Transcript Diapositiva 1

ASCO 2010
Non-Small Cell Lung Cancer
Roman Perez-Soler, M.D.
Director, Medical Oncology
Albert Einstein College of Medicine
Bronx, NY
Clinical Activity of the Oral
ALK Inhibitor,
Crizotinib (PF-02341066), in Patients
with ALK-positive Non-Small Cell Lung
Cancer
Bang Y,1 Kwak EL,2 Shaw A,2 Camidge DR,3
Iafrate AJ,2 Maki RG,4
Solomon B,5 Ou SI,6 Salgia R,7 Clark J2
1Seoul
National University, Seoul, Korea; 2Massachusetts General Hospital, Boston, MA, USA;
3University of Colorado Cancer Center, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center,
New York, NY, USA; 5Peter MacCallum Cancer Centre, East Melbourne, Australia;
6University of California at Irvine, Irvine, CA, USA; 7University of Chicago Cancer Center, Chicago, IL,
USA
ASCO Annual Meeting 2010
Abstract 3
ALK Pathway
Or
Inversion
Translocation
ALK fusion protein*
ALK
RAS
PI3K
PLC-Y
STAT3/5
MEK
AKT
mTOR
ErK
BAD
S6K
Cell survival
*Subcellular localization of the ALK fusion gene,
while likely to occur in
the cytoplasm, is not confirmed.1,2
PIP2
IP3
Tumor cell
proliferation
1. Inamura K et al. J Thorac Oncol 2008;3:13–17
2. Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897
Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23;
Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc.
Patients with ALK-positive NSCLC
Do not Appear to Respond to EGFR TKIs
Platinum-based chemotherapy
EGFR TKI
ALK
(N=12)
EGFR
(N=8)
WT/WT*
(N=34)
Response rate, %
25
50
35
TTP, months
9
10
8
TTP for chemotherapy1
100
ALK
(N=10)
EGFR
(N=23)
WT/WT*
(N=23)
Response rate, %
0
70
13
TTP, months
5
16
6
TTP for EGFR TKI1
100
60
60
%
80
%
80
40
40
EGFR
20
EML4–ALK
0
0
12
20
WT/WT
0
24
36
Months
48
60
*WT/WT = wild type: no ALK fusion or EGFR mutation
1Shaw AT et al. J Clin Oncol 2009;27:4247–4253
WT/WT
EGFR
EML4–ALK
0
12
24
36
Months
48
60
Crizotinib Selectivity Profile
Upstate 102
kinase
Kinase
Met(h)
Tie2(h)
TrkA(h)
ALK(h)
TrkB(h)
Abl(T315I)(h)
Yes(h)
Lck(h)
Rse(h) [SKY]
Axl(h)
Fes(h)
Lyn(h)
Arg(m)
Ros(h)
CDK2/cyclinE(h)
Fms(h)
EphB4(h)
Bmx(h)
EphB2(h)
Fgr(h)
Fyn(h)
IR(h)
CDK7/cyclinH/MAT1(h)
cSRC(h)
IGF-1R(h)
Aurora-A(h)
Syk(h)
FGFR3(h)
PKCµ(h)
BTK(h)
CDK1/cyclinB(h)
p70S6K(h)
PRK2(h)
PAR-1Bα(h)
PKBß(h)
Ret(h)
GSK3ß(h)
Flt3(h)
MAPK1(h)
ZAP-70(h)
Abl(h)
c-RAF(h)
PKD2(h)
ROCK-II(h)
Rsk3(h)
GSK3α(h)
CDK5/p35(h)
PDGFRα(h)
Rsk1(h)
SGK(h)
CHK1(h)
ErbB4(h)
Rsk2(h)
JNK1α1(h)
PKBα(h)
Blk(m)
CDK3/cyclinE(h)
PKCι(h)
PKCθ(h)
CDK2/cyclinA(h)
PAK2(h)
PKCßI(h)
Pim-1(h)
PKCη(h)
SAPK4(h)
CaMKII(r)
MKK7ß(h)
CaMKIV(h)
CHK2(h)
CK2(h)
JNK2α2(h)
MKK6(h)
CK1δ(h)
PKCα(h)
MAPK2(h)
MEK1(h)
PKCδ(h)
PKCε(h)
Plk3(h)
PKCßII(h)
MSK1(h)
PDGFRß(h)
PKCζ(h)
SAPK3(h)
MAPKAP-K2(h)
PKA(h)
AMPK(r)
CDK6/cyclinD3(h)
CSK(h)
SAPK2a(h)
JNK3(h)
PKBγ(h)
IKKα(h)
NEK2(h)
% Inhibition
94
103
102
100
100
98
96
95
94
93
93
93
91
90
87
84
80
79
77
73
68
64
58
58
56
54
52
50
50
35
25
24
22
21
21
21
18
17
17
17
16
16
15
14
14
11
10
10
7
6
5
5
5
4
4
3
3
3
3
2
2
2
1
1
1
0
0
-1
-1
-1
-1
-1
-2
-2
-3
-3
-3
-3
-3
-5
-6
-6
-6
-6
-7
-7
-9
-9
-9
-9
-10
-10
-11
-11
Cellular selectivity on 10 of 13
relevant hits
13 kinase “hits”
<100X
selective for
c-MET
Kinase
IC50 (nM)
mean*
Selectivity
ratio
c-MET
8
–
ALK
20
2X
298
34X
189
22X
294
34X
322
37X
Tie-2
448
52X
Trk A
580
67X
Selectivity findings
Trk B
399
46X
Abl
1,159
166X
IRK
2,887
334X
• Crizotinib – ALK and
c-MET inhibition at clinically
relevant dose levels
Lck
2,741
283X
Sky
>10,000
>1,000X
VEGFR2
>10,000
>1,000X
PDGFR
>10,000
>1,000X
RON
Axl
*The cellular kinase activities were
measured using ELISA capture method
Crizotinib
(PF-02341066)
• Crizotinib – low probability of
pharmacologically relevant
inhibition of any other kinase
at clinically relevant dose
levels
Pfizer Inc. Data on file
Crizotinib: First-in-human/Patient Trial
Cohort 5 (n=6)
2 DLTs: grade 3 fatigue
300 mg BID
Part 1:
Dose escalation
Cohort 6 (n=9)
Cohort 4 (n=7)
250 mg BID
MTD/RP2D
200 mg BID
Cohort 3 (n=8)
200 mg QD
1 DLT: grade 3
ALT
elevation
Cohort 2 (n=4)
100 mg QD
Cohort 1 (n=3)
50 mg QD
ALT = alanine aminotransferase
Part 2:
Molecularly enriched cohorts
(ALK and c-MET)
Enrolling patients with ALK-positive NSCLC
after preliminary observation of impressive
activity in a few patients
• Data from database April 7, 2010
• Data presented for 82 patients, study
ongoing
Clinical and Demographic Features of
Patients with ALK-positive NSCLC
Mean (range) age, years
Gender, male/female
N=82
51 (25–78)
43/39
Performance
status,* n (%)
0
1
2
3
24 (29)
44 (54)
13 (16)
1 (1)
Race, n (%)
Caucasian
Asian
46 (56)
29 (35)
Smoking
history, n (%)
Never smoker
Former smoker
Current smoker
62 (76)
19 (23)
1 (1)
Histology, n (%)
Adenocarcinoma
Squamous
Other
79 (96)
1 (1)
2 (2)
Prior treatment
regimens, n (%)
0
1
2
≥3
Not reported
5 (6)
27 (33)
15 (18)
34 (41)
1 (1)
*Performance status = Eastern Cooperative Oncology Group
Tumor Responses to Crizotinib for
Patients with ALK-positive NSCLC
60
Progressive disease
Stable disease
Maximum change in tumor size (%)
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
*
*Partial response patients with 100% change have non-target disease present
Clinical Activity of Crizotinib in
Patients with ALK-positive NSCLC

