New Strategies on Horizon
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Transcript of New Strategies on Horizon
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New Strategies on Horizon
Tony Mok MD
Dept of Clinical Oncology
The Chinse University of Hong Kong
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TKI is foreverTKI is forever
Addressing the
difference
Addressing the
differenceNovel TargetNovel Target
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TKI is foreverTKI is forever
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5cm5cm
PR at 2cmPR at 2cm
RECIST PDAt 2.6cm
RECIST PDAt 2.6cm
6m0m 12m 18m
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5cm5cm
PR at 2cmPR at 2cm
Symptomatic PD at 4cm
Symptomatic PD at 4cm
6m0m 12m 18m
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5cm5cm
PR at 2cmPR at 2cm
RECIST PDAt 2.6cm
RECIST PDAt 2.6cm
Symptomatic PD at 4cm
Symptomatic PD at 4cm
MolecularresistanceMolecularresistance
6m0m 12m 18m
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ASPIRATION: To optimize treatment duration
Advance stageNSCLC with
EGFR Mutation
Advance stageNSCLC with
EGFR Mutation
EGFR TKIEGFR TKI
PDBy RECIST
PDBy RECIST
PDBy doctor
Discretion*
PDBy doctor
Discretion*
PFS 1PFS 1
PFS 2 PFS 2
*Doctor Discretion: Symptomatic progression, multiple progressionThreat to major organ…etc*Doctor Discretion: Symptomatic progression, multiple progressionThreat to major organ…etc
EGFR TKIEGFR TKI
PI: K Park
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TKI Resistance after ASCO 2012
Oncogenic driven cancer with tumor response to TKI
Oligo-ProgressionSystemic
Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant
gene
Chemotherapy
Chemotherapy + TKI
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Treatment of TKI ResistanceOncogenic driven cancer with tumor response to TKI
Oligo-ProgressionSystemic
Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant
gene
Chemotherapy
Chemotherapy + TKI
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Local Therapy in Acquired Resistance: MSKCC
• 18/184 pts/7+ yrs underwent local therapy for extracranial PD – CNS PD excluded
• From time of local therapy– Median TTP: 10 months– Median time to new systemic Rx: 22 months – Median OS: 41 months
Yu, ASCO 2012, Abst#7527
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Local treatment to oligo-progression plus continuation of TKI
• Colorado University collection of 65 patients with oncogenic driven cancer (EGFR mutation or ALK positive)
• All received EGFR TKI or Crizotinib• PFS 1 defined as <4 sites of progression
– Local ablative therapy offered to all sites of involvement and continue TKI
• PFS 2 defined as from time of local therapy to second progression
ASCO 2012 Abst 7526
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Ϯ Includes 3 patients who progressed systemically (eCNS) and simultaneously within the CNS
Site of first progression
Number of patients
PFS1(months)(95% CI)
PFS2(months)(95% CI)
Site of 2nd progression
CNS 1010.9
7.3 – 18.37.1
1.7 – 11.3
2 (20%) no prog3 (30%) CNS5 (50%) eCNS
eCNSϮ 159.0
6.5 – 13.84.0
2.7 -7.4
4 (27%) no prog3 (20%) CNS8 (53%) eCNS
All patients 259.8
8.8 – 13.86.2
3.7 – 8.0
6 (24%) no prog7 (28%) CNS
12 (48%) eCNS
PFS of patients treated with LAT and continuation of TKI therapy
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Future Prospective Study?Oncogenic driven cancer with tumor response to TKI
PD by RECIST <4 sites of PD
Local therapy + continuation of TKI
Chemotherapy
Randomized
Primary endpoint: PFSSecondary endpoint: OS, RR, QOL
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Treatment of TKI ResistanceOncogenic driven cancer with tumor response to TKI
Oligo-ProgressionSystemic
Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant
gene
Chemotherapy
Chemotherapy + TKI
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Chemo/Erlotinib vs. Chemo Alone at Progression after Acquired Resistance
• N = 78 retrospective review of outcomes – chemo alone (N = 44) or– chemo/erlotinib (N = 34)
• RR 18% (chemo) vs. 41% with chemo/erlotinib)
• No differences in PFS or OS between these two strategies
Goldberg, ASCO 2012, Abst#7524
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IMPRESS: Chemotherapy with or with gefitinib at progression
Advance stageNSCLC with
EGFR Mutation
Advance stageNSCLC with
EGFR Mutation
GefintinibGefintinib
PDBy RECIST
PDBy RECIST
Gefitinib +Alimta/Platinum
Gefitinib +Alimta/Platinum
Alimta/PlatinumAlimta/Platinum
Primary endpoint: PFSPrimary endpoint: PFS
Co-PI: Soria J; Mok T
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Addressing the
difference
Addressing the
difference
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Classic concept of cancer
Cancer cell division
Fourth orlater mutation
Third mutation
Second mutation
First mutation
Uncontrolled growth
Cell Suicide or Apoptosis
Cell damage—no repair
Normal cell division
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What if the cancer is not homogenous?
