Clinical data on EGFR-TKIs and
Overcoming Resistance in
Metastatic NSCLC
2nd Quebec Conference on
Therapeutic Resistance in Cancer
Vera Hirsh, MD, FRCPC
McGill University Health Centre
Montreal, QC, CANADA
EGFR expression in human tumours
Tumours showing
high EGFR expression
High expression
generally associated
with
NSCLC
40-80%
Invasion
Prostate
40-80%
Metastasis
Gastric
33-74%
Late-stage disease
Head and neck
90-100%
Poor outcome
Breast
14-91%
Colorectal
25-77%
Pancreatic
30-50%
Ovarian
35-70%
EGFR mutation causes conformational change and
increased activation
Wild Type EGFR
Mutant EGFR
Ligand
Extracellular domain
Trans-membrane domain
Tyrosine kinase domain
ATP
Tyrosine phosphorylation
Ras-Raf-MAPK
Proliferation
EGFR internalisation
Degradation/recycling
Pi3K-AKT
Survival
EGFR signals for longer
at the cell membrane
Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004
The distribution of activating mutations among EGFR mutation
positive patients is similar in Asian and non-Asian studies
ATP binding
cleft
Regulatory
domain
C-lobe
Transmembrane
region
Extracellular
domain
N-lobe
TK
domain
Chelix
A-loop
21
20
P-loop
19
18
Distribution of mutation types (% of mutations)
Literature review
Asian studies
Non-Asian studies
Most prevalent mutation types
Literature (n=1523)
Literature (n=583)
Exon 19 deletion
51%
58%
Exon 21 point mutation
L858R
42%
32%
Exon 20
2%
6%
Exon 18 G719A/C
3%
2%
Exon 21 L861Q
1%
1%
Some patients had more than one mutation type
BR.21 Study Design
Stratified by:
Centre
PS, 0/1 vs 2/3
Response to prior Rx
(CR/PR:SD:PD)
Prior regimens,
(1 vs 2)
Prior platinum,
(Yes vs no)
R
A
N
D
O
M
I
Z
E
Erlotinib*
150 mg daily
Placebo
“150 mg” daily
*2:1
Randomization
BR.21: Overall Survival
Survival distribution function
1.00
0.75
Erlotinib
(n=488)
Placebo
(n=243)
Median survival (months)
6.7
4.7
1-year survival (%)
31
21
HR=0.70 (95% CI, 0.58-0.85); P < 0.001*
0.50
31%
42.5% improvement in median survival
0.25
Erlotinib
Placebo
21%
0
0
5
10
15
20
25
30
Survival time (months)
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
Shepherd et al. N Engl J Med. 2005;353:123-132.
IPASS: first-line study design
Endpoints
Patients
Primary
• Chemo-naïve
• Age
≥18 years
• Adenocarcinoma
histology
• Never or light exsmokers*
• 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†
• PFS (non-inferiority)
Secondary
• ORR
• OS
• QoL
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
• EGFR mutation
• EGFR-gene-copy number
• EGFR protein expression
*Never smokers, <100 cigarettes in lifetime; light ex-smokers,
stopped 15 years ago and smoked 10 pack years
†Maximum of 6 cycles
Carboplatin / paclitaxel was offered to gefitinib patients upon progression;
AUC, area under curve
Mok et al 2009
IPASS: ORR
Odds ratio (95% CI) = 1.59 (1.25, 2.01) p=0.0001
Patients
(%)
(n=609)
Odds ratio >1 implies a greater chance of response on gefitinib
Odds ratio and p-value from logistic regression with covariates
(n=608)
Mok et al 2009
IPASS: pre-planned analysis of ORR by
EGFR mutation status
Gefitinib
Carboplatin / paclitaxel
ORR (%)
71.2
EGFR M+
OR (95% CI) 2.75 (1.65, 4.60), p=0.0001
47.3
EGFR MOR (95% CI ) 0.04 (0.01, 0.27), p=0.0013
23.5
1.1
(n=132)
(n=129)
ITT population
OR>1 implies greater chance of response on gefitinib
OR and p-value from logistic regression with covariate
(n=91)
(n=85)
Mok et al 2009
IPASS: PFS
Probability 1.0
of PFS
Gefitinib
N
Events
0.8
