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Title: NSCLC


1
NSCLC
Progress in the treatment
Optimal Treatment with EGFR-TKI Therapy Gefitinib
vs. Erlotinib
? ? ? Chun-Ming Tsai, MD Section of Thoracic
Oncology Chest Department Taipei Veterans
General Hospital School of Medicine National
Yang-Ming University
2
(No Transcript)
3
EGFR Signaling Biomarkers Inhibitors
Anti-EGFR Abs Cetuximab, Panitumumab, Matuzumab,
h-R3, MDX-447 Anti-HER1,HER2,HER4
TKIs Gefitinib, Erlotinib, BIBW-2992, PKI-166,
GW-572016, CI-1033, AEE788 RAS
farnesyltransferase inhibitors MMS214662,
R115777, SCH66336 RAF inhibitors Sorafenib,
L-779450 MEK inhibitors CI-1040, U-0126 mTOR
inhibitors Temsirolimus, RAD001
Small molecule tyrosine kinase inhibitors
ATP
ATP
PI3K
Grb-2
Ras
SOS
Raf
Akt
MEK
STAT 3/5
MAPK
mTOR
Tumour cell proliferation
Tumour cell survival
4
EGFR Mutations in Adenocarcinoma
Mitsudomi, IJCO, 2006
Response Rate vs. Clinical Background
Never
Non-Asian
Female
RR ()
Non-Adeno
Adeno
Ever
Male
Asian
Clinical Background vs. EGFR Mutations
Never
EGFR mutation ()
Non-Asian
Female
Adeno
Non-Adeno
Ever
Male
Asian
5
Gefitinib- and erlotinib-sensitizing mutations of
EGFR
Mutations associated with drug resistance
L747S
D761Y
E884K
T854A
Mutations associated with drug sensitivity
Sharma, et al. Nat Rev Cancer 2007
6
Salvage Treatment in Non-Small Cell Lung
Cancer Comparison of Docetaxel, Pemetrexed
EGFR-TKIs
Gefitinib
117
100 55 125
288 283 TAX317 TAX320
JMEI
428
428
63.4
60
53.1
54.1
47.3
46.6
27
9.1
8.8
6.7
5.8
10
8.3
7.9
7
1-yr Survival () MS (m) DCR
()
5.7
4.6
40
32
30
30
29
19
Pemetrexed
Docetaxel
Docetaxel
Docetaxel
BSC
7
BR.21 versus ISEL placebo-controlled studies
Erlotinib (BR.21)130 reduction in risk of
deathp0.001
Gefitinib (ISEL)211 reduction in risk of
deathNot significant
0.40
0.60
0.80
1.00
1.20
HR
Favours EGFR TKI
Favours placebo
1Shepherd FA, et al. N Engl J Med
200535312332 2Thatcher N, et al. Lancet
2005366152737
8
Why Gefitinib Failed? BR21 vs ISEL
Patient selection and inclusion criteria
Criteria for inclusion in ISEL and BR21 clinical
trials
ISEL development of progressive disease within
90 days of the preceding round of chemotherapy
(early relapse) BR21 no selection for early
relapse
9
Salvage Treatment in Non-Small Cell Lung
Cancer Comparison of Docetaxel, Pemetrexed
EGFR-TKIs
Gefitinib
117
100 55 125
288 283 TAX317 TAX320
JMEI
428
428
63.4
60
53.1
54.1
47.3
46.6
27
9.1
8.8
6.7
5.8
10
8.3
7.9
7
1-yr Survival () MS (m) DCR
()
5.7
4.6
40
32
30
30
29
19
Pemetrexed
Docetaxel
Docetaxel
Docetaxel
BSC
10
Consistent OS with placebo in BR.21 and ISEL
demonstrates similar study populations
1.0 0.8 0.6 0.4 0.2 0
Placebo (BR.21)1
Placebo (ISEL)2
Proportion surviving
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time (months)
1Shepherd FA, et al. N Engl J Med
200535312332 2Thatcher N, et al. Lancet
2005366152737
11
Why Gefitinib Failed? BR21 vs ISEL
Drug dosing
12
Erlotinib and GefitinibSimilar structures,
Different activity?
  • Structural differences may affect
  • plasma, tumour and normal tissue distribution
  • metabolism
  • in-vitro activity
  • clinical efficacy and toxicity

