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
NSCLC 40-80%
Prostate 40-80%
Gastric 33-74%
Head and neck 90-100%
Breast 14-91%
Colorectal 25-77%
Pancreatic 30-50%
Ovarian 35-70%
Invasion
Metastasis
Late-stage disease
Poor outcome
Tumours showinghigh EGFR expression
High expressiongenerally associatedwith
ATP
Ras-Raf-MAPKProliferation
Pi3K-AKTSurvival
Ligand
Extracellular domain
Trans-membrane domain
Tyrosine kinase domain
Tyrosine phosphorylation
EGFR internalisationDegradation/recycling
EGFR signals for longerat the cell membrane
Wild Type EGFR Mutant EGFR
EGFR mutation causes conformational change and EGFR mutation causes conformational change and
increased activationincreased activation
Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004
181921 20
N-lobe
Transmembraneregion
Extracellulardomain
ATP binding cleft
C-lobe
A-loop Chelix P-loop
TK domain
Regulatory domain
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%
The distribution of activating mutations among EGFR mutation The distribution of activating mutations among EGFR mutation positive patients is similar in Asian and non-Asian studiespositive patients is similar in Asian and non-Asian studies
Some patients had more than one mutation type
BR.21 Study Design
RANDOM I ZE
Erlotinib* 150 mg daily
Placebo “150 mg”
daily
*2:1 Randomization
Stratified by:CentrePS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)Prior regimens, (1 vs 2)Prior platinum, (Yes vs no)
21%
31%
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
BR.21: Overall Survival
42.5% improvement in median survival
Survival time (months)
Erlotinib
Placebo
HR=0.70 (95% CI, 0.58-0.85); P < 0.001*
Erlotinib (n=488)
Placebo (n=243)
Median survival (months) 6.7 4.7
1-year survival (%) 31 21
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
Shepherd et al. N Engl J Med. 2005;353:123-132.
IPASS: first-line study design
Gefitinib(250 mg/day)
Carboplatin (AUC 5 or 6)/
paclitaxel (200 mg/m2)
3 weekly†
1:1 randomisation
*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
Patients• Chemo-naïve• Age ≥18 years • Adenocarcinoma histology
• Never or light ex-smokers*
• Life expectancy≥12 weeks
• PS 0-2• Measurable stage IIIB/ IV disease
Primary• PFS (non-inferiority)
Secondary• ORR• OS • QoL• Disease-related symptoms • Safety and tolerability
Exploratory• Biomarkers
• EGFR mutation• EGFR-gene-copy number• EGFR protein expression
Endpoints
Mok et al 2009
IPASS: ORR
Odds ratio (95% CI) = 1.59 (1.25, 2.01) p=0.0001
Patients (%)
(n=609) (n=608)
Odds ratio >1 implies a greater chance of response on gefitinibOdds ratio and p-value from logistic regression with covariates Mok et al 2009
IPASS: pre-planned analysis of ORR by EGFR mutation status
Gefitinib Carboplatin / paclitaxel
EGFR M+ OR (95% CI) 2.75 (1.65, 4.60), p=0.0001
EGFR M- OR (95% CI ) 0.04 (0.01, 0.27), p=0.0013
ORR (%)
(n=132) (n=129) (n=91) (n=85)
ITT populationOR>1 implies greater chance of response on gefitinibOR and p-value from logistic regression with covariate
71.2
47.3
1.1
23.5
Mok et al 2009
IPASS: PFS
Primary Cox analysis with covariates; ITT populationHR <1 implies a lower risk of progression on gefitinibITT, intent-to-treat
0 4 8 12 16 20 24 Months0.0
0.2
0.4
0.6
0.8
1.0Probabilityof PFS
609453 (74.4%)
608497 (81.7%)
NEvents
HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
GefitinibCarboplatin /
paclitaxel
Median PFS (months)4 months progression-free6 months progression-free12 months progression-free
5.761%48%25%
5.874%48%7%
Mok et al 2009
IPASS: pre-planned analysis of PFSby EGFR mutation status
0 4 8 12 16 20 24
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f P
FS
N
Median (m)
Gefitinib
132
9.5
Carboplatin / paclitaxel
129
6.3
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
Primary Cox analysis with covariates; intent-to-treat (ITT) populationHazard ratio (HR) <1 implies a lower risk of progression on gefitinib Mok et al 2009
EGFR M+
0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f P
FS
Time from randomisation (months)