Carboplatin /
paclitaxel
609
608
453 (74.4%) 497 (81.7%)
HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
0.6
Median PFS (months)
4 months progression-free
6 months progression-free
12 months progression-free
0.4
5.7
61%
48%
25%
5.8
74%
48%
7%
0.2
0.0
0
4
8
Primary Cox analysis with covariates; ITT population
HR <1 implies a lower risk of progression on gefitinib
ITT, intent-to-treat
12
16
20
24 Months
Mok et al 2009
IPASS: pre-planned analysis of PFS
by EGFR mutation status
EGFR M+
N
0.8
1.0
Gefitinib Carboplatin /
paclitaxel
132
129
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
Median (m)
9.5
6.3
0.6
0.4
Probability of PFS
Probability of PFS
1.0
EGFR M-
16
20
Time from randomisation (months)
24
5.5
0.4
0.0
12
1.5
0.6
0.0
8
HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001
Median (m)
0.2
4
N
0.8
0.2
0
Gefitinib Carboplatin /
paclitaxel
91
85
0
4
8
12
16
20
24
Time from randomisation (months)
Primary Cox analysis with covariates; intent-to-treat (ITT) population
Hazard ratio (HR) <1 implies a lower risk of progression on gefitinib
Mok et al 2009
IPASS: EGFR mutation is a strong predictor for differential
PFS benefit between gefitinib and doublet chemotherapy
Probability
of PFS
Gefitinib EGFR M+ (n=132)
Gefitinib EGFR M- (n=91)
Carboplatin / paclitaxel EGFR M+ (n=129)
Carboplatin / paclitaxel EGFR M- (n=85)
1.0
0.8
Treatment
by
subgroup
interaction
test,
p<0.0001
EGFR M+
HR=0.48, 95% CI 0.36, 0.64
p<0.0001
0.6
EGFR M-
HR=2.85, 95% CI 2.05, 3.98
p<0.0001
0.4
0.2
0.0
0
4
8
12
16
Time from randomisation (months)
M+, mutation positive; M-, mutation negative
20
24
PFS by EGFR mutation type: IPASS
Exon 19 deletion
Gefitinib Carboplatin /
paclitaxel
66
74
N
1.0
L858R
N
1.0
HR (95% CI) = 0.553 (0.352, 0.868) p=0.0101
Probability of PFS
Probability of PFS
HR (95% CI) = 0.337 (0.255, 0.560) p<0.0001
0.8
0.6
0.4
0.2
0.0
Gefitinib Carboplatin /
paclitaxel
64
47
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
Time from randomisation (months)
Post hoc Cox analysis with covariates; ITT population
0
4
8
12
16
20
24
Time from randomisation (months)
Mok et al 2009
IPASS: QoL and symptom improvement
rates for overall population
Gefitinib (n=590)
% patients
with sustained
clinically
relevant
improvementa
p=0.0148
Carboplatin/paclitaxel (n=561)
p<0.0001
Evaluable for QoL population ; logistic regression model with covariates
a≥6-point improvement (FACT-L and TOI); ≥2-point improvement (LCS),
maintained ≥21 days
p=0.3037
Mok et al 2009
IPASS: post hoc QoL and symptom improvement
rates for EGFR M+ patients
Gefitinib (n=131)
p<0.0001
% patients
with sustained
clinically
relevant
improvementa
80
70
60
50
40
30
20
10
0
70.2
Carboplatin / paclitaxel (n=128)
p<0.0001
p=0.0003
75.6
70.2
53.9
44.5
Total FACT-L
38.3
TOI
Evaluable for QoL population; logistic regression model with covariates
a6-point improvement (FACT-L and TOI); 2-point improvement (LCS),
maintained ≥21 days
LCS
Mok et al N Engl J Med 2009
IPASS: 2010 updated OS analysis (ITT)
Gefitinib (n=609)
Carboplatin / paclitaxel (n=608)
Probability 1.0
of survival
HR (95% CI)
0.90 (0.79, 1.02); p=0.109
No. events
G 484 (80%)
C / P 470 (77%)
Median OS
G 18.8 months
C / P 17.4 months
0.8
0.6
0.4
0.2
0.0
Patients at risk:
Gefitinib
C/P
0
4
8
12
16
20
24
28
32
36
40
44
48
52
609
608
514
525
468 400
443 364
331
301
270
232
227
183
192
151
148
119
97
65
44
28
13
9
3
1
0
0
Primary Cox analysis with covariates
