?????EGFR?????????????

1
?????EGFR?????????????
? ? ?????????? ??????
2
IPASS StudyProgression-free survival by EGFR
mutation type (ITT population)
Exon 19 deletion
L858R
Gefitinib (n66)Carboplatin/paclitaxel (n74)
Gefitinib (n64)Carboplatin/paclitaxel (n47)
1.0
1.0
HR (95 CI) 0.377 (0.255, 0.560) No. events
gefitinib, 46 (69.7)No. events C/P, 65 (87.8)
HR (95 CI) 0.553 (0.352, 0.868)No. events
gefitinib, 48 (75.0)No. events C/P, 40 (85.1)
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
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Months
Months
Patients at risk
66
40
18
6
2
0
61
Gefitinib
64
30
13
5
1
0
48
74
15
4
2
1
0
56
C/P
47
17
2
0
0
0
39
Time from randomization (months)
Post-hoc Cox analysis with covariatesp-values
not calculated due to small patient numbers
3
SLOG StudySurvival in patients with EGFR
mutation disease
Median OS HR n (months) (95
CI) 217 27.0 22.731.3
Median PFS HR n (months) (95
CI) 217 14.0 11.316.7
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Probability of PFS
Probability of OS
14.0
27.0
0 12 24 36 48
0 12 24 36 48
Time (months)
Time (months)
Rosell R, et al. N Eng J Med 200936195867
4
Randomized Study on Japanese Population with EGFR
Mutation NEJGSG002
Gefitinib N98 P/C N100
CR 4 0
PR 69 29
SD 13 50
PD 8 15
NE 4 6
??? 73 (74.5) 29(29)
Plt0.001 Plt0.001
HR0.357 95 CI 0.252-0.507, Plt0.001
Kobayashi K, et al. 2009 ASCO Abstract 8016.
5
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6
WJTOG 3405

• Chemotherapy-
• naïve stage IIIb/IV
• NSCLC
• EGFR mutation
• (Exon 19 or 21)
• PS 02
• Age 18y

R A N D O M I S E
Gefitinib
Progression Free Survival
Docetaxel Cisplatin
11
Progression Free Survival

• Primary endpoint PFS
• Secondary endpoint OS ORR QOL Safety

Overall Survival
7
???EGFR????
??/????DNA

• ???????????DNA(?????10?)?
• ??????DNA??????????????
• ?,????????????DNA???

CTC NSCLC???? ??-???74?/??

• CTC

????MALDI-MS
8
??/????DNA EGFR?????????

• ???EGFR???????????
• (???????)?
• ???EGFR??????????????

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Finding EGFR Mutation in Plasma DNA by PCR
Spanish Study
Value
Erlotinib therapy, n () First-line Second- or third-line 113 (52.1)104 (47.9)
EGFR mutation, n () del 19 L858R 135 (62.2) 82 (37.8)
EGFR mutation in serum, n () del 19 L858R Not detected 64 (39.0) 33 (20.1)67 (40.9)
Response (all patients) n ()
CR 24 (12.2)
PR 115 (58.4)
CR / PR 139 (70.6)
SD 38 (19.3)
PD 20 (10.2)
SD / PD 58 (29.4)
Evaluated in 197 patients
False Negative Rate
Evaluated in the serum of 164 patients
CR complete response PR partial response SD
stable disease PD progressive disease
Rosell R, et al. N Eng J Med 200936195867
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?????????
230 pts with tumor samples for EGFR mutation
analysis DHPLC performed in plasma 102 pts
received gefitinib (second line)
Bai and Wang JCO 272653, 2009
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??DNA?????EGFR??????
False negative Rate18.8
False Positive Rate20.2
???78

Bai and Wang JCO 272653, 2009
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IPASS Japanese Population
Patients recruited in Japan (n233)
DNA extracted from paraffin-embedded archival
tumor tissue
cfDNA extracted from pre-dose serum samples
and/or
EGFR mutations detected by ARMS
cfDNA
Tumor tissue
EGFR M ?1/29 mutationsb (n56) EGFR M- 0/29
mutations (n35) EGFR M unknownc (n142)
EGFR M ?1/21 mutationsa (n46) EGFR M- 0/21
mutations (n148) EGFR M unknownc (n39)
Comparison of cfDNA vs tumor tissue EGFR
mutations based on 22 mutations analyzed for cfDNA
ESMO 2009