N
Median (m)
Gefitinib
91
1.5
Carboplatin / paclitaxel
85
5.5
HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001
EGFR M-
IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy
EGFR M+HR=0.48, 95% CI 0.36, 0.64
p<0.0001
EGFR M-
HR=2.85, 95% CI 2.05, 3.98
p<0.0001
0 4 8 12 16 20 24
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof PFS
Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)
M+, mutation positive; M-, mutation negative
Treatment by
subgroup interaction
test, p<0.0001
PFS by EGFR mutation type: IPASS
Post hoc Cox analysis with covariates; ITT population
Exon 19 deletion L858R
0 4 8 12 16 20 24 0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S
Time from randomisation (months)Time from randomisation (months)
N
Gefitinib
66
Carboplatin / paclitaxel
74
HR (95% CI) = 0.337 (0.255, 0.560) p<0.0001
N
Gefitinib
64
Carboplatin / paclitaxel
47
HR (95% CI) = 0.553 (0.352, 0.868) p=0.0101
Mok et al 2009
IPASS: QoL and symptom improvement rates for overall population
p=0.0148 p<0.0001 p=0.3037% patients with sustained clinically relevant improvementa
Evaluable for QoL population ; logistic regression model with covariatesa≥6-point improvement (FACT-L and TOI); ≥2-point improvement (LCS), maintained ≥21 days
Gefitinib (n=590) Carboplatin/paclitaxel (n=561)
Mok et al 2009
IPASS: post hoc QoL and symptom improvement rates for EGFR M+ patients
Evaluable for QoL population; logistic regression model with covariatesa6-point improvement (FACT-L and TOI); 2-point improvement (LCS),maintained ≥21 days
70.2 70.275.6
44.538.3
53.9
0
10
20
30
40
50
60
70
80
Total FACT-L TOI LCS
p<0.0001 p<0.0001 p=0.0003
% patients with sustained clinically relevant improvementa
Gefitinib (n=131) Carboplatin / paclitaxel (n=128)
Mok et al N Engl J Med 2009
IPASS: 2010 updated OS analysis (ITT)
0 8 16 28 36 44 52
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof survival
Patients at risk:
4 12 20 24 32 40 48
C / PGefitinib 609
608468443
331301
192151
9765
139
00
514525
400364
270232
227183
148119
4428
31
Primary Cox analysis with covariatesA hazard ratio <1 implies a lower risk of death on gefitinibNo formal adjustment made for multiple testing
Gefitinib (n=609)
Carboplatin / paclitaxel (n=608)
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
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%
Platinum based** 60% 9%
C / P** 49% 1%
EGFR TKI** 20% 52%
Gefitinib# 5% 41%
Erlotinib# 12% 14%
Other# 5% 6%
*% 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 exclusiveRadiotherapy, surgery, medical procedures and other treatments excluded
Yang CH et al. ESMO 2010
IPASS: 2010 OS by EGFR mutation status (ITT)
EGFR mutation +
00
Patients at risk:GefitinibC / P
132129
126123
10395
7068
2426
1115
121112
8880
5855
4648
3840
67
30
Time from randomisation (months)
Pro
bab
ilit
y o
f su
rviv
al
EGFR mutation -
520 4 8 12 16 20 44 4824 28 32 36 40
1.0
0.8
0.6
0.4
0.2
0.0
00
51
9185
6976
5257
4044
2933
2625
11
1919
1616
1111
83
01
Time from randomisation (months)
520 4 8 12 16 20 4424 28 32 36 40 48
1.0
0.8
0.6
0.4
0.2
0.0
Pro
bab
ilit
y o
f su
rviv
al
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)
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
Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)
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
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)
0 4 8 24 32 40 52
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof survival
Patients at risk:
12 16 20 28 36 44 48
386394C / P
Gefitinib 319326
295274
150109
9968
2812
00
257225
214188
174139
13087
6536
61
00
Time from randomisation (months)
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
Gefitinib (n=386)
Carboplatin / paclitaxel (n=394)
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
Yang CH et al. ESMO 2010
4 8 16 2412 20
10821
10358
7143714
11120
0000
31271
3010
IPASS: PFS and OS by known EGFR mutation status
Time from randomisation (months)
Pro
bab
ilit
y o
f p
rog
ress
ion
-fre
e su
rviv
al
