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First-line therapy for
metastatic EGFR mutationpositive NSCLC
John Heymach, MD, PhD
Associate Professor
Thoracic/Head and Neck Medical Oncology and
Cancer Biology
9th Annual Winter Lung Cancer Conference
Hollywood, FL
Evolving world of NSCLC into
molecularly defined subsets
EGFR
wild-type
squamous
EGFR
mutant
Nonsquamous
Platinum doublet
EML4-ALK
fusion
KRAS,
other
drivers
EGFR
TKI
Platinum doublet
(Pem)
Bevacizumab
ALK
inhibitor
Other
First-line treatment of EGFR-mutant NSCLC
EGFR
mutant
EGFR
TKI
1.
2.
3.
4.
5.
Is EGFR TKI monotherapy better than chemo?
What about combinations of TKI and chemo?
Are all the mutants the same?
Why are responses to EGFR TKIs heterogenous?
What pathways are driving (relative) resistance?
IPASS trial design
Endpoints
Patients
• Chemonaïve
• Age
≥18 years
• Adenocarcinoma
Primary
Gefitinib
(250 mg daily)
histology
• Never
or light
ex-smokers*
• Life
expectancy
≥12 weeks
• PS
0-2
• Measurable
IV disease
stage IIIB /
1:1 randomization
Carboplatin
(AUC 5 or 6)/
paclitaxel
(200 mg/m2)
3 weekly#
* Never smokers, <100 cigarettes in lifetime; light ex-smokers,
stopped 15 years ago and smoked 10 pack years; # limited to a
maximum of 6 cycles
Carboplatin/paclitaxel was offered to IRESSA patients at progression
PS, performance status; EGFR, epidermal growth factor receptor
• Progression-free survival
(non-inferiority)
Secondary
• Objective response rate
• Overall survival
• Quality of life
• Disease-related symptoms
• Safety and tolerability
Exploratory
• Biomarkers
• EGFR mutation
• EGFR gene copy number
• EGFR protein expression
Mok et al 2009, Fukuoka 2009
IPASS study: PFS by EGFR
mutational status
Mutation positive
Mutation negative
Gefitinib
Carboplatin/
paclitaxel
Gefitinib
Carboplatin/
paclitaxel
97 (73.5%)
111 (86.0%)
88 (96.7%)
70 (82.4%)
PFS
Events, n (%)
p-value
HR
p < 0.001
p < 0.001
0.48 (95% CI, 0.36-0.64)
2.85 (95% CI, 2.05-3.98)
Mok et al, NEJM 2009
Randomized Phase III studies established improved PFS and
RR for EGFR TKIs vs chemo in patients with EGFR mutations
Study
Patient group
EGFR
mut+ (n)
RR (TKI vs
chemo)
PFS months
HR (95%CI)
OS months
HR (95%CI)
IPASS†
(Gefitinib vs Carb/Pac)
East Asian,
light non-smoker,
adenocarcinoma
261
71.2% vs 47.3%
9.8 vs 6.4
0.48 (0.36, 0.64)
21.6 vs 21.9
1.00 (0.76, 1.33)
p=0.990
First-SIGNAL†
(Gefitinib vs Gem/Cis)
Korean, non-smoker,
adenocarcinoma
42
84.6% vs 37.5%
8.4 vs 6.7
0.61 (0.31, 1.22)
30.6 vs 26.5
0.82 (0.35, 1.92)
WJTOG3405 (Gefitinib
vs Cis/Doc)
Japanese,
EGFR mutation
172
62.1% vs 32.2%
9.2 vs 6.3
0.49 (0.34, 0.71)
Not available yet
NEJGSG002 (Gefitinib
vs Carb/Pac)
Japanese,
EGFR mutation
224
73.7% vs 30.7%
10.8 vs 5.4
0.30 (0.22, 0.41)
30.5 vs 23.6
OPTIMAL
(Erlotinib vs
Gem/Carb)
China,
EGFR mutation
150
83% vs 36%
13.1 vs 4.6
0.16 (0.10, 0.26)
Not available yet
EURTAC
(Erlotinib vs platinum
doublet)
Europe,
EGFR mutation
150
54.5% vs 10.5%
5.2 vs 9.4
0.42 (0.27, 0.64)
Not available yet
LUX Lung 3
(Afatinib* vs Cis/Pem)
Global,
Adenocarcinoma,
EGFR mutation
330
Not available yet
Not available yet
Not available yet
*This is an investigational agent. Its efficacy and safety have not been established. †Patients selected according to
clinical background. All other trials selected patients according to EGFR mutation status. Mok TS, et al. N Engl J
Med 2009;361:947–957; Lee JS, et al. WCLC 2009;Abs PRS.4; Mitsudomi T, et al. Lancet Oncology 2010;12:121–
128; Maemondo M, et al. N Engl J Med 2010;362:2380–2388
OPTIMAL study design
Phase III study initiated by Tongji University, Shanghai, China
Recruitment ongoing in China
Erlotinib 150 mg/day
until PD
• Chemo-naїve advanced
NSCLC (N~150)
• EGFR mutation positive
(exon 19 or 21)
• ECOG PS 0–2
Primary endpoint
• PFS
Secondary endpoints
• OS, ORR, QoL and safety
R
1:1
Gemcitabine +
carboplatin (1,000 mg/m2 d1,
8; AUC5 d1) q3w, up to 4 cycles
OPTIMAL: 1st-line erlotinib is associated with
longer PFS vs GC in EGFR-mutant NSCLC
Median PFS
• Erlotinib (N = 82), 13.1 months
• Gemcitabine plus carboplatin (N = 72), 4.6 months
– Hazard ratio 0.16 (95% CI 0.10-0.26)
– Log-rank p < 0.0001
Zhou, You, Lancet Oncology 2011
EURTAC study design
Phase III study initiated by the Spanish Lung Cancer Group (GECP)
Recruitment ongoing in Spain, Italy and France
Erlotinib 150 mg/day
until PD
• Chemo-naїve advanced
NSCLC
• EGFR mutation positive
(exon 19 or L858R)
R
1:1
• ECOG PS 0–2
• (n~150)
Primary endpoint
• PFS
Secondary endpoints
• ORR, 1-year survival, OS, safety, QoL, localization of PD
Platinum-based doublet
chemotherapy
Primary endpoint: PFS in ITT population
(interim analysis 2 Aug 2010)
PFS
• Erlotinib (n = 77), 9.4 months
• Chemotherapy (n = 76), 5.2 months
– HR = 0.42 (0.27-0.64)
– Log-rank p < 0.0001
Rosell et al. Proc ASCO 2011.