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Early finding of intratumor heterogeneity in lung cancer
• Twenty-one patients with recurrent EGFR mutation positive lung cancer
• Surgical specimens were retrieved from archive
• Using laser capture microdissection and analyzed 50–60 areas from each tissue
• Fifteen tissues consisted only of cells with EGFR mutations
• Six tissues contained both mutated and non-mutated cells.
Taniguchi K, Cancer Sci, 2008 May;99(5):929-35
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Combination strategy for heterogeneous tumor
• Chemotherapy is standard cytotoxic for adenocarcinoma
• Adenocarcinoma has a higher incidence of harboring driver oncogene, especially among the non-smoker adenocarcinoma
• Cancer patient may have heterogeneous mix of tumor with or without the driver oncogenes
• We need a rational approach to “Chemotherapy + Targeted Therapy”
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Intercalated combination ofChemotherapy + EGFR TKI
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NVALT-10:Design
Patients
Locally advanced or metastatic NSCLC(IIIB-IV)
Failed first line platinum therapy
WHO PS 0-2
Combinationtherapy
Monotherapy
Squamous
Erlotinib 150mg p.o. day 2-16+ Docetaxel 75 mg/m2 day 1 q3 weeks
Non- Squamous
Erlotinib 150mg p.o. day 2-16+ Pemetrexed 500 mg/m2 day 1 q3 weeks
Squamous and Non Squamous
Erlotinib 150mg p.o. daily
Chemotherapy planned 4 cyclesErlotinib until disease progression Aerts et al ESMO 2012
Primary endpoint: PFS
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PFS and OS
Adjusted for stratification factors: p=0.09, HR=0.78 (0.59-1.04)
Adjusted for stratification factors: p=0.02, HR=0.67 (0.50 – 0.93)
Improvement in patients with or without EGFR mutation?
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Improvement limited to non-squamous cell carcinoma
• Lack of improvement in squamous cell carcinoma– No improvement in
EGFR wild type
• Slight improvement in non-squamous cell carcinoma– May imply benefit in a
small portion of patients with EGFR mutations
For a population dominated by EGFR wild type, control arm should be Alimta
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Placebo
Erlotinib 150mg/day
Previously untreated stage IIIB/IV NSCLC,
PS 0/1(n=451)
R
PD
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin
75mg/m2 (d1) + placebo (d15–28); q4wks x 6 cycles
GC-placebo (n=225)
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin
75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles
GC-erlotinib (n=226)
PD
Study treatment Maintenance phaseScreening
Erlotinib 150mg/dayPrimary endpoint: PFS with IRC confirmation
Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL
FASTACT-2 (MO22201; CTONG0902) study design
NSCLC = non-small cell lung cancer; PS = performance status; PD = disease progression; AUC = area under the curve; q4wks = every 4 weeks; IRC = independent review committee; OS = overall survival; ORR = objective response rate; TTP = time to progression; NPR = non-progression rate; QoL = quality of life
1:1; stratified by stage, histology, smoking status and chemo regimen