A hazard ratio <1 implies a lower risk of death on gefitinib
No formal adjustment made for multiple testing
Yang CH et al. ESMO 2010
IPASS: 2010 summary of subsequent
systemic therapy (ITT)
Gefitinib (n=609)*
C / P (n=608)
No further systemic treatment
31%
38%
Chemotherapy
65%
41%
60%
9%
49%
1%
20%
52%
Gefitinib#
5%
41%
Erlotinib#
12%
14%
Other#
5%
6%
Platinum based**
C / P**
EGFR TKI**
*% exclude 20 patients in the gefitinib arm with ongoing randomised treatment
**Patients may have also received other chemotherapy and / or EGFR TKI during the study. Excludes single platinum based
chemotherapy
#Categories are not mutually exclusive
Radiotherapy, surgery, medical procedures and other treatments excluded
Yang CH et al. ESMO 2010
IPASS: 2010 OS by EGFR mutation status
(ITT)
EGFR mutation EGFR mutation +
Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)
Probability of survival
0.8
0.6
0.4
0.2
0.0
HR (95% CI)
1.18 (0.86, 1.63); p=0.309
No. events
G 82 (90%)
C / P 74 (87%)
Median OS
G 11.2 months
C / P 12.7 months
1.0
Probability of survival
HR (95% CI)
1.00 (0.76, 1.33); p=0.990
No. events
G 104 (79%)
C / P 95 (74%)
Median OS
G 21.6 months
C / P 21.9 months
1.0
0.8
0.6
0.4
0.2
0.0
0
4 8 12 16 20 24 28 32 36 40 44 48 52
0
Time from randomisation (months)
Patients at risk:
Gefitinib
132 126 121 103 88 70 58 46 38 24 11
C/P
129 123 112 95 80 68 55 48 40 26 15
6
7
3
0
4 8 12 16 20 24 28 32 36 40 44 48 52
Time from randomisation (months)
0
0
91
85
69 52 40 29 26 19 16 11
76 57 44 33 25 19 16 11
8
3
5
1
1
1
0
1
0
0
Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib
No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed
Yang CH et al. ESMO 2010
IPASS: 2010 overall survival:
EGFR mutation non-evaluable (ITT)
Probability 1.0
of survival
Gefitinib (n=386)
Carboplatin / paclitaxel (n=394)
0.8
HR (95% CI)
0.82 (0.70, 0.96); p=0.015*
No. events
G 298 (77%)
C / P 301 (76%)
Median OS
G 18.9 months
C / P 17.2 months
0.6
0.4
0.2
0.0
0
4
Patients at risk:
Gefitinib 386 319
C/P
394 326
8
12
16
20
24
28
32
36
40
44
48
52
28
12
6
1
0
0
0
0
Time from randomisation (months)
295 257 214 174 150 130
274 225 188 139 109 87
99
68
65
36
Primary Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib
*No formal adjustment for multiple testing was made, therefore statistical significance at the traditional
5% level cannot be claimed
Yang CH
et al. ESMO 2010
PFS (2008)
1.0
Gefitinib EGFR M+
Gefitinib EGFR MC / P EGFR M+
C / P EGFR M-
0.8
0.6
0.4
0.2
0.0
OS (2010)
1.0
Probability of survival
Probability of progression-free survival
IPASS: PFS and OS by known EGFR
mutation status
0.8
Mutation +
0.6
0.4
0.2
Mutation -
0.0
0 4
8 12 16 20 24
0
Time from randomisation (months)
Patients at risk:
Gefitinib M+ 132
Gefitinib M- 91
C / P M+
129
C / P M85
108
21
103
58
71
4
37
14
31
2
7
1
11
1
2
0
3
0
1
0
0
0
0
0
4 8 12 16 20 24 28 32 36 40 44 48 52
Time from randomisation (months)
132
91
129
85
126
69
123
76
121
52
112
57
Patients at risk excludes censored patients and those who have experienced an event
103
40
95
44
88
29
80
33
70
26
68
25
58
19
55
19
46
16
48
16
38 24 11
11 8
5
40 26 15
11 3
1
6
1
7
1
3
0
0
1
0
0
0
0
Yang CH et al. ESMO 2010
IPASS conclusions:
updated survival analysis
•
•
•
•
Mature OS (secondary endpoint) was similar for gefitinib
and carboplatin / paclitaxel with no statistically significant
difference between treatments in the overall population
