Transcript Slide 1

New Strategies on Horizon
Tony Mok MD
Dept of Clinical Oncology
The Chinse University of Hong Kong
TKI is
forever
Addressing
the
difference
Novel Target
TKI is
forever
5cm
PR at 2cm
RECIST PD
At 2.6cm
0m
6m
12m
18m
5cm
PR at 2cm
Symptomatic
PD at 4cm
0m
6m
12m
18m
5cm
PR at 2cm
RECIST PD
At 2.6cm
Symptomatic
PD at 4cm
Molecular
resistance
0m
6m
12m
18m
ASPIRATION: To optimize treatment duration
EGFR TKI
Advance stage
NSCLC with
EGFR Mutation
EGFR TKI
PD
By RECIST
PD
By doctor
Discretion*
PFS 1
PFS 2
*Doctor Discretion: Symptomatic progression, multiple progression
Threat to major organ…etc
PI: K Park
TKI Resistance after ASCO 2012
Oncogenic driven
cancer with tumor
response to TKI
Oligo-Progression
Systemic
Progression
Local therapy +
continuation of TKI
Systemic therapy
Targeting the
resistant
gene
Chemothera
py
Chemothera
py + TKI
Treatment of TKI Resistance
Oncogenic driven
cancer with tumor
response to TKI
Oligo-Progression
Systemic
Progression
Local therapy +
continuation of TKI
Systemic therapy
Targeting the
resistant
gene
Chemothera
py
Chemothera
py + TKI
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
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
PFS of patients treated with LAT and
continuation of TKI therapy
Site of first
progression
Number of
patients
PFS1
PFS2
(months)(95% CI)
(months)(95% CI)
7.1
1.7 – 11.3
CNS
10
10.9
7.3 – 18.3
eCNSϮ
15
9.0
6.5 – 13.8
4.0
2.7 -7.4
All patients
25
9.8
8.8 – 13.8
6.2
3.7 – 8.0
Ϯ Includes
3 patients who progressed systemically (eCNS) and simultaneously within the CNS
Site of 2nd progression
2 (20%)
3 (30%)
5 (50%)
4 (27%)
3 (20%)
8 (53%)
6 (24%)
7 (28%)
12 (48%)
no prog
CNS
eCNS
no prog
CNS
eCNS
no prog
CNS
eCNS
Future Prospective Study?
Oncogenic driven
cancer with tumor
response to TKI
PD by RECIST
<4 sites of PD
Randomized
Local therapy +
continuation of TKI
Primary endpoint: PFS
Secondary endpoint: OS, RR, QOL
Chemotherapy
Treatment of TKI Resistance
Oncogenic driven
cancer with tumor
response to TKI
Oligo-Progression
Systemic
Progression
Local therapy +
continuation of TKI
Systemic therapy
Targeting the
resistant
gene
Chemothera
py
Chemothera
py + TKI
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
IMPRESS: Chemotherapy with or
with gefitinib at progression
Gefitinib +
Alimta/Platinum
Gefintinib
Advance stage
NSCLC with
EGFR Mutation
PD
By RECIST
Primary endpoint: PFS
Alimta/Platinum
Co-PI: Soria J; Mok T
Addressing
the
difference
Classic concept of cancer
Normal
cell division
Cell Suicide or Apoptosis
Cell damage—
no repair
Cancer
cell division
First
mutation
Second
mutation
Third
mutation
Fourth or
later mutation
Uncontrolled growth
What if the cancer is not
homogenous?
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
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”
Intercalated combination of
Chemotherapy + EGFR TKI
NVALT-10:Design
Squamous
Erlotinib 150mg p.o. day 2-16
+ Docetaxel 75 mg/m2 day 1 q3 weeks
Combination
therapy
Primary endpoint: PFS
Patients
Non- Squamous
Locally advanced or
metastatic NSCLC
(IIIB-IV)
Erlotinib 150mg p.o. day 2-16
+ Pemetrexed 500 mg/m2 day 1 q3 weeks
Failed first line
platinum therapy
WHO PS 0-2
Mono
therapy
Chemotherapy planned 4 cycles
Erlotinib until disease progression
Squamous and Non Squamous
Erlotinib 150mg p.o. daily
Aerts et al ESMO 2012
PFS and OS
Improvement in patients
with or without EGFR
mutation?