Objective response rate (ORR): 57% (95% CI: 46, 68%)
– 63% including 5 as yet unconfirmed PRs
– 57% (8/14) for patients with performance status 2 or 3
No. prior
regimens*
ORR
% (n/N)
0
80 (4/5)
1
52 (14/27)
2
67 (10/15)
≥3
56 (19/34)
* Unknown for 1 patient
● Response duration: 1 to 15 months
● DCR† (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%)
†Disease control rate
Median PFS has Not been Reached
70% of Patients in Follow-up for PFS
Progression-free survival probability
1.00
PFS probability at 6 months: 72%
(95% CI: 61, 83%)
0.75
0.50
0.25
Median follow-up for PFS: 6.4 months
(25–75% percentile: 3.5–10 months)
95% Hall–Wellner confidence bands
0.00
0
2.5
5.0
7.5
10.0
12.5
Progression-free survival (months)
15.0
17.5
Treatment-related Adverse Events in
ALK-positive NSCLC (≥10%)
Adverse event
Grade 1
n (%)
Grade 2
n (%)
Grade 3
n (%)
Grade 4
n (%)
Total
n (%)
Nausea
43 (52)
1 (1)
0
0
44 (54)
Diarrhea
38 (46)
1 (1)
0
0
39 (48)
Vomiting
35 (43)
1 (1)
0
0
36 (44)
Visual disturbance*
34 (42)
0
0
0
34 (42)
Constipation
18 (22)
2 (2)
0
0
20 (24)
Peripheral edema
13 (16)
0
0
0
13 (16)
Dizziness
12 (15)
0
0
0
12 (15)
Decreased appetite
11 (13)
0
0
0
11 (13)
Fatigue
8 (10)
0
0
0
8 (10)
*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)
N=82
Treatment-related Grade 3/4 Adverse
Events in ALK-positive NSCLC
Adverse event
Grade 3
n (%)
Grade 4
n (%)
Any adverse event
10 (12)
1 (1)
ALT elevation*
4 (5)
1 (1)
AST elevation
5 (6)
0
Lymphopenia
2 (2)
0
Hypophosphatemia
1 (1)
0
Neutropenia
1 (1)
0
Hypoxia
1 (1)
0
Dyspnea
1 (1)
0
Pulmonary embolism
1 (1)
0
*Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4%
(In preclinical toxicology studies, no histologic changes in the liver were observed)
1 patient discontinued for ALT elevation
Summary