• 5 patients had a known mutation result by tumor
  tissue but not cfDNA
• 108 patients had a known mutation result by cfDNA
  but not by tumor tissue
• 86 patients had a known mutation status by both
  tumor tissue and cfDNA

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IPASSComparison of EGFR mutation statusin cfDNA
and tumor samples
Patients with known cfDNA and tumorEGFR mutation
status (n86)
Tumor tissue, n
EGFR M
EGFR M-
Total
cfDNA, n EGFR M EGFR M- Total
22 29 51
0 35 35
22 64 86
False Positive Rate0
False negative Rate57.7

• No false positive results
• Specificity and positive predictive value 100
• 29/51 (56.9) of tumor EGFR M were cfDNA EGFR M-
  (false negatives)
• Sensitivity 43.1 (22/51), negative predictive
  value 54.7 (35/64)
• 57/86 (66.3) concordance

Japanese ITT population
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Plasma DNA as Predictive Biomarker in IPASS
(Japanese Subgroup)
EGFR M
EGFR M-
1.0
1.0
HR (95 CI) 0.29 (0.14, 0.60) p0.0009
HR (95 CI) 0.88 (0.61, 1.28) p0.5013
0.8
0.8
0.6
0.6
Probability of progression-free survival
0.4
0.4
0.2
0.2
0.0
0.0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Months
Months
Patients at risk
24
4
2
0
0
21
Gefitinib
70
14
7
1
0
36
12
23
22
4
1
0
0
0
15
78
24
7
1
1
0
54
C/P
C/P 78 67 (85.9)
Gefitinib 70 51 (72.9)
n Events, n ()
C/P 22 19 (86.4)
n Events, n ()
Gefitinib 24 15 (62.5)
Treatment by subgroup interaction test, p0.0448
Japanese ITT population Cox analysis HR lt1
implies a lower risk of progression/death on
gefitinib
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??/????DNA EGFR??????????
???? ??????/???? ??? ???? ??/?????? ??? ??? ??RR ??PFS/OS
Rosell 2009? ??? 164 ARMS 59.1 40.9 --- 70 PFSHR1.48, P0.044, OSHR1.50, P0.910
?????? 2009? ??? 230 DHPLC 78 18.8 20.2 69 PFSP0.04 OSP0.910
IPASS 2009? ??? 86 ARMS 66.3 57.7 0 71.2 HR0.29 P0.0009
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????,????????????????
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Wang, et al Clin.Can.Res. 2010,
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????(I)

• ??????EGFR?????????????
• ?????????
• ???????????

18
2009 WCLC, Okimi et al
19
??,?,65?,?????????????(IIb)3????????
2007.8 Iressa ??? 2009.5 Iressa??21???
20
????(II)

• ???EGFR?????????

21
????EGFR?????-???????????
?? 35.7
?? 28.6
?? 44
?? 28
22
????(III)

• ???????????

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Comparison of Somatic Gene Mutation Analysis
Methods
Method Principle Sensitivity (MT/WT ) Sensitivity (MT/WT ) Turnaround Disadvantages
Direct Sequencing Non-mutation-specific determination of test case nucleotide sequence and comparison with normal sequence 20-50 Slow turnaround (4 days to 2 weeks from paraffin) Slow turnaround (4 days to 2 weeks from paraffin) Poorly quantitative Insensitive Prolonged turnaround
Allele specific probe Polymerase chain reaction/selective detection 10 Rapid (lt2 days from paraffin) Rapid (lt2 days from paraffin) Relatively low sensitivity
High resolution melting analysis, confirmed by direct sequencing Sequences with mutations hybridize at different, fixed temperatures 3-5 Slow turnaround (4 days to 2 weeks from paraffin) Slow turnaround (4 days to 2 weeks from paraffin) Complicated Requires sequencing confirmation Considerable manual input required
Amplification Refractory Mutation System (ARMS) Mutation specific polymerase chain reaction/detection 1 Rapid (lt2 days from paraffin) Rapid (lt2 days from paraffin) Detects only single specific mutation per reaction Requires specially engineered primer/probe
Abbreviations MT Mutant, WT Wild Type Abbreviations MT Mutant, WT Wild Type Abbreviations MT Mutant, WT Wild Type Abbreviations MT Mutant, WT Wild Type Abbreviations MT Mutant, WT Wild Type Abbreviations MT Mutant, WT Wild Type
Jimeno et al. JCO 2008
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