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EGFR mutation status in FASTACT-2
9797
210 patients in the study had unknown EGFR mutation status
136136
Erlotinib n=49
Placebo n=48
Erlotinib n=69
Placebo n=67
500
400
300
200
100
0
451
241
All patients Tested for EGFR mutation
EGFR mutation-positive (Mut+)EGFR wild-type (WT)Single resistance mutation
300
250
200
150
100
50
0EGFR mutation status
**
* n=8: one with T790M (received placebo); one with S768I (received placebo); six with exon 20 mutations (two received erlotinib, four received placebo)* n=8: one with T790M (received placebo); one with S768I (received placebo); six with exon 20 mutations (two received erlotinib, four received placebo)
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PFS in ITT population (22 Jun 2012)P
FS
pro
babi
lity
Time (months)
1.0
0.8
0.6
0.4
0.2
00 3836343230282624222018161412108642
6.0 7.6
GC-erlotinib (n=226)
GC-placebo (n=225)
HR=0.57 (95% CI 0.47–0.69) p<0.0001
E 226 192 162 136 102 81 70 59 52 45 39 32 24 17 12 6 1 0 0 0P 225 185 156 114 57 31 22 15 12 9 7 6 4 3 3 2 1 1 1 0
CI = confidence intervals
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OS in ITT population (22 Jun 2012)
15.2 18.3
GC-erlotinib (n=226)
GC-placebo (n=225)
HR=0.79 (95% CI 0.64–0.99) p=0.0420
OS
pro
babi
lity
Time (months)
1.0
0.8
0.6
0.4
0.2
00 3836343230282624222018161412108642
E 226 219 202 191 176 165 154 138 129 114 98 85 68 52 39 23 9 6 1 0 P 225 218 206 185 168 156 138 120 103 92 78 68 53 37 24 13 6 4 0 0
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PFS and OS in EGFR WT subgroup (22 Jun 2012)
1.0
0.8
0.6
0.4
0.2
0
Time (months)
PF
S p
roba
bilit
y
1.0
0.8
0.6
0.4
0.2
0
Time (months)
0 8 12 16 20 24 28 40
OS
pro
babi
lity
0 4 8 12 16 20 24 28 3632 40
5.9 6.7 12.2 14.9
GC-erlotinib (n=69)
GC-placebo (n=67)
HR=0.77 (0.53–1.11)p=0.1612
GC-erlotinib (n=69)
GC-placebo (n=67)HR=0.97 (0.69–1.36)p=0.8467RR: 26.1% vs 19.4%
PFS OS
4 32 36
E 69 60 49 43 30 19 12 6 4 0 0P 67 57 43 34 23 15 7 3 2 1 0
E 69 45 15 7 5 3 2 1 0 0 0P 67 46 16 5 3 2 1 1 1 1 0
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PFS and OS in EGFR Mut+ subgroup (22 Jun 2012)
1.0
0.8
0.6
0.4
0.2
0
Time (months)
PF
S p
roba
bilit
y
1.0
0.8
0.6
0.4
0.2
0
Time (months)
OS
pro
babi
lity
0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 36
6.9 16.8 20.6 31.4
GC-erlotinib (n=49)
GC-placebo (n=48)
HR=0.48 (0.27–0.84)p=0.0092
GC-erlotinib (n=49)GC-placebo (n=48)
HR=0.25 (0.16–0.39)p<0.0001RR: 83.7% vs 14.6%
PFS OS
E 49 46 42 33 25 19 11 6 0P 48 35 16 5 4 2 2 1 0
E 49 48 46 45 41 33 24 15 3 0P 48 48 43 36 26 24 14 6 0 0
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Novel TargetNovel Target
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MET PathwaysTarget HGFAMG 102AVEO299
Target HGFAMG 102AVEO299
Target Met receptorMetMab
Target Met receptorMetMabTarget TK
ARQ197, XL184 + many
Target TKARQ197, XL184
+ many
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Phase 2 Study Design: Ficlatuzumab + Gefitinib in NSCLC in the First Line
Stratification:•ECOG PS•Smoking history•Gender
Stratification:•ECOG PS•Smoking history•Gender
Ficlatuzumab+ gefitinib(n=94)
Ficlatuzumab+ gefitinib(n=94)
Early discontinuations, nonresponders, or patients