Treatment with crizotinib resulted in impressive clinical activity in
patients with ALK-positive advanced NSCLC
–
ORR: 57%
–
DCR at 8 weeks: 87%
–
PFS probability at 6 months: 72%
Crizotinib was well tolerated
–
The most frequent adverse events were mild and moderate
gastrointestinal events and mild visual disturbances
Randomized Phase II trial of erlotinib (E)
alone or in combination with
carboplatin/paclitaxel (CP) in never or light
former smokers with advanced lung
adenocarcinoma: CALGB 30406
P.A. Jänne1, X. Wang2, M. A. Socinski3, J. Crawford4, M. Capelletti1,
M. Edelman5, M.A. Villalona-Calero6, R. Kratzke7, E. Vokes8 and V.A.
Miller9
1Dana
Farber Cancer Institute; 2CALGB Statistical Center; 3University of North
Carolina; 4Duke University; 5University of Maryland; 6Ohio State University;
7University of Minnesota; 8University of Chicago; 9Memorial Sloan Kettering Cancer
Center
EGFR TKI Therapy in 2010


Efficacy (RR & PFS) greatest in EGFR mutant
patients
Single agent activity in EGFR mutants
–
–

1st line response rate: 60%-80%
1st line PFS 8 – 10 months
Gefitinib superior to 1st line chemotherapy
–
–
Higher RR and longer PFS
Better toxicity profile
Chemotherapy With Erlotinib or
PlaceboTRIBUTE Trial
Never Smokers
1.0
1.0
0.8
0.8
Survival rate
Survival rate
Intent-to-Treat
0.6
0.4
0.2
0.6
0.4
0
0
0
5
10
Erlotinib
Placebo
0.2
Erlotinib (n = 539)
Placebo (n = 539)
15
20
Months
25
0
5
(n = 72)
(n = 44)
10
15
20
25
Months
Median survival 10.6 vs. 10.5 mos
Median survival 22.5 vs. 10.1 mos
RR: 22% vs. 19 %
RR: 30% vs. 11 %
Herbst RS, et al. J Clin Oncol. 2005;23:5892-5899.
CALGB 30406 Randomized Phase II
Study: Trial Design
Chemotherapy-naive patients with stage III/IV
adenocarcinoma or BAC who are never or “light” former smokers*
ECOG PS 0-1

Daily oral erlotinib
Daily oral erlotinib +
6 cycles carboplatin/paclitaxel
Daily oral erlotinib
Daily oral erlotinib
Patients can continue therapy until evidence of
disease progression or toxicity
* never smoker:  100 cigarettes/lifetime; “light” former smoker: quit  1 year ago and  10 pack years
CALGB 30406