Adjusted for stratification
factors: p=0.09, HR=0.78 (0.591.04)
Adjusted for stratification factors:
p=0.02, HR=0.67 (0.50 – 0.93)
Improvement limited to nonsquamous cell carcinoma
• Lack of improvement
in squamous cell
For a population dominated
by EGFR wild type,carcinoma
control
– No improvement in
arm should be Alimta
EGFR wild type
• Slight improvement in
non-squamous cell
carcinoma
– May imply benefit in a
small portion of
patients with EGFR
mutations
FASTACT-2 (MO22201; CTONG0902)
study design
Screening
Previously
untreated stage
IIIB/IV NSCLC,
PS 0/1
(n=451)
Study treatment
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)
R
Maintenance phase
Erlotinib
150mg/day
PD
Placebo
PD
1:1; stratified by stage, histology,
smoking status and chemo regimen
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)
Primary endpoint: PFS with IRC confirmation
Erlotinib
150mg/day
Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of
response, TTP, NPR at 16 weeks, safety, QoL
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
EGFR mutation status in FASTACT-2
EGFR mutation-positive (Mut+)
EGFR wild-type (WT)
Single resistance mutation
500
300
451
250
400
200
300
241
200
Placebo
n=48
100
Erlotinib
n=69
50
0
0
Tested for
EGFR mutation
97
150
100
All patients
Erlotinib
n=49
136
*
EGFR mutation status
Placebo
n=67
210 patients in the study had
unknown EGFR 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)
PFS in ITT population (22 Jun 2012)
1.0
GC-erlotinib (n=226)
PFS probability
0.8
GC-placebo (n=225)
HR=0.57 (95% CI 0.47–0.69)
p<0.0001
0.6
0.4
0.2
6.0
0
0
2
4
6
7.6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time (months)
E
P
226 192 162 136 102 81 70 59 52 45 39 32
225 185 156 114 57 31 22 15 12 9 7 6
CI = confidence intervals
24 17 12
4 3 3
6
2
1
1
0
1
0
1
0
0
OS in ITT population (22 Jun 2012)
1.0
GC-erlotinib (n=226)
OS probability
0.8
GC-placebo (n=225)
HR=0.79 (95% CI 0.64–0.99)
p=0.0420
0.6
0.4
0.2
15.2
0
0
2
4
6
18.3
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time (months)
E
P
226 219 202 191 176 165 154 138 129 114 98 85
225 218 206 185 168 156 138 120 103 92 78 68
68 52 39 23
53 37 24 13
9
6
6
4
1
0
0
0
PFS and OS in EGFR WT subgroup
(22 Jun 2012)
PFS
1.0
1.0
GC-erlotinib (n=69)
GC-placebo (n=67)
HR=0.97 (0.69–1.36)
p=0.8467
RR: 26.1% vs 19.4%
GC-erlotinib (n=69)
GC-placebo (n=67)
HR=0.77 (0.53–1.11)
p=0.1612
0.8
OS probability
0.8
PFS probability
OS
0.6
0.4
0.2
0.6
0.4
0.2
5.9
0
0
4
6.7
8
12.2
0
12 16 20 24 28 32 36 40
0
4
8
Time (months)
E
P
69
67
45
46
15
16
7
5
5
3
3
2
2
1
1
1
14.9
12 16 20 24 28 32 36 40
Time (months)
0
1
0
1
0
0
E
P
69
67
60
57
49
43
43
34
30
23
19
15
12
7
6
3
4
2
0
1
0
0
PFS and OS in EGFR Mut+ subgroup
(22 Jun 2012)
PFS
1.0
1.0
GC-erlotinib (n=49)
GC-placebo (n=48)
HR=0.25 (0.16–0.39)
p<0.0001
RR: 83.7% vs 14.6%
GC-erlotinib (n=49)
GC-placebo (n=48)
0.8
OS probability
0.8
PFS probability
OS
0.6
0.4
0.2
HR=0.48 (0.27–0.84)
p=0.0092
0.6
0.4
0.2
6.9
0
0
4
16.8
8
12
16
20.6
0
20
24
28
32
0
4
8
Time (months)
E
P
49
48
46
35
42
16
33
5
25
4
19
2
31.4
12 16 20 24 28 32 36
Time (months)
11
2
6
1
0
0
E
P
49
48
48
48
46
43
45
36
41
26
33
24
24
14
15
6
3
0
0
0
Novel Target
Target HGF
AMG 102
AVEO299
MET Pathways
Target TK
ARQ197, XL184
+ many
Target Met receptor
MetMab
Phase 2 Study Design: Ficlatuzumab + Gefitinib
in NSCLC in the First Line
Key entry criteria:
•Stage IIIB/IV NSCLC
•Treatment naïve
•Adeno histology
•Asian, nonsmoker
or light former
smoker
Stratification:
• ECOG PS
• Smoking
history
• Gender
Crossover permitted:
gefitinib + ficlatuzumab
(progressive disease after initial
response, partial response or
stable disease
>3 months)
R
1:1
Gefitinib
(n=94)
Treatment:
Gefitinib: 250 mg qd
Ficlatuzumab: 20 mg/kg q2w in 28-day cycles
Off-study
Ficlatuzumab+
gefitinib
(n=94)
Early discontinuations,
nonresponders, or patients
who do not want to participate
in crossover
Study Endpoints:
Primary: ORR
Secondary: PFS, OS
Enrollment initiated in May 2010 & completed in May 2011
Mok et al ESMO 2012 (Poster)
Biomarker Analyses
188 patients enrolled
May 2010 – May 2011
144 (77%) tissue samples
collected
Biomarker
s
EGFR mutation
(n=125)
c-Met IHC level
(n=123)
SM+
SM-
High*
Definition
TKI
sensitive
mutation
No or
insensitive
mutation
n, (%
known)
71 (57)
54 (43)
Tumor HGF IHC level
(n=114)
Stroma HGF level
(n=99)
Low
High
Low
S-HGF
high
S-HGF
low
Score 2-3+
distribution:
> 75%
Remainin
g
Score 2-3+
distributio
n:
> 25%
Remaini
ng
Score:
strong
moderate
Score:
weak
negative
78 (63)
45 (37)
64 (56)
50 (44)
17 (17)
82 (83)
Mok et al ESMO 2012 (Poster)
PFS and OS (c-Met Low)
Mok et al ESMO 2012 (Poster)
Tivantinib (ARQ 197)/Erlotinib Combination in
Non-Small Cell Lung Cancer (Study 209)
NSCLC
 N =154
 Age ≥18 years
 Inoperable LA/
metastatic disease
 ≥1 prior chemo
(no prior EGFR TKI)
Endpoints
1° PFSa
2° ORR, OS
Subset analyses
Crossover: ORR
R
A
N
D
O
M
I
Z
E
Arm A: Tivantinib + Erlotinib
150 mg PO QD
(ARQ 197)
b
360 mg PO BID
Arm B: Placebo + Erlotinib
PO BID
150 mg PO QD
 Accrual complete
 Archival tissue evaluated for EGFR /
c-MET / K-Ras status in pre-planned subset
analyses
a
Based on investigator assessment. PFS defined by histology, molecular profile, and other prognostic characteristics.
