Transcript NSCLC Progress in the treatment Optimal Treatment with EGFR-TKI Therapy Gefitinib vs. Erlotinib

NSCLC
Progress in the treatment
Optimal Treatment with EGFR-TKI Therapy
Gefitinib vs. Erlotinib
蔡 俊 明
Chun-Ming Tsai, MD
Section of Thoracic Oncology
Chest Department
Taipei Veterans General Hospital
School of Medicine
National Yang-Ming University
EGFR Signaling Biomarkers & Inhibitors
I
Anti-EGFR Abs
Cetuximab, Panitumumab, Matuzumab,
h-R3, MDX-447
Small molecule
tyrosine kinase inhibitors
ATP
Anti-HER1,HER2,HER4 TKIs
I
ATP
PI3K
Gefitinib, Erlotinib, BIBW-2992, PKI-166,
GW-572016, CI-1033, AEE788
Grb-2
SOS
Ras
I
RAS farnesyltransferase inhibitors
MMS214662, R115777, SCH66336
Raf
Akt
I
RAF inhibitors
Sorafenib, L-779450
MEK
STAT 3/5
MAPK
mTOR I
Tumour cell
survival
I
MEK inhibitors
CI-1040, U-0126
mTOR inhibitors
Tumour cell
proliferation
Temsirolimus, RAD001
EGFR Mutations in Adenocarcinoma
Mitsudomi, IJCO, 2006
Response Rate vs. Clinical Background
60
RR (%)
50
40
40
33
33
29
30
20
13
10
11
10
5
0
EGFR mutation (%)
Ethnicity
Gender
Smoking Hx
Histology
Clinical Background vs. EGFR Mutations
60
47
50
40
38
32
30
30
20
10
7
10
7
2
0
Ethnicity
Gender
Smoking Hx
Histology
Gefitinib- and erlotinib-sensitizing mutations of EGFR
Mutations associated
with drug resistance
L747S
D761Y
T854A
Mutations associated
with drug sensitivity
Sharma, et al.
Nat Rev Cancer 2007
E884K
Salvage Treatment in Non-Small Cell Lung Cancer
Comparison of Docetaxel, Pemetrexed & EGFR-TKIs
Gefitinib
100 55
DCR (%)
75
60
45
125
TAX317
47.3 46.6
288 283
TAX320
104
JMEI
63.4
53.1
102
IDEAL1
IDEAL2
66.8
54.1
563 1126
243 488
117
ISEL
BR21
428 428
58.6
53
48
6.7
5.8
8.8
9.1
18.4
28
8.9
8
11.8
~60 ~60
~ 70
32
30
15
~ 80
~27~27
12
8
7
4.6
7.9 8.3
5.7
~ 14
~10 ~10
7.6
6.5
6.7
5.1 5.6
4.7
HR= 0.89
P= 0.087
27
21
0.70
< 0.001
31
22
BSC
Erlotinib
29
Gefitinib
30 30
35
Gefitinib
32
Docetaxel
Pemetrexed
0
19
29
Docetaxel
40
30
20
10
Docetaxel
0
BSC
Gefitinib
4
BSC
1-yr Survival (%)
MS (m)
0
~40
~40
~ 47
BR.21 versus ISEL
placebo-controlled studies
Erlotinib (BR.21)1
30% reduction in risk of death
p=0.001
Gefitinib (ISEL)2
11% reduction
in risk of death
Not 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 2005;353:123–32
N, et al. Lancet 2005;366:1527–37
2Thatcher
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
Salvage Treatment in Non-Small Cell Lung Cancer
Comparison of Docetaxel, Pemetrexed & EGFR-TKIs
Gefitinib
100 55
DCR (%)
75
60
45
125
TAX317
47.3 46.6
288 283
TAX320
104
JMEI
63.4
53.1
102
IDEAL1
IDEAL2
66.8
54.1
563 1126
243 488
117
ISEL
BR21
428 428
58.6
53
48
6.7
5.8
8.8
9.1
18.4
28
8.9
8
11.8
~60 ~60
~ 70
32
30
15
~ 80
~27~27
12
8
7
4.6
7.9 8.3
5.7
~ 14
~10 ~10
7.6
6.5
6.7
5.1 5.6
4.7
HR= 0.89
P= 0.087
27
21
0.70
< 0.0001
31
22
BSC
Erlotinib
29
Gefitinib
30 30
35
Gefitinib
32
Docetaxel
Pemetrexed
0
19
29
Docetaxel
40
30
20
10
Docetaxel
0
BSC
Gefitinib
4
BSC
1-yr Survival (%)
MS (m)
0
~40
~40
~ 47
Consistent OS with placebo in BR.21 and ISEL
demonstrates similar study populations
1.0
Placebo (BR.21)1
Proportion surviving
0.8
Placebo (ISEL)2
0.6
0.4
0.2
0
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 2005;353:123–32
N, et al. Lancet 2005;366:1527–37
2Thatcher
Why Gefitinib Failed? BR21 vs ISEL
Drug dosing
Erlotinib and Gefitinib
Similar structures, Different activity?