who do not want to participate in crossover
Early discontinuations, nonresponders, or patients
who do not want to participate in crossover
Crossover permitted:gefitinib + ficlatuzumab
(progressive disease after initial response, partial response or
stable disease >3 months)
Crossover permitted:gefitinib + ficlatuzumab
(progressive disease after initial response, partial response or
stable disease >3 months)
R1:1R
1:1
Key entry criteria:•Stage IIIB/IV NSCLC•Treatment naïve•Adeno histology•Asian, nonsmoker or light former smoker
Key entry criteria:•Stage IIIB/IV NSCLC•Treatment naïve•Adeno histology•Asian, nonsmoker or light former smoker
Gefitinib(n=94)
Gefitinib(n=94)
Study Endpoints:Primary: ORRSecondary: PFS, OS
Enrollment initiated in May 2010 & completed in May 2011
Treatment:Gefitinib: 250 mg qd Ficlatuzumab: 20 mg/kg q2w in 28-day cycles
Mok et al ESMO 2012 (Poster)
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Biomarker Analyses
144 (77%) tissue samples collected
Biomarkers
EGFR mutation(n=125)
c-Met IHC level(n=123)
Tumor HGF IHC level
(n=114)
Stroma HGF level
(n=99)
SM+ SM- High* Low High LowS-HGF high
S-HGF low
Definition
TKI sensitiv
e mutatio
n
No or insensitiv
e mutation
Score 2-3+distribution:
> 75%
Remaining
Score 2-3+
distribution:
> 25%
Remaining
Score: strong
moderate
Score: weak
negative
n, (% known)
71 (57) 54 (43) 78 (63)45
(37)64 (56) 50 (44) 17 (17) 82 (83)
188 patients enrolled
May 2010 – May 2011
188 patients enrolled
May 2010 – May 2011
Mok et al ESMO 2012 (Poster)
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PFS and OS (c-Met Low)
Mok et al ESMO 2012 (Poster)
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40
Tivantinib (ARQ 197)/Erlotinib Combination in Non-Small Cell Lung Cancer (Study 209)
a Based on investigator assessment. PFS defined by histology, molecular profile, and other prognostic characteristics.b Patients in the control arm will be allowed to crossover to receive ARQ 197. Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; LA, locally advanced; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; TKI, tyrosine kinase inhibitor.Schiller JH, et al. J Clin Oncol. 2010;28(18 suppl II):954s. Abstract LBA7502.
Endpoints 1° PFSa
2° ORR, OS Subset analyses Crossover: ORR
Accrual complete Archival tissue evaluated for EGFR /
c-MET / K-Ras status in pre-planned subset analyses
RANDOMIZE
NSCLC N =154 Age ≥18 years Inoperable LA/
metastatic disease ≥1 prior chemo
(no prior EGFR TKI)
bArm A: Tivantinib
(ARQ 197)360 mg PO BID
Erlotinib150 mg PO QD+
Arm B: Erlotinib150 mg PO QD
PlaceboPO BID +
Sequist et al JCO 29:3307, 2011
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PFS and OS (ITT population and Non-squamous cell)
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42
Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib Plus Placebo in Non-Squamous NSCLC (MARQUEE)
Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; FACT-L, functional assessment of cancer therapy-lung; ITT, intent-to-treat; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; wt, wild type; QOL, quality of life; TKI, tyrosine kinase inhibitor.http://clinicaltrials.gov/ct2/show/NCT01244191.