13
Erlotinib is less lipophilic than gefitinib
cLogP 3.30
cLogP 3.87
  • Greater susceptibility to metabolism
  • Increased biliary elimination
  • Increased protein binding
  • Reduced free drug plasma concentration
  • Three-fold difference in lipophilicity

14
Differences in activity of major metabolites
CI
F
MW 446.9
MW 429.2
NH
NH
NH
O
O
O
O
N
H
O
N
N
O
O
O
O
H
N
N
Gefitinib
Desmethyl-gefitinib
Erlotinib
OSI-420
OSI-420 Desmethyl-gefitinib
Activity in cells Erlotinib 10 of gefitinib
Activity in xenograft models Erlotinib Minimal
Li J, et al. Clin Cancer Res 20071337317McKill
op D, et al. Xenobiotica 2006362939
15
Erlotinib phase I monotherapy studies
pharmacokinetics (daily dosing schedule)
  • Dose-proportional Cmax and AUC
  • Repeated daily dosing does not result in drug
    accumulation
  • High plasma exposure at 150mg/day p.o.

Cmax (ng/mL)
AUC024 (nghour/L)
2,500 2,000 1,500 1,000 500 0
45,000 40,000 35,000 30,000 25,000 20,000 15,000 1
0,000 5,000 0
Erlotinib 150mg/day
Gefitinib 225mg/day
Gefitinib 525mg/day
Hidalgo M, et al. J Clin Oncol 200119326779Ran
son M, et al. J Clin Oncol 200220224050
Gefitinib 700mg/day
16
EGFRL858R is More Sensitive to Gefitinib than
EGFRWT
Paez, Science 2004
Gefitinib induces apoptosis in the H3255
17
Characteristics of the Tested Cell Lines
Cell line Cell line Cell Type Pgp EGFR mutation Gefitinib IC50 (?M) Ras mutation
1 H23 A 1 - 10.676 0.1927 K-ras 12
2 H125 AS 0 - 15.822 0.0789 -
3 H226 S 0 - 8.9903 0.6832 -
4 H322 BAC 0 - 0.2689 0.0554 -
5 H358 BAC 0 - 6.0863 0.0574 K-ras 12
6 H460 LC 0 - 10.089 0.232 K-ras 61
7 H522 A 0 - 12.679 0.299 -
8 H647 AS 0 - 12.474 0.215 K-ras 13
9 H820 A 0 del 746-749, T790M, Met 4.7165 0.0112 -
10 H838 AS 0 - 12.372 0.137 -
11 H1155 LC 177.2 - 7.0430 0.0600 K-ras 61
12 H1299 LC 161.5 - 6.1619 0.0809 N-ras 61
13 H3255 A 0 L858R 0.0042 0.0002 -
14 HCC827 A 0 del 746-750 0.0025 0.0001 -
15 PC-9 A NE del 746-750 0.0235 0.0000
Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp Cell lines with high levels of induced Pgp
15 H23 A0.1 A 61.4 - 12.593 0.3104 K-ras 12
16 H23 A0.3 A 129.4 - 12.008 0.5550 K-ras 12
A adenocarcinoma AS adenosquamous carcinoma
BAC bronchioloalveolar cell carcinoma LC large
cell carcinoma S squamous cell carcinoma
Mitsudomi, et al. Oncogene 1991.
18
NSCLC cell lines in vitro surrogates of in vivo
drug sensitivity
19
Gefitinib response of Erlotinib-Refractory Lung
Cancer Involving Meninges Role of EGFR
Mutation
70 y/o Japanese-American woman, never
smoked Stage IV adenocarcinoma, RML with rib
metastases 2002/02 Mediastinoscopic LN
biopsy 2002/04 TRIBUTE trial (TXLCaerlotinib)
42? 2003/11 WBRT due to brain mets 2004/08 Hemipa
resis, diplopia, incontinence (bowel
bladder), wheelchair bound Brain spine MRI
leptomengeal carcinomatosis 2004/10 Could not
tolerated temozolomideCPT-11 in progression.
ECOG PS 4 2004/10 On gefitinib Symptoms
significantly improved in 3 wks 2005/02 Ambulating
independently with a walker 2005/04 ECOG PS
2 2005/06 Aspiration pneumonia and died.
Choong NW, Nature CP Oncol 350, 2006
20
EGFR Mutations Their Effects on Sensitivity
Resistance Towards Inhibition by EGFR TKIs
Choong NW, Nature CP Oncol 350, 2006
21
Differential Responses to Erlotinib in
EGFR-Mutated NSCLC With Acquired Resistance to
Gefitinib Carrying the L747S or T790M Secondary
Mutations
Gefitinib (mean conc.) Gefitinib (mean conc.) Erlotinib (median conc.) Erlotinib (median conc.)
225 mg/day 0.16µg/ml (0.03-0.32) 0.358µmol/L
300 mg/day 0.24µg/ml
1000 mg/day 1.1 µg/ml 150 mg/day 1.26 ? 0.62µg/ml (0.33-2.64) 2.9µmol/L
Costa, JCO, 261182, 2008
22
Differential Responses to Erlotinib in
EGFR-Mutated NSCLC With Acquired Resistance to
Gefitinib Carrying the L747S or T790M Secondary
Mutations
Costa, JCO, 261182, 2008
23
Identification of Agents That Overcome
T790M-Mediated Resistance
Screen 47 known kinase inhibitors for ability to
inhibit H1975 proliferation gt 85 inhibition at 2
?M
Compound IC50 (µM) CI-1033 0.023 EKB-
569 0.033 CL-387,785 0.051
SU-11464 0.450 ZD6474 1.900 GW572016 3.500
Gefitinib 6.600 PKI-166 7.700
Erlotinib 10.000 Inhibition of H1975 cell
proliferation
Identification 3 compounds CL-387,785 EKB-569
CI-1033
Measure EGFR Autophos inhibition
Determine IC50
Ambit Biosciences
24
Erlotinib and Gefitinib AE profiles
Incidence of AEs () Incidence of AEs () Incidence of AEs () Incidence of AEs ()
Erlotinib (n485) Erlotinib (n485) Gefitinib (n1,126) Gefitinib (n1,126)
All Grade 3 All Grade 3
Rash 76 9 37 2
Diarrhea 55 6 27 3
Nausea 40 3 17 1
Anorexia 69 9 17 2
Vomiting 25 3 14 1
Dry skin 12 0 11 0
25
Comparison of Erlotinib (TarcevaTM) versus
Gefitinib (Iressa) as Salvage therapy for the
Treatment of Advanced NSCLC Patients
Retrospective Paired matched analysis
Myung-Ju Ahn, M.D.
Sungkyunkwan University, School of
Medicine Samsung Medical Center
26