Patients at risk:Gefitinib M+Gefitinib M-C / P M+C / P M-
1.0
0.8
0.6
0.4
0.2
0.00
13291
12985
PFS (2008)
Gefitinib EGFR M+
Gefitinib EGFR M-
C / P EGFR M+
C / P EGFR M-
13291
12985
1.0
0.8
0.6
0.4
0.2
0.00 4 8 12 16 20 5244
Time from randomisation (months)P
rob
abil
ity
of
surv
ival
OS (2010)
24 28 32 36 40 48
12669
12376
12152
11257
103409544
88298033
70266825
0000
6171
58195519
46164816
38114011
248263
115151
3001
Mutation +
Mutation -
Patients at risk excludes censored patients and those who have experienced an event 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
Kobayashi et al 2009; Lee et al 2009
†Eastern Cooperative Oncology Group*Maximum 9 cycles
Recently reported Phase III studies of gefitinib as first-line treatment for NSCLC in selected
populations
Patients• Chemo-naïve
• EGFR mutation-positive
• PS 0–1
Gefitinib250 mg/day
Carboplatin AUC 6 & paclitaxel 200 mg/m2
3-weekly
Endpoints
Primary• PFS (superiority)
Secondary• OS, ORR, QoL,
disease-related symptomssafety and tolerability
NEJ002 (Japan)
Gefitinib250 mg/day
Gemcitabine (1250 mg/m2) &
cisplatin (80 mg/m2) 3-weekly*
Endpoints
Primary• OS
Secondary• PFS, ORR, QoL,
disease-related symptomssafety and tolerability
First-SIGNAL (Korea)
Patients• Chemo-naïve
• Adenocarcinoma
• Never smokers
• ECOG† PS 0–2
84.6
37.5
0
20
40
60
80
100
PFS and ORR with first-line gefitinib versus doublet chemotherapy in EGFR mutation-positive Asian patients across three Phase III studies
71.2
47.3
0
20
40
60
80
100
p<0.0001
74.5
29.0
0
20
40
60
80
100
p<0.001p=0.002IPASS NEJ002First-SIGNAL
0 4 8 12 16 20 24
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
months
0 100 200 300 400 500
HR (95% CI) = 0.36 (0.25, 0.51) p<0.001
days
Mok et al 2009; Lee et al 2009; Kobayashi et al 2009
Gefitinib (n=98)C / P (n=100)
OR
R %
OR
R %
OR
R %
Gefitinib (n=132)C / P (n=129)
Gefitinib (n=26)G / C (n=16)
HR (95% CI) = 0.613 (0.308, 1.221) p=0.084
0 5 10 15 20 25 30
months
Pro
ba
bil
ity
of
PF
S
Pro
ba
bil
ity
of
PF
S
Pro
ba
bil
ity
of
PF
S
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
1st-line treatment for mutation positive patients with NSCLC
IIIB/IV NSCLCchemotherapy-naïve
EGFR mutation
Erlotinib
Platinum +taxane or gemcitabine
EURTAC – Spanish Lung Cancer GroupPhase III1:
New-generation erbB inhibitors
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
Reversible Irreversible
Gefitinib BIBW 2992
Erlotinib Neratinib (HKI-272)
AV-412
XL647
Lapatinib PF-00299804
EGFR [nM] 0.5
HER2 [nM] 14
c-Met [nM] >10000
VEGFR [nM] >10000
BIBW 2992 – potency and selectivity (IC50):
Resistance mutationsMutations known to cause resistance to 1st-generation EGFRi include:•Exon 20 in-frame insertions•Exon 20 point-mutations (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
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)
• 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)
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
Demographics/prior treatment
31
Afatinib (n=390) Placebo (n=195)
Median age, (range) 58 (30–85) yrs 59 (32–82) yrs
Female (%) 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
Median duration of prior E/G 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
Disease control rate and objective responses
Independent Review
Afatinib (%) Placebo (%)
PR, (regardless of confirmation)
PR, (confirmed)
13*
7*
0.5
0.5
SD ≥ 8 wks 51 18
DCR (PR+SD) ≥ 8 wks 58** 19
Median duration of confirmed response: 24 weeks
* P < 0.01 compared to placebo** P < 0.0001 compard to placebo
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
EGFR TKI 12 24
Anti-angiogenesis 4 6
Radiotherapy 9 14
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 rateSecondary endpoints: PFS, clinical benefit;
time to OR; duration of OR; OS; safety
ResultsHigh 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 ChemonaiveECOG 0 or 1
Randomization
Oral BIBW 2992 40 mg once-daily
Cisplatin/pemetrexed
2:1
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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