Phase 3 in NSCLC Inoperable locally adv/metastatic
disease Non-squamous histology 1-2 regimens prior chemo (no prior
EGFR TKI) Prior platinum-based doublet
therapy required
RANDOMIZE
Endpoints1° OS (ITT population)2°/Exploratory:
- PFS (ITT population)- OS and PFS in EGFR wt patients- Safety and toxicity- QOL/FACT-L- Biologic sub-group analysis
988 patients Stratification by EGFR and KRAS
mutation status (tissue required) Interim analysis performed at 50% of
events
Arm A: Tivantinib(ARQ 197)
360 mg PO BID
Erlotinib150 mg PO QD
+
Arm B: Erlotinib150 mg PO QD
PlaceboPO BID
+
Early termination at interim analysis (2012)
Early termination at interim analysis (2012)
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OAM4558g: A Phase II randomized, placebo controlled study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC
*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010
Arm AErlotinib (150 daily) + MetMAb (15 mg/kg IV q3w)
** Must be eligible and treated with
MetMAb
Arm BTarceva (150 daily) + Placebo (IV q3w)
RANDOMIZATION
1:1
Key eligibility:
• Stage IIIB/IV NSCLC• 2nd/3rd-line NSCLC• Tissue required• PS 0–2
n=137*n=69
n=68
ADD** MetMAb
Progressivedisease
n=27
Co-primary objectives:
• PFS in ‘Met DiagnosticPositive’ patients (est 50%)
• PFS in overall ITT population
Other key objectives:
• OS in ‘Met Diagnostic Positive’ patients
• OS in overall ITT patients
• Overall response rate
• Safety/tolerability
Stratification factors:
• Tobacco history
• Performance status
• Histology
Spiegel et al ASCO 2011Spiegel et al ASCO 2011
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MetMAb plus erlotinib leads to a better outcome than erlotinib alone in Met Diagnostic Positive NSCLC patients
Time to progression (months)
0 3 6 9 12 15 18
Pro
bab
ilit
y o
f p
rog
ress
ion
fre
e
0.0
0.2
0.4
0.6
0.8
1.0
Placebo +erlotinib
3.8
26
MetMAb +erlotinib
12.60.37
(0.19–0.72)0.002
16
Median (mo)HR(95% CI)Log-rank p-valueNo. of events
Overall survival (months)
0 3 6 9 12 15 18 21P
rob
abil
ity
of
surv
ival
0.0
0.2
0.4
0.6
0.8
1.0
Placebo +erlotinib
1.5
27
MetMAb +erlotinib
2.90.53
(0.28–0.99)0.042
20
Median (mo)HR(95% CI)Log-rank p-valueNo. of events
The addition of MetMAb in this population resulted in a 2-fold reduction in therisk of progression and a near 3-fold reduction in the risk of death
PFS: HR=0.53 OS: HR=0.37
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Met Dx Negative
Development of Met IHC for use as a companion diagnostic
• Technical metrics– Tissue was obtained from 100% of patients.– 95% of patients had adequate tissue for evaluation of Met by IHC
• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories
• Met diagnostic status was assessed after randomization and prior to unblinding– ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining
intensity52% patients enrolled were ‘Met Diagnostic Positive’
Negative (0) Weak (1+)
Moderate (2+) Strong (3+)
Met Dx Negative
Met Dx Positive
MET IHC score
1 2 30
1
10
100
1000
0
Met Dx Positive
ME
T m
RN
A (
2-c
t )
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Phase III study design
Registeredpatients
Registeredpatients
Centralized lab (Met IHC or T-score)
Centralized lab (Met IHC or T-score)
Met DiagnosticPositive
Met DiagnosticPositive
Met DiagnosticNegative
Met DiagnosticNegative
Erl +MetMab
Erl +MetMab ErlErl Erl +
MetMabErl +
MetMab ErlErl
Marker-by-treatment-interaction DesignMarker-by-treatment-interaction Design
Registeredpatients
Registeredpatients
Centralized lab (Met IHC or T-score)
Centralized lab (Met IHC or T-score)
Met DiagnosticPositive
Met DiagnosticPositive
Met DiagnosticNegative excluded
Met DiagnosticNegative excluded
Erl +MetMab
Erl +MetMab ErlErl
Marker-based Strategy DesignMarker-based Strategy Design
Mandrekar SJ et al J Biopharm Stat 19:530, 2009Mandrekar SJ et al J Biopharm Stat 19:530, 2009
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Summary• TKI is forever
– Redefine TKI resistance. RECIST criteria may not be applicable
• Addressing the difference– Intercalated combination of chemotherapy and EGFR
TKI may potentially improve treatment outcome
• Novel targets– C-MET is a promising target but we are still in search
of a biomarker
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Old Strategy New Strategy