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.
b
40
Sequist et al JCO 29:3307, 2011
PFS and OS (ITT population and
Non-squamous cell)
Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib
Plus Placebo in Non-Squamous NSCLC (MARQUEE)
R
Arm A:
A
Inoperable locally adv/metastatic
N
disease
Non-squamous histology
D
1-2 regimens prior chemo (no priorEarly termination at interim
O (2012)
analysis
EGFR TKI)
M
Arm B:
Prior platinum-based doublet
therapy required
IZ
E
Phase 3 in NSCLC




Endpoints
1° 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
Tivantinib + Erlotinib
150 mg PO QD
(ARQ 197)
360 mg PO BID
Placebo
PO BID
+
Erlotinib
150 mg PO QD
 988 patients
 Stratification by EGFR and KRAS
mutation status (tissue required)
 Interim analysis performed at 50% of
events
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.
42
OAM4558g: A Phase II randomized, placebo controlled
study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC
n=137*
Key eligibility:
•
•
•
•
Stage IIIB/IV NSCLC
2nd/3rd-line NSCLC
Tissue required
PS 0–2
Co-primary objectives:
• PFS in ‘Met Diagnostic
Positive’ 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
n=69
1:1
R
A
N
D
O
M
I
Z
A
T
I
O
N
Stratification factors:
Arm A
Erlotinib (150 daily) +
MetMAb (15 mg/kg IV q3w)
• Tobacco history
n=68
• Performance status
• Histology
Arm B
Tarceva (150 daily) + Placebo
(IV q3w)
Progressive
disease
*128 NSCLC patients enrolled from
3/2009 to 3/2010 plus 9 SCC
patients enrolled through 8/2010
ADD**
MetMAb
** Must be
eligible and
treated with
MetMAb
n=27
Spiegel et al ASCO 2011
MetMAb plus erlotinib leads to a better outcome than erlotinib
alone in Met Diagnostic Positive NSCLC patients
OS: HR=0.37
Placebo + MetMAb +
erlotinib erlotinib
Median (mo)
1.5
2.9
HR
0.53
(95% CI)
(0.28–0.99)
Log-rank p-value
0.042
No. of events
27
20
1.0
0.8
0.6
0.4
0.2
0.0
Placebo + MetMAb +
erlotinib
erlotinib
Median (mo)
3.8
12.6
HR
0.37
(95% CI)
(0.19–0.72)
Log-rank p-value
0.002
No. of events
26
16
1.0
Probability of survival
Probability of progression free
PFS: HR=0.53
0.8
0.6
0.4
0.2
0.0
0
3
6
9
12
15
Time to progression (months)
18
0
3
6
9
12
15
Overall survival (months)
The addition of MetMAb in this population resulted in a 2-fold reduction in the
risk of progression and a near 3-fold reduction in the risk of death
18
21
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
Negative (0)
Met Dx
Negative
Moderate (2+)
1000
Weak (1+)
Strong (3+)
Met Dx
Positive
MET mRNA (2-Dct)
•
Development of Met IHC for use as a companion
diagnostic
Met Dx
Negative
Met Dx
Positive
100
10
1
0
0
1
2
MET IHC score
•
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
intensity
52% patients enrolled were ‘Met Diagnostic Positive’
3
Phase III study design
Registered
patients
Registered
patients
Centralized lab
(Met IHC or T-score)
Centralized lab
(Met IHC or T-score)
Met Diagnostic
Positive
Erl +
MetMab
Erl
Met Diagnostic
Negative
Erl +
MetMab
Met Diagnostic
Positive
Erl
Marker-by-treatment-interaction Design
Erl +
MetMab
Met Diagnostic
Negative excluded
Erl
Marker-based Strategy Design
Mandrekar SJ et al J Biopharm Stat 19:530, 2009
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
Old Strategy
New Strategy