFR mutation subjected to Taqman sequencing for exon 20 T790M
35% found to have pre-treatment co-existence of T790M mutation
PFS in T790M +ive: HR 4.35; (p = 0.001)
Study N
Median
95% CI
p-value
T790M positive 45 12
7.6–16.4
0.05(*)
T790M negative 84 18
14.1–21.9
Rosell R et al. Proc ASCO 2010;Abstract 7514.

26. Implication of “Acquired T790M”
Post-progression survival
Median T790M positive (n = 58), 19 months
Median T790M negative (n = 35), 12 months
p-value = 0.036
Overall survival
Median T790M positive (n = 58), 39 months
Median T790M negative (n = 35), 26 months
p-value = 0.007
Oxnard et al. CCR publication online Dec 2010

27. Current Treatment Options
Continue TKI
Continue TKI and add chemotherapy
Continue TKI and add cetuximab
Stop TKI and use chemotherapy
Irreversible TKI (trial)
Clinical trials

28. Current Treatment Options
Continue TKI
Continue TKI and add chemotherapy
Continue TKI and add cetuximab
Stop TKI and use chemotherapy
Irreversible TKI (trial)
Clinical trials

29. Treatment-Beyond-Progression Study Design
EGFR TKI till PD
by doctor’s discretion*
EGFR TKI
Advanced stage
NSCLC with
EGFR mutation PD
by RECIST
Primary endpoint: OS
Platinum-based
doublet
chemotherapy
* Doctor’s discretion: Symptomatic progression, multiple progression, threat to major organ…etc

30. Current Treatment Options
Continue TKI
Continue TKI and add chemotherapy
Phase II study
BIBW + cetuximab
Continue TKI and add cetuximab
Stop TKI and use chemotherapy
Irreversible TKI (trial)
Clinical trials

31. Current Treatment Options
Continue TKI
Continue TKI and add chemotherapy
Continue TKI and add cetuximab
Stop TKI and use chemotherapy
LUX Lung 1
PF299804
Irreversible TKI (trial)
Clinical trials

32. BIBW 2992 Maintains Inhibitory Activity in Cell Line with Resistant Mutation (T790M)
In vitro kinase assay
Kinases
BIBW 2992
Lapatinib
Gefitinib
EGFR wt
0.5 3
EGFR L858R
0.4 8
0.8
EGFR L858R/T790M 10
>4,000
1,013
Anchorage independent growth
EC50 [nM] 
Wild-type
H1666
L858R
H3255
L858R + T790M
NCI1975
Target
Binding mode
Gefitinib
157 5
>4,000
EGFR
Reversible
Erlotinib
110 40
BIBW 2992 60
0.7 99
EGFR/HER2
Irreversible
CP 714,724
561
HER2
Lapatinib
534 63
Li D et al. Oncogene 2008;27; 32 32

33. LUX-Lung 1 – Trial Design
BISansCond 10
LUX-Lung 1 – Trial Design
Patients with:
Adenocarcinoma of the lung
Stage IIIB/IV
Progressed after one or two lines of chemotherapy (incl one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib
ECOG 0–2
N = 585
Randomization
2:1
Oral BIBW mg once daily
plus best supportive care
Oral placebo once daily
plus best supportive care
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL, safety
Countries: North America, Europe, Asia
Status: Recruitment complete, DBL for primary analysis 6 July 2010 33

34. PFS by Independent Review
Placebo, PFS events = 133, median = 1.1 months
Afatinib, PFS events = 275, median = 3.3 months
Hazard ratio = 0.38
p-value < 0.001
Statistically significant across almost all subgroups
Miller VA et al. Proc ESMO 2010;Abstract LBA1.

35. Overall Survival
Placebo, deaths = 114 (58.5%), median = months (est 4.7 months)
Afatinib, deaths = 244 (62.6%), median = months
Hazard ratio (afatinib vs placebo) = 1.077
p-value (one-sided) =
Miller VA et al. Proc ESMO 2010;Abstract LBA1.

36. Summary EGFR mutation: Biology
Lung cancer with EGFR mutation is driven by oncogenic addiction to EGFR signaling
High affinity to EGFR TKI inhibit tumor growth
EGFR TKI: Clinical evidence
IPASS confirmed the role of EGFR TKI as first-line therapy in patients with EGFR mutation
Higher tumor response rate, longer PFS and better QOL
Similar survival is explained by crossover
Five other randomized studies confirmed the findings
EGFR TKI: Resistance
T790M and c-MET inhibition are two known mechanisms of EGFR TKI resistance
Active investigation ongoing