A consistent OS outcome was observed across clinical
subgroups with no significant difference in OS
There was no significant difference in OS across the
EGFR biomarker subgroups
The true effect of the initial randomised treatment on OS
is likely to have been confounded by the subsequent
therapy, in particular the switching of patients to the
alternative study therapy
Yang CH et al. ESMO 2010
IPASS conclusions:
overall summary
•
IPASS has demonstrated that positive EGFR mutation status is
predictive of benefit from treatment with gefitinib over
chemotherapy in terms of PFS, ORR and HRQoL
•
PFS is an endpoint unlikely to be confounded by subsequent
treatments, therefore is a more appropriate endpoint for
evaluation of treatment effect in first-line treatment of NSCLC
than OS
•
IPASS has demonstrated the importance of biomarker testing in
NSCLC, making a significant step towards personalised
medicine
•
IPASS has changed clinical practice and treatment guidelines for
patients with advanced NSCLC who harbour an EGFR mutation
HRQoL, health-related quality of life; NSCLC, non-small-cell lung cancer; ORR, objective response rate
Yang CH et al. ESMO 2010
Recently reported Phase III studies of gefitinib as
first-line treatment for NSCLC in selected
populations
NEJ002 (Japan)
Patients
•
Chemo-naïve
• EGFR mutationpositive
• PS 0–1
Gefitinib
250 mg/day
•
Chemo-naïve
Carboplatin AUC
6 & paclitaxel
200 mg/m2
3-weekly
Gefitinib
250 mg/day
• Adenocarcinoma
• Never smokers
• ECOG† PS 0–2
• PFS (superiority)
Secondary
First-SIGNAL (Korea)
Patients
Endpoints
Primary
• OS, ORR, QoL,
disease-related
symptoms
safety and tolerability
Endpoints
Primary
• OS
Secondary
Gemcitabine
(1250 mg/m2) &
cisplatin
(80 mg/m2)
3-weekly*
• PFS, ORR, QoL,
disease-related
symptoms
safety and tolerability
†
Eastern Cooperative Oncology Group
9 cycles
*Maximum
Kobayashi et al 2009; Lee et al 2009
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
12 16
months
20
0
24
5
10
15
20
25
0.8
0.6
0.4
0.2
0
30
months
100
200 300
days
IPASS
First-SIGNAL
NEJ002
p<0.0001
p=0.002
p<0.001
100
71.2
47.3
84.6
80
60
40
37.5
20
0
Gefitinib (n=132)
C / P (n=129)
Gefitinib (n=26)
G / C (n=16)
ORR %
8
ORR %
100
80
60
40
20
0
4
1.0
HR (95% CI) = 0.36 (0.25, 0.51)
p<0.001
0.0
0.0
0
ORR %
HR (95% CI) = 0.613 (0.308, 1.221)
p=0.084
Probability of PFS
HR (95% CI) = 0.48 (0.36, 0.64)
p<0.0001
Probability of PFS
Probability of PFS
PFS and ORR with first-line gefitinib versus doublet chemotherapy
in EGFR mutation-positive Asian patients across three Phase III studies
100
80
60
40
20
0
400
500
74.5
29.0
Gefitinib (n=98)
C / P (n=100)
Mok et al 2009; Lee et al 2009; Kobayashi et al 2009
1st-line treatment for mutation positive
patients with NSCLC
EURTAC – Spanish Lung Cancer Group
Phase III1:
Erlotinib
IIIB/IV NSCLC
chemotherapy-naïve
EGFR mutation
Platinum +
taxane or gemcitabine
New-generation erbB inhibitors
Reversible
Irreversible
Gefitinib
BIBW 2992
Erlotinib
Neratinib (HKI-272)
AV-412
XL647
Lapatinib
PF-00299804
BIBW 2992 – potency and selectivity (IC50):
EGFR
[nM]
0.5
HER2
[nM]
14
c-Met
[nM]
>10000
VEGFR
[nM]
>10000
Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A242
Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A244
Resistance mutations
Mutations known to cause resistance to 1st-generation
EGFRi include:
•Exon 20 inframe insertions
•Exon 20 pointmutations
(e.g. T790M)
Sharma et al. Nat Rev Cancer. 2007;7:169–181