Study conduct
–
–
–

Tissue submission part of eligibility
–
–


Written 2004; activated 8/05; closed 4/09
Median follow-up: 30 months
26 pts (14%) still receiving study therapy
Routine genotyping not available in 2004
Prospective evaluation of EGFR mutations
Primary Endpoint
–
PFS in each arm; sample size 180 pts. (80 E; 100 ECP)
–
RR, PFS and OS in EGFR WT and EGFR mutant pts.
Secondary Endpoints
Progression Free and Overall Survivals
Progression Free Survival
Overall Survival
1.0
E
(n=81)
ECP (n=100)
Survival Probability
Proportion Progression Free
1.0
E
(n=81)
ECP (n=100)
0.8
0.6
0.4
0.8
0.6
0.4
0.2
0.2
0.0
0.0
0
6
12
18
24
30
36
42
6.7 (4.0-8.3)
Erlotinib/CP: 6.6 (5.4-8.2)
Response Rate
6
12
18
24
30
36
42
Time (months)
Time (months)
Erlotinib :
0
Erlotinib: 35%
Erlotinib :
24.3 (18.4 –31.3)
Erlotinib/CP: 19.6 (14.4 – 28.7)
Erlotinib/CP: 48%
Tumor genotyping analyses
181 patients
17 patients
Insufficient
material or no DNA
91%
164 patients
EGFR mutant: 72
Exon 19: 39
Exon 21: 27
Erlotinib
Erlotinib/CP
Total: 77/80 (96%)
Total: 87/100 (87%)
HER2 mutant: 3
EGFR mutant: 33
EGFR mutant: 33
KRAS mutant: 17
EGFR WT: 44
EGFR WT: 54
Wild Type: 72
Exon 20: 6
Erlotinib – PFS and OS by EGFR mutation
Overall Survival
Progression Free Survival
EGFR mut (n=33)
EGFR WT (n=44)
0.8
0.6
0.4
Survival Probability
Proportion Progression Free
EGFR mut (n=33)
EGFR WT (n=44)
1.0
1.0
0.8
0.6
0.4
0.2
0.2
0.0
0.0
0
6
12
18
24
30
36
42
0
6
Time (months)
18
30
36
2.7 (1.4 – 4.4)
EGFR mutant : 31.3 (23.8–42.8)
EGFR WT:
P < 0.0001
Response Rate
24
Time (months)
EGFR mutant : 15.7 (8.6 – 20.4)
EGFR WT:
12
18.1 (9.5 -25.0)
P = 0.0093
EGFR mutant: 67%
EGFR WT: 9%
P < 0.0001
42
Erlotinib/CP – PFS and OS by EGFR mutation
Progression Free Survival
Overall Survival
1.0
EGFR mut (n=33)
EGFR WT (n=54)
EGFR mut (n=33)
EGFR WT (n=54)
0.8
0.6
0.4
Survival Probability
Proportion Progression Free
1.0
0.8
0.6
0.4
0.2
0.2
0.0
0.0
0
6
12
18
24
30
36
42
0
6
12
Time (months)
EGFR mutant : 17.2 (10.3 – NA)
EGFR WT:
4.8 (3.1 – 5.6)
24
30
36
Time (months)
EGFR mutant : 39.0 (38.1 –NA)
EGFR WT:
P < 0.0001
Response Rate
18
EGFR mutant: 73%
13.7 (8.7-20.7)
P = 0.0012
EGFR WT: 33%
P = 0.0004
42
Conclusions




Erlotinib and Erlotinib/CP yield similar outcomes
in a clinically enriched population of NSCLC
patients
EGFR mutations identify patients most likely to
benefit from E or ECP
E is better tolerated than ECP
EGFR TKIs alone are an acceptable first line
therapy for advanced EGFR mutant NSCLC
Abstract 7500
Randomized, Open Label, Phase III Trial
of Figitumumab in Combination
with Paclitaxel and Carboplatin versus
Paclitaxel and Carboplatin in Patients
with Non-Small Cell Lung Cancer (NSCLC)
J. Jassem, C. L. Langer, D. D. Karp, T. Mok,
S. Novello, K. Park, J. Strausz, R. J. Benner,
S. Green and A. Gualberto
Medical University, Gdansk, Poland; Abramson Cancer Center, Philadelphia, PA;
MD Anderson Cancer Center, Houston, TX; Chinese University, Hong Kong, New
Territories; University of Turin, Italy; Sungkyunkwan University, Seoul, Korea; Koranyi
Natl. Inst. for Pulmonology, Budapest, Hungary; Pfizer Oncology, New London, CT
Insulin Like Growth Factor I Receptor
• Central component of a signal transduction pathway
that includes the IGF-1 and IGF-2 ligands and their binding
proteins (IGFBPs 1 to 7)1
– IGFBPs regulate IGFs bioavailability and biological
activity
• IGFs are survival factors for normal and cancer cells
– High circulating IGF-1 levels are associated
with increased risk of cancer related death2
– Low circulating IGF-1 levels are associated with increased
risk of heart failure and myocardial events3
1.
2.
3.
Pollak M. Nat Rev Cancer 2008;8:915-928
Major JM et al. J Clin Endocrinol Metab. 2010;95:1054-9.
Laughlin GA et al. J Clin Endocrinol Metab. 2004; 89:114-20.
Figitumumab (CP-751,871)