First-line treatment of EGFR
mutant NSCLC: Is more better?
• Rationale for chemotherapy plus EGFR TKI
– EGFR-mutant tumors are more sensitive to
chemotherapy than EGFR wt
– Chemotherapy and EGFR TKI may target
different populations
– Greater reduction in tumor bulk  delay in the
emergence of resistant clones
– BUT: EGFR TKIs with chemotherapy did not
improve outcomes in unselected patients
(TRIBUTE, TALENT, INTACT studies)
TRIBUTE: ECP not better than
CP in unselected NSCLC pts
Erlotinib
Placebo
Hazard ratio
p-value
Median survival, ITT
population
10.6 mo
10.5 mo
0.995
.95
Median TTP, ITT
population
5.1 mo
4.9 mo
0.937
.36
Median survival,
never smokers
22.5 mo
10.1 mo
0.49
.01
TTP, never smokers
6.0 mo
4.3 mo
0.50
.002
©2005 by American Society of Clinical Oncology
Herbst R S et al. JCO 2005;23:5892-5899
Prognostic and predictive value of
EGFR mutation from TRIBUTE
ECP in mut+:
53% ORR, 12.5m TTP
CP in mut+:
21% ORR, 6.6m TTP
©2005 by American Society of Clinical Oncology
Eberhard D A et al. JCO 2005;23:5900-5909
CALGB 30406: Randomized phase II trial of E vs ECP
for first-line NSCLC in never or light former smokers
Erlotinib (n = 33)
ECP (n = 33)
p-value
PFS
14.1 (7.0-19.6) mo
17.2 (8.2-27.8) mo
0.3490
OS
31.3 (23.8-NA) mo
38.1 (19.6-NA) mo
0.9227
Janne et al, J Clin Oncol 2010;28:15s (suppl);abstr 7503
Different outcomes for L858R
and exon19 mutations
Exon 19 (n = 39)
L858R (n = 27)
p-value
PFS
17.7 (9.4-27.5) mo
12.1 (7.0-20.1) mo
0.1777
OS
37.5 (24.6-NA) mo
35.5 (17.4-NA) mo
0.5556
Janne et al, Proc IASLC World Lung 2011
Secondary mutations in EGFR (T790M) lead
to acquired resistance to EGFR TKIs
• T790M known as a major mechanism of acquired
resistance
• Data suggests that it often is present at a low frequency
at baseline and selected for after treatment with EGFR
TKI
– EGFR TKIs may kill non-T790M containing clones preferentially,
enriching for T790M+ population
Kobayashi et al, NEJM 2005
Baseline T790M associated with worse outcome in
EGFR-mutant NSCLC after treatment with TKI
T790M+
(n = 45)
T790M(n = 84)
95% CI
p-value
Median PFS
12 mo
18 mo
7.6-16.4
0.05*
Median survival
27 mo
29 mo
24.8-33.2
0.47
* Tarone-Ware
p = 0.02
Rosell et al, CCR 2011;17(5):1160-8
Pretreatment EGFR T790M mutation predicts
shorter EGFR TKI response duration in NSCLC
Cox Regression Model
Variable
Hazard ratio
95% CI
p-value
L858R or Del19 without T790M
1.000
L858R or Del19 with T790M
1.854
1.044–3.292
0.35
Without L858R, Del19 and T790M
4.965
2.524–9.765
< .001
Su et al, JCO 2012: 30:433-440
High IGF-1R is associated with shorter
PFS in EGFR-mutant NSCLC
• High expression ≤165 (n = 41), median OS = 22.6 mo
• Low expression >165 (n = 14), median OS = 16.3 mo
– p = .1445
• Low expression ≤165, median PFS = 12.0 mo
• High expression >165, median PFS = 7.3 mo
– p = .0435
Kato et al, Proc IASLC World Lung, 2011
Summary: First-line treatment of EGFRmutant NSCLC
Which mutant?
EGFR
mutant
T790M?
Other markers?
1. EGFR monotherapy is a standard. PFS for TKI is better than chemo.
Addition of chemo not beneficial thus far.
2. All mutants are not the same.
3. We may be missing baseline T790M  should we be using
combinations for these patients at onset? Or different TKIs?
4. In the future, other markers (e.g. IGF-1R) may predict worse outcome 
combination Rx?
Saturday, February 11, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Mark A Socinski, MD
Co-Chair and Moderator
Neil Love, MD
Faculty
Chandra P Belani, MD
John Heymach, MD, PhD
Pasi A Jänne, MD, PhD
Thomas J Lynch Jr, MD
Heather Wakelee, MD