Baseline Characteristics
Gfitinib 2002-2005 Erlotinib
2006-2008 Gefitinib 316 vs Erlotinib 257
(Matched Age, Sex, PS, Smoking, No of PriorTx)
Ahn et al, Unpublished data
Characteristics Gefitinib (N174) Erlotinib (N174) P-value
Age Median (Range) 58.0 (25.0-87.0) 59.0 (20.0-82.0)
Age 60 years 100 100 NA
Age gt 60 years 74 74 NA
Sex Male 111 111 NA
Sex Female 63 63 NA
ECOG 0-1 116 116 NA
ECOG 2 58 58 NA
Histology Adenocarcinoma 125 125 NA
Histology Non-adenoca. 49 49 NA
No of prior chemo 2 145 145 NA
No of prior chemo 2lt 29 29 NA
Smoking Never smoker 87 98 0.237
Smoking Current or Ever 87 76 0.237
36 72 50-56
27
Tumor response
Response Gefitinib (N174) Erlotinib (N174) P-value
CR 3 1 -
PR 44 51 -
SD 45 57 -
PD 73 60 -
Not evaluable 9 5 -
Overall response 27.0 29.8 NS
Disease control rate 52.8 62.6 0.103
Ahn et al, Unpublished data
28
(A) Kaplan-Meier curves for overall survival in
all patients and (B) Comparison Kaplan-Meier
curves for overall survival between
gefitinib- and erlotinib treated patients
Ahn et al, Unpublished data
  • Total
  • OS Median 10.7 months

(B) Gefitinib OS Median 10.0 months
Erlotinib OS Median 12.4 months (p0.07)