CI
MW 446.9
MW 429.2
NH
O
O
O
O
N
F
NH
O
N
N
Erlotinib
O
O
Gefitinib
• Structural differences may affect
–
–
–
–
plasma, tumour and normal tissue distribution
metabolism
in-vitro activity
clinical efficacy and toxicity
N
N
Erlotinib is less lipophilic than gefitinib
CI
MW 446.9
MW 429.2
NH
O
O
O
O
Erlotinib
cLogP = 3.30
N
N
F
NH
O
N
O
O
Gefitinib
cLogP = 3.87
 Greater susceptibility to metabolism
Increased biliary
elimination
 Three-fold
difference
in lipophilicity
 Increased protein binding
 Reduced free drug plasma concentration
N
N
Differences in activity of major metabolites
CI
MW 446.9
MW 429.2
NH
HO
O
O
O
N
NH
O
N
O
N
HO
N
Erlotinib
OSI-420
F
N
Gefitinib
Desmethyl-gefitinib
OSI-420
Desmethyl-gefitinib
Activity in cells
= Erlotinib
≈ 10% of gefitinib
Activity in xenograft models
= Erlotinib
Minimal
Li J, et al. Clin Cancer Res 2007;13:3731–7
McKillop D, et al. Xenobiotica 2006;36:29–39
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.
2,500
Cmax (ng/mL)
2,000
1,500
1,000
500
0
Hidalgo M, et al. J Clin Oncol 2001;19:3267–79
Ranson M, et al. J Clin Oncol 2002;20:2240–50
45,000
40,000
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
AUC0–24 (ng·hour/L)
Erlotinib 150mg/day
Gefitinib 225mg/day
Gefitinib 525mg/day
Gefitinib 700mg/day
EGFRL858R is More Sensitive to Gefitinib than EGFRWT
Paez, Science 2004
400-600 mg p.o.
~ 1.1 - 1.4 M
250 mg p.o.
~ 0.4 M
Gefitinib induces
apoptosis in the H3255
Gefitinib (1.0 µM)
PARP
-tubulin
A549 H1666 H3255
-
+
-
+
-
+
-116 kDa
- 89 kDa
Characteristics of the Tested Cell Lines
Cell line
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H23
H125
H226
H322
H358
H460
H522
H647
H820
H838
H1155
H1299
H3255
HCC827
PC-9
Cell
Type*
Pgp
EGFR mutation
A
AS
S
BAC
BAC
LC
A
AS
A
AS
LC
LC
A
A
A
1
0
0
0
0
0
0
0
0
0
177.2
161.5
0
0
NE
del 746-749, T790M, Met
L858R
del 746-750
del 746-750
Gefitinib
IC50 (M)
Ras
mutation**
10.676 ± 0.1927
K-ras 12
K-ras 12
K-ras 61
K-ras 13
K-ras 61
N-ras 61
-
15.822 ± 0.0789
8.9903 ± 0.6832
0.2689 ± 0.0554
6.0863 ± 0.0574
10.089 ± 0.232
12.679 ± 0.299
12.474 ± 0.215
4.7165 ± 0.0112
12.372 ± 0.137
7.0430 ± 0.0600
6.1619 ± 0.0809
0.0042 ± 0.0002
0.0025 ± 0.0001
0.0235 ± 0.0000
Cell lines with high levels of induced Pgp
15
16
H23 A0.1
H23 A0.3
A
A
61.4
129.4
-
12.593 ± 0.3104
12.008 ± 0.5550
K-ras 12
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.