BIBW 2992 – active against resistance
mutation
NCI-H1975 cells express L858R/T790M double-mutant EGFR
Li et al. Oncogene. 2008;27:4702–4711
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
(Double Blind)
Oral afatinib 50 mg once daily
plus BSC
Oral placebo once daily
plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter
• Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)
Serum EGFR mutational analysis (all patients)
Demographics/prior treatment
Afatinib (n=390)
Median age, (range)
Placebo (n=195)
58 (30–85) yrs
59 (32–82) yrs
59
60
ECOG PS 0/1/2 (%)
24/69/8
27/65/8
Caucasian/East Asian/other (%)
31/58/11
37/56/7
Never smoker/Light ex-smoker/Other (%)
63/7/30
62/7/31
Stage IIIB/IV (%)
4/96
3/97
Prior chemo: 1 line/> 1 line (%)
59/41
61/39
Prior EGFR TKI: E/G/E+G (%)
55/39/6
55/41/4
10.2 mos
9.7 mos
≥ 48 wks duration on prior E/G (%)
45
47
< 8 wks between prior E/G and randomization (%)
57
63
CR/PR on prior E/G (%)
46
44
Female (%)
Median duration of prior E/G
31
Disease control rate and
objective responses
Independent Review
Afatinib (%)
Placebo (%)
PR, (regardless of confirmation)
13*
0.5
PR, (confirmed)
7*
0.5
SD ≥ 8 wks
51
18
58**
19
DCR (PR+SD) ≥ 8 wks
Median duration of confirmed response: 24 weeks
* P < 0.01 compared to placebo
** P < 0.0001 compard to placebo
PFS by independent review
Primary analysis: Overall survival
Summary of anticancer therapy after
treatment discontinuation
Anticancer therapy
Afatinib (%)
Placebo (%)
Any
68
79
Chemotherapy
61
70
Pemetrexed
36
47
Docetaxel
21
26
Vinorelbine
15
19
Other
26
26
12
24
Anti-angiogenesis
4
6
Radiotherapy
9
14
EGFR TKI
Patient reported outcomes
*All scores were estimated from the EORTC QLQ-LC13 except for “Short of Breath” and “Pain” which used EORTC QLQ-C30;
improved means that EORTC symptom scores were ≥10 points lower than baseline at any time during the study
**EORTC cough, dyspnea and pain endpoints as pre-specified in the trial protocol
LUX-Lung 2: Study design
Patients with: Adenocarcinoma of the lung
Stage IIIB/IV
EGFR mutation
Chemo-naïve or progressive disease following first-line chemotherapy
ECOG 0–2
N=120
Oral BIBW 2992 once-daily
until disease progression or undue toxicity
Response assessment at 4, 8, 12 weeks;
every 8 weeks thereafter
Primary endpoint: objective response rate
Secondary endpoints: PFS, clinical benefit;
time to OR; duration of OR; OS; safety
Results
High degree of efficiency observed:
- For all patients:
Confirmed ORR: 60%
DCR: 86%
Median PFS: 14 months
Median OS: 24 months
-For patients with del19/L858R
Confirmed ORR: 64%
DCR: 88%
Median PFS: 15 months
-Similar efficacy results in the first and second-line settings and across all subgroups
-Similar magnitude of efficacy in patients with L858R as with del19 mutations
LUX-Lung 3: Phase III first-line trial in lung
cancer patients with EGFR mutations
Patients (n=330) with:
Stage IIIB/IV adenocarcinoma of the lung
Presence of EGFR mutation in the tumour tissue
Chemonaive
ECOG 0 or 1
Randomization
2:1
Oral BIBW 2992 40 mg
once-daily
Cisplatin/pemetrexed
Primary endpoint: PFS
Conclusion
• EGFR-TKIs for EGFR-mutated tumours are
becoming standard Rx in first-line metastatic
NSCLC
• BIBW 2992 activity in NSCLC, especially in
EGFR-mutated tumours
- Active against receptors that are resistant to first
generation inhibitors (e.g.EGFRL858R/T790M)
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MC GILL UNIVERSITY