29
Methods
  • Study scheme
  • Statistics
  • Target N 48 for each group
  • Simons optimal two-stage
    design
  • P010, P125, a-error 5, ß-error
    20, 10 drop-out rates
  • 1st stage responders gt 2/18 ? 2nd
    stage additional 25 pts
  • At least 2 of 3
  • Adenoca.
  • Female
  • Never
  • smoker
  • or
  • EGFR mutant

Gefitinib 250mg/d Q4wKs
Until Disease progression or Intolerable
toxicities
4 weeks
8 weeks
RANDOMI ZAT ION
REEVALUAT ION
REEVALUAT ION
Erlotinib 150mg/d Q4wks
30
Patients Characteristics
Characteristics Characteristics All (n96, ) Gefitinib (n48, ) Erlotinib (n48, ) P value
Age (yrs) Median Range 59 32-83 60 37-83 56 32-81 0.161
Sex Male Female 14 (14.6) 82 (85.4) 7 (14.6) 41 (85.4) 7 (14.6) 41 (85.4) 1.000
ECOG PS 1 2 82 (85.4) 14 (14.6) 41 (85.4) 7 (14.6) 41 (85.4) 7 (14.6) 1.000
Stage IIIB IV Recurred 12 (12.5) 69 (71.9) 13 (13.5) 7 (14.6) 35 (72.9) 6 (12.5) 5 (10.4) 34 (70.8) 7 (14.6) 0.489
Histology Adenocarcinoma Squamous Others 87 (90.6) 6 (6.3) 3 (3.1) 44 (91.7) 3 (6.3) 1 (2.1) 43 (89.6) 3 (6.3) 2 (4.1) 0.798
Prior treatment Neoadjuvant CCRT Adjuvant CCRT Adjuvant Chemo Definitive CCRT Platinum Chemo 2 (2.1) 3 (3.1) 5 (5.2) 3 (3.1) 93 (96.9) 1 (2.1) 2 (4.2) 2 (4.2) 2 (4.2) 45 (93.8) 1 (2.1) 1 (2.1) 3 (6.3) 1 (2.1) 48 (100) 0.078
Smoking Ever-smoker Never-smoker 6 (6.2) 90 (93.7) 4 (8.3) 44 (91.7) 2 (4.2) 46 (95.8) 0.512
EGFR mutation EGFR mutation Wild type Not tested 17 (17.7) 23 (24.0) 56 (58.3) 9 (18.8) 8 (16.7) 31 (64.6) 8 (16.7) 15 (31.3) 25 (52.1) 0.243
31
Response Rates
Gefitinib Gefitinib Erlotinib Erlotinib P value
N (n48) N (n48) P value
CR 1 2.1 1 2.1 0.942
PR 22 45.8 18 37.5 0.942
SD 12 25.0 13 27.1 0.942
PD 12 25.0 15 31.3 0.942
NE 1 2.1 1 2.1 0.942
ORR 23 47.9 (33.8-62.0) 19 39.6 (25.8-53.4) 0.411
DCR 35 72.9 (60.3-85.4) 32 66.7 (53.4-80.0) 0.505
  • Numbers of treatment cycles median 5 (range,
    0.5-20), total 605 cycles
  • Gefitinib group median 6 (range, 0.5-19), total
    331 cycles
  • Erlotinib group median 4 (range, 0.5-20), total
    274 cycles