NSCLC cell lines: in vitro surrogates of in vivo drug
sensitivity
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
2002/04
2003/11
2004/08
Mediastinoscopic LN biopsy
TRIBUTE trial (TXL+Ca+erlotinib) 42%
WBRT due to brain mets
Hemiparesis, diplopia, incontinence
(bowel & bladder), wheelchair bound
Brain & spine MRI: leptomengeal
Prior to gefitinib
2 ms
4.5 Ms
carcinomatosis
2004/10
not tolerated temozolomide+CPT-11
PriorCould
to gefitinib
2 ms
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 3:50, 2006
EGFR Mutations & Their Effects on Sensitivity &
Resistance Towards Inhibition by EGFR TKIs
Choong NW, Nature CP Oncol 3:50, 2006
Differential Responses to Erlotinib in EGFR-Mutated NSCLC With Acquired
Resistance to Gefitinib Carrying the L747S or T790M Secondary Mutations
Gefitinib (mean 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
Erlotinib (median conc.)
150 mg/day
1.26  0.62μg/ml (0.33-2.64) [2.9μmol/L]
Costa, JCO, 26:1182, 2008
Differential Responses to Erlotinib in EGFR-Mutated NSCLC With Acquired
Resistance to Gefitinib Carrying the L747S or T790M Secondary Mutations
Costa, JCO, 26:1182, 2008
Identification of Agents That Overcome
T790M-Mediated Resistance
Screen 47 known kinase inhibitors
for ability to inhibit H1975 proliferation
> 85% inhibition at 2 M
Identification 3 compounds
CL-387,785; EKB-569; CI-1033
Determine IC50
Ambit Biosciences
Measure EGFR
Autophos inhibition
Compound
IC50 (µM)
CI-1033
EKB-569
CL-387,785
SU-11464
ZD6474
GW572016
Gefitinib
PKI-166
Erlotinib
0.023
0.033
0.051
0.450
1.900
3.500
6.600
7.700
10.000
Inhibition of H1975 cell proliferation
Erlotinib and Gefitinib: AE profiles*
Incidence of AEs (%)*
Erlotinib (n=485)
Gefitinib (n=1,126)
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
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
Baseline Characteristics
Ahn et al, Unpublished data
Gfitinib: 2002-2005; Erlotinib: 2006-2008
Gefitinib: 316 vs Erlotinib: 257 (Matched Age, Sex, PS, Smoking, No of PriorTx)
Gefitinib
(N=174)
Erlotinib
(N=174)
Median (Range)
58.0 (25.0-87.0)
59.0 (20.0-82.0)
≤ 60 years
〉 60 years
Male
Female
0-1
≥2
Adenocarcinoma
Non-adenoca.
≤2
2<
Never smoker
Current or Ever
100
74
111
63
116
58
125
49
145
29
87
87
Characteristics
Age
Sex
ECOG
Histology
No of prior
chemo
Smoking
P-value
100
NA
74
111
NA
63 36%
116
NA
58
125 72%
NA
49
145
NA
29
98 50-56%
0.237
76
Tumor response:
Gefitinib
(N=174)
Erlotinib
(N=174)
3
1
44
51
45
57
73
60
9
5
Overall response
27.0%
29.8%
NS
Disease control rate
52.8%
62.6%
0.103
Response
CR
PR
SD
PD
Not evaluable
P-value
-
Ahn et al, Unpublished data
(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
1.0
1.0
0.8
0.8
Probability (Overall Survival)
Probability (Overall Survival)
Ahn et al, Unpublished data
0.6
0.4
0.2
0.6
0.4
Erlotinib
0.2
Gefitinib
0.0
0.0
0
12
24
36
48
60
0
12
(A) Total
OS; Median 10.7 months
24
36
48
60
Months
Months
(B) Gefitinib OS; Median 10.0 months
Erlotinib OS; Median 12.4 months
(p=0.07)
Methods
Adenoca.