32
Survival Curves
PFS by Treatment
OS and PFS
Median PFS (95 CI)
4.9 months (1.5-8.3)
3.1 months (0.0-6.4)
Median (95 CI)
20.4 months (8.8-32.0)
4.8 months (2.7-6.9)
P0.167
Median follow-up duration 11.5 months (range,
6.7-20.8)
33
Toxicities
Gefitinib Gefitinib Gefitinib Gefitinib Erlotinib Erlotinib Erlotinib Erlotinib
Toxicity grade Toxicity grade Toxicity grade Toxicity grade Toxicity grade Toxicity grade Toxicity grade Toxicity grade
1 2 3 Total 1 2 3 Total P value
Skin rash 25 (52.1) 25 (52.1) 4 (8.3) 1 (2.1) 30 (62.5) 14 (29.2) 16 (33.3) 5 (10.4) 35 (72.9) 0.003
Dry skin 8 (16.7) 8 (16.7) 0 (0) - 8 (16.7) 9 (18.8) 1 (2.1) - 10 (20.9) 0.733
Paronychia 4 (8.3) 4 (8.3) 1 (2.1) - 5 (10.4) 4 (8.3) 0 (0) - 4 (8.3) 0.767
Diarrhea 8 (16.7) 8 (16.7) 8 (16.7) - 16 (33.4) 14 (29.2) 3 (6.3) - 17 (35.5) 0.238
Mucositis 1 (2.1) 1 (2.1) 2 (4.2) - 3 (6.3) 4 (8.3) 1 (2.1) - 5 (10.4) 0.300
Fatigue 0 (0) 0 (0) 0 (0) - 0 (0) 5 (10.4) 3 (3.1) - 8 (16.7) 0.027
Anorexia 7 (14.6) 7 (14.6) 0 (0) - 7 (14.6) 4 (8.3) 1 (2.1) - 5 (10.4) 0.587
Alopecia 3 (6.3) 3 (6.3) - - 3 (6.3) 1 (2.1) - - 1 (2.1) 0.463
Neuropathy 2 (4.2) 2 (4.2) 2 (4.2) - 4 (8.4) 3 (6.3) 0 (0) - 3 (6.3) 0.414
Infection - - - 1 (2.1) 1 (2.1) - - 1 (2.1) 1 (2.1) 1.000
ILD - - - - - - - - - -
Except 3 mortalities from pneumonia. (2 of
gefitinib and 1 of erlotinib)
34
Clinical Outcomes in Patients with EGFR
Mutations Pooled Analysis of NSCLC Patients
Treated with Either an EGFR TKI or
Chemotherapy L Paz-Ares, et al. ESMO/ECCO
Berlin 2009 J Cell Mol Med 2010 1451-69
35
Summary of search strategy
Reports identified from broad literature search
(n564)
Studies identified from ASCO 20089 search (n42)
Excluded based on abstract or title no clinical
data related to question (- n431)
Studies retained for full paper review (n175)
  • Excluded (n121)
  • PFS/TTP/n not reported for pts with mutations
    (n96)
  • EGFR-TKIs given sequentially or as maintenance
    or
  • adjuvant therapy (n10)
  • Data duplicated in another publication (n15)

Studies included (n54)
36
Summary of data included
Erlotinib Gefitinib Chemotherapy
Pts treated in any line n 365 1,069 375
Pts treated in first-line setting 57 57 95
37
Median PFS from individual studies90 accuracy
intervals (any line of therapy)
Erlotinib
Gefitinib
Chemotherapy
38
EGFR mutation-positive diseaseefficacy of
therapeutic options
Pooled median PFS(95 accuracy interval)
Erlotinib N 365 (2/12)
13.2 (12.014.7)
Pooled studies
Gefitinib N 1069 (19/39)
9.8 (9.210.4)
Chemotherapy N 375
5.9 (5.36.5)
Permutation test for estimated pooled median PFS
(1,000 iterations) EGFR TKI vs chemotherapy
p0.000 (two-sided)
39
SATURN study design
Erlotinib 150mg/day
PD
Chemonaïve advanced NSCLC n1,949
4 cycles of 1st-line platinum-based doublet
Non-PD n889
11
Placebo
PD
Mandatory tumour sampling
  • Stratification factors
  • EGFR IHC (positive vs negative vs indeterminate)
  • Stage (IIIB vs IV)
  • ECOG PS (0 vs 1)
  • CT regimen (cis/gem vs carbo/doc vs others)
  • Smoking history (current vs former vs never)
  • Region
  • Co-primary endpoints
  • PFS in all patients
  • PFS in patients with EGFR IHC tumours
  • Secondary endpoints
  • Overall survival (OS) in all patients and those
    with EGFR IHC tumours, OS and PFS in EGFR IHC
    tumours biomarker analyses safety time to
    symptom progression quality of life (QoL)

Cisplatin/paclitaxel cisplatin/gemcitabine
cisplatin/docetaxel cisplatin/vinorelbine
carboplatin/gemcitabine carboplatin/docetaxel
carboplatin/paclitaxel EGFR epidermal growth
factor receptor IHC immunohistochemistry
40
Randomized phase III study of platinum-doublet CT
followed by gefitinib vs continued CT in pts with
advanced NSCLC Results of WJTOG trial
LBA8012
41
WJTOG 0203 - OS
All
42
SATURN - OS
Non-Squamous cell ca
All
43
WJTOG0203 Hazard Ratios for Death according to
the Subgroup Analysis
44
SATURN OS subgroup analyses by clinical
characteristics
HR (95 CI) n 0.88 (0.741.05) 659 0.64
(0.460.91) 230 0.86 (0.731.01) 746 0.66
(0.421.05) 131 0.77 (0.610.97) 403 0.86
(0.681.10) 360 0.69 (0.451.05) 152 0.75
(0.561.00) 244 0.88 (0.721.08) 493
All
0.81 (0.700.95)
889
Male Female Caucasian Asian Adenocarcinoma Squamo
us-cell Never smoker Former smoker Current smoker
0.4
0.6
0.8
1.0
1.2
HR
Favourserlotinib
Favoursplacebo
45
SATURN PFS (wild type vs. squamous)
Squamous-cell carcinoma
EGFR wild-type
PFS probability
HR0.78 (0.630.96)
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
HR0.76 (0.600.95)
Log-rank p0.0185
Log-rank p0.0148
Erlotinib (n199)
Placebo (n189)
Erlotinib (n166)
Placebo (n193)
0 8 16 24 32 40 48 56 64
72 80 88
0 8 16 24 32 40 48 56 64 72 80
88 96
Time (weeks)
Time (weeks)
46
Comparison of gefitinib and erlotinib in Taiwanese patients with advanced NSCLC A retrospective multi-center study
Total 1122 Female 45 Never/light
smoker 53 Adenocarcinoma 77 Stage
IV 79 Chemo-naive 41
Gefitinib Erlotinib P
N 715 407
ORR 34.4 35.6 0.68
DCR 58.9 65.6 0.02
PFS 3.6 m 4.6 m
Erlotinib group more male, smoker and
non-adeno.
????? 2009 ?? ???
47
Response and Resistance in a NSCLC Patient With
an EGFR Mutation and Leptomeningeal Metastases
Treated With High-Dose Gefitinib
09/2004
Exon 19 deletion, IC50 10-50 nM.
12/2004
Pasi A. Janne and Bruce E. Johnson JCO 2006
48
Efficacy of Erlotinib for Brain and
Leptomeningeal Metastases in Patients with Lung
Adenocarcinoma Who Showed Initial Good Response
to Gefitinib
Katayama, et al. JTO 2009
49
Phase II Study of Erlotinib in NSCLC Patients Who
Failed Prior Gefitinib
Shih et al, WCLC 2007
Response to erlotinib based on RECIST (N24)
50
Erlotinib after gefitinib failure
07/13/2006
Intracranial lesions minimal response
10/09/2006
51
F/1953 Adenocarcinoma, RLL with brain metastasis
2008/02/05 2008/02/26
2008/04/22
2004 - 05 10 02 NVB/Ifo X 6
2005
2008 05
04

2003 01 02 WBRT
2004 02 06 Doc X 6
2003 03 06 Gem/Cis X 6
2007 04 05 WBRT
2008 02/12-25 Erlotinib
Gefitinib
52
Clinical Implications
Gefitinib (250 mg daily) Erlotinib (150 mg daily)
Mean steady-state serum level (?M) 0.4 1.12 3.4
IC50 (?M) of NSCLC cell lines - wild type - activating mutants gt 1 lt 0.05 gt 1 lt 0.05
Patients harbouring tumors with activating-EGFR mutations Preferred, less toxicity Active, more toxic
Patients harbouring wild-type EGFR tumors Inactive Modestly active, preferred over gefitinib, but chemotherapy better
Tsai CM, 2010
53
Clinical Implications
Gefitinib (250 mg daily) Erlotinib (150 mg daily)
Enriched patients IPASS population Active Active, more toxic
Non IPASS population Likely inactive Preferred over gefitinib, but chemotherapy better
Patients harbouring tumors with activating-EGFR mutations have brain metastasis Active More active and toxic also could defer until gefitinib failure (?)
Adenocarcinoma in never or ex-light smokers
Tsai CM, 2010
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