 Female
 Never
smoker

or
EGFR mutant
Gefitinib
250mg/d
Q4wKs
Erlotinib
150mg/d
Q4wks
R
E
E
V
A
L
U
A
T
IO
N
8 weeks
At least 2 of 3
R
A
N
D
O
MI
Z
A
T
IO
N
4 weeks
Study scheme
R
E
E
V
A
L
U
A
T
IO
N
Until
Disease
progression
or
Intolerable
toxicities
Statistics
Target N =48 for each group
Simon’s optimal two-stage design
P0=10%, P1=25%, α-error 5%, ß-error 20%, 10% drop-out rates
1st stage: responders > 2/18  2nd stage: additional 25 pts
Patients’ Characteristics
Age (yrs)
Median
Range
All
(n=96, %)
59
32-83
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
Characteristics
Gefitinib
(n=48, %)
60
37-83
Erlotinib
(n=48, %)
56
32-81
P value
0.161
Response Rates
Gefitinib
N
(n=48)
CR
Erlotinib
P value
%
N
(n=48)
%
1
2.1
1
2.1
PR
22
45.8
18
37.5
SD
12
25.0
13
27.1
PD
12
25.0
15
31.3
NE
1
2.1
1
2.1
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
0.942
Survival Curves
OS and PFS
PFS by Treatment
Median PFS (95% CI)
Median (95% CI)
OS
20.4 months (8.8-32.0)
PFS 4.8 months (2.7-6.9)
Gefitinib
4.9 months (1.5-8.3)
Erlotinib
3.1 months (0.0-6.4)
P=0.167
Median follow-up duration: 11.5 months (range, 6.7-20.8)
Toxicities
1
Gefitinib
Erlotinib
Toxicity grade
Toxicity grade
2
3
Total
1
2
3
Total
P value
Skin rash
25 (52.1)
4 (8.3)
1 (2.1)
30 (62.5)
14 (29.2)
16 (33.3)
Dry skin
8 (16.7)
0 (0)
-
8 (16.7)
9 (18.8)
1 (2.1)
-
10 (20.9)
0.733
Paronychia
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)
-
16 (33.4)
14 (29.2)
3 (6.3)
-
17 (35.5)
0.238
Mucositis
1 (2.1)
2 (4.2)
-
3 (6.3)
4 (8.3)
1 (2.1)
-
5 (10.4)
0.300
0 (0)
0 (0)
-
0 (0)
5 (10.4)
3 (3.1)
-
8 (16.7)
0.027
Anorexia
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)
1 (2.1)
-
-
1 (2.1)
0.463
Neuropathy
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
-
-
-
-
-
-
-
-
-
Fatigue
¶
Except 3 mortalities from pneumonia. (2 of gefitinib and 1 of erlotinib)
5 (10.4) 35 (72.9)
0.003
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 14:51-69
Summary of search strategy
Reports identified from broad literature search (n=564)
Studies identified from
ASCO 2008–9 search (+n=42)
Excluded based on abstract
or title: no clinical data
related to question (- n=431)
Studies retained for full paper review (n=175)
Excluded (n=121)
• PFS/TTP/n not reported for pts with mutations (n=96)
• EGFR-TKIs given sequentially or as maintenance or
adjuvant therapy (n=10)
• Data duplicated in another publication (n=15)
Studies included (n=54)
Summary of data included
Pts treated in any line; n
Pts treated
in first-line setting
Erlotinib
Gefitinib
Chemotherapy
365
1,069
375
57%
57%
95%
Total number of patients = 1,809
(65% treated in first-line setting)
Median PFS from individual studies
90% accuracy intervals (any line of therapy)
Erlotinib
Gefitinib
Chemotherapy
EGFR mutation-positive disease:
efficacy of therapeutic options
Pooled studies
Pooled median PFS
(95% accuracy interval)
Erlotinib N = 365 (2/12)
13.2 (12.0–14.7)
Gefitinib N = 1069 (19/39)
9.8 (9.2–10.4)
Chemotherapy N = 375
5.9 (5.3–6.5)
Permutation test for estimated pooled median PFS (1,000 iterations)
EGFR TKI vs chemotherapy p=0.000 (two-sided)
SATURN study design
Erlotinib
150mg/day
Chemonaïve
advanced
NSCLC
n=1,949
4 cycles of
1st-line platinumbased doublet*
Non-PD
n=889
PD
1:1
Placebo
PD
Mandatory tumour
sampling
Stratification factors:
Co-primary endpoints:







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

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
Randomized phase III study of platinum-doublet CT
followed by gefitinib vs continued CT in pts with advanced
NSCLC: Results of WJTOG trial
LBA#8012
WJTOG 0203 - OS
All
OS- Adenocarcinoma
SATURN - OS
All
Non-Squamous cell ca
WJTOG0203: Hazard Ratios for Death
according to the Subgroup Analysis
SATURN: OS subgroup analyses by clinical
characteristics
HR (95% CI)
n
All
0.81 (0.70–0.95)
Male
0.88 (0.74–1.05)
659
Female
0.64 (0.46–0.91)
230
Caucasian
0.86 (0.73–1.01)
746
Asian
0.66 (0.42–1.05)
131
Adenocarcinoma
0.77 (0.61–0.97)
403
Squamous-cell
0.86 (0.68–1.10)
360
Never smoker
0.69 (0.45–1.05)
152
Former smoker
0.75 (0.56–1.00)
244
Current smoker
0.88 (0.72–1.08)
493
0.4
0.6
0.8
Favours
erlotinib
1.0
1.2
HR
Favours
placebo
889
SATURN: PFS (wild type vs. squamous)
EGFR wild-type
Squamous-cell carcinoma
PFS probability
HR=0.78 (0.63–0.96)
1.0
1.0
HR=0.76 (0.60–0.95)
Log-rank p=0.0185
0.8
Erlotinib (n=199)
Placebo (n=189)
0.6
0.8
0.6
0.4
0.4
0.2
0.2
0
0
0
8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
Log-rank p=0.0148
Erlotinib (n=166)
Placebo (n=193)
0
8 16 24 32 40 48 56 64 72 80 88
Time (weeks)
Comparison of gefitinib and erlotinib in Taiwanese patients with
advanced NSCLC: A retrospective multi-center study
Total:
1122
Female
Never/light smoker
Adenocarcinoma
Stage IV
Chemo-naive
45%
53%
77%
79%
41%
Gefitinib
Erlotinib*
715
407
ORR
34.4%
35.6%
0.68
DCR
58.9%
65.6%
0.02
PFS
3.6 m
4.6 m
N
P
* Erlotinib group: more male, smoker and non-adeno.
胸腔醫學會 2009 北榮 范紋健
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.
Pasi A. Ja¨nne and Bruce E. Johnson JCO 2006
12/2004
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
Phase II Study of Erlotinib in NSCLC Patients Who
Failed Prior Gefitinib
Shih et al, WCLC 2007
Response to erlotinib based on RECIST (N=24)
Response
N (%)
PR
2 (8.3)
SD
5 (20.8)
PD
17 (70.8)
ORR
2 (8.3)
DCR
7 (29.2)
Survival time
MS
TTP
95%CI
0 - 19.6
13.0 - 45.4
Days
95%CI
379
126 - 632
64
29 - 99
Response of Brain Metastases
(total N=10)
SD
4 (40%)
PD
6 (60%)
Duration of Intracranial Disease
Control (days) *
39
0 - 200
ORR: objective response rate, DCR: desease control rate (CR+PR+SD)
MS: median survival, TTP= time to progression
* All 4 cases with intra-cranial disease control had progression of extra-cranial lesions.
Erlotinib after gefitinib failure
Intracranial lesions: minimal response
07/13/2006
10/09/2006
F/1953 Adenocarcinoma, RLL with brain metastasis
2008/02/05
2003
01– 02
2003
03 – 06
WBRT Gem/Cis
X6
2008/02/26
2004
02 – 06
2004 - 05
10 – 02
Doc
X6
NVB/Ifo
X6
2008/04/22
2005
05
2007
04 – 05
WBRT
2008
04
Gefitinib
2008
02/12-25
Erlotinib
Clinical Implications:
Mean steady-state serum
level (M)
IC50 (M) of NSCLC cell lines
－ wild type
－ activating mutants
Patients harbouring tumors
with activating-EGFR
mutations
Patients harbouring wild-type
EGFR tumors
Gefitinib
Erlotinib
(250 mg daily)
(150 mg daily)
0.4
1.12 – 3.4
>1
< 0.05
>1
< 0.05
Preferred,
less toxicity
Active,
more toxic
Inactive
Modestly active,
preferred over gefitinib,
but chemotherapy
better
Tsai CM, 2010
Clinical Implications:
Gefitinib
Erlotinib
(250 mg daily)
(150 mg daily)
Active
Active, more toxic
Likely inactive
Preferred over gefitinib,
but chemotherapy
better
Active
More active and toxic;
also could defer until
gefitinib failure (?)
Enriched patients
IPASS population*
Non IPASS population
Patients harbouring tumors
with activating-EGFR
mutations have brain
metastasis
* Adenocarcinoma in never or ex-light smokers
Tsai CM, 2010