Fully human IgG2 subtype monoclonal antibody against
the IGF-IR with a T1/2 of approximately 28 days1
Well tolerated as a single agent and in combination
with chemotherapy/targeted agents in early studies2
Phase I single-agent activity in Ewing’s sarcoma3
Phase II activity in first-line NSCLC in combination
with paclitaxel/carboplatin4
1.
2.
3.
4.
Cohen et al. Clin Cancer Res 2005;11:2063-73
Gualberto A. Expert Opin Biol Ther 2010;10:575-85
Olmos et al. Lancet Oncol 2010;11:129-35
Karp et al. J Clin Oncol. 2009 27:2516-22.
Rationale for Studying Figitumumab
in Non-Adenocarcinoma Histologies,
•
High IGF-IR expression in squamous cell carcinoma1
•
High phase 2 activity of the paclitaxel, carboplatin
and figitumumab combination in squamous cell carcinoma
ORR = 64%, N=42, single arm phase 2 study2
•
No significant difference in the toxicity of figitumumab
in squamous cell carcinoma vs other histologies in phase 22
•
No regulatory requirement for the combination
of paclitaxel, carboplatin and figitumumab
with bevacizumab in non-adenocarcinoma histologies3
1.
2.
3.
Gualberto et. J Clin Oncol 27:15s, 2009 (suppl; abstr 8091)
Karp et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8072)
Pfizer Inc, data in file (2007)
Study A1016: Phase III Study of Carboplatin
+ Paclitaxel +/- Figitumumab in 1st Line NSCLC
of non-adenocarcinoma histology
Trial Design
Multi-center,
randomized,
open-label
Endpoints
Stratification
Primary: OS
Secondary: PFS, ORR, Safety,
QoL, biomarkers,
pharmacoeconomics
Key Entry Criteria
● Other than Adenoca
● Brain mets allowed
● Adjuvant > 12 month prior
• Gender
• Histology
(Sq vs non-Sq)
• Prior Adj Chemo (Y/N)
Study
Sites
FSFV
Global
2Q08
R
A
N
D
O
M
I
Z
E
Figitumumab (20 mg/kg)
Paclitaxel
Carboplatin
N=820
N = 410
N = 410
Paclitaxel
Carboplatin
AEs with the Largest
Difference between Study Arms
Grade 5
Arm/N
PCF/338
PC/333
3.5%
0.6%
3%
1.2%
Arm/N
PCF/338
PC/333
Anorexia
39% (7%)
23% (2%)
Nausea
39% (4%)
30% (1%)
Fatigue
32% (6%)
25% (4%)
Diarrhea
30% (4%)
12% (1%)
Vomiting
25% (3%)
13% (1%)
Hyperglycemia
23% (13%)
5% (1%)
Asthenia
22% (8%)
18% (5%)
Weight loss
19% (3%)
8% (<1%)
Dehydration
12% (6%)
3% (1%)
Infection
Cardiovascular
All Grades & (Grades 3-5)
Overall Survival
% Probability of Survival
PC
mOS = 10.3 mo
Event
Total
PCF
184
342
PC
165
339
PCF
mOS = 8.5 mo
HR (95%CI):1.23 (1.0,1.5), p=0.051
Months
Overall Survival by Subsets: HR 95% CI
Clinical Parameters did not Provide Positive Subsets
Favors PCF
Favors PC
Overall
Never or Ex Smoker
Current Smoker
Stage IIIB
Stage IV
Non-squamous
Squamous
ECOG PS 0
ECOG PS 1
Female
Male
0.6
1.0
1.6
2.7
Ongoing Phase 2 Biomarker Analysis Suggested a Free Plasma
(unbound to IGFBPs) IGF-1/Treatment Interaction
12
8
PC
PC + F 10 mg/kg
PC + F 20 mg/kg
P=0.0533
P=0.0009
6
4 months
PFS (months)
10
Free IGF-1 quartiles Study 1002
4
2
0
1st
2nd
3rd
4th (>0.9 ng/mL)
Hixon et al. J Clin Oncol. 27:15s, 2009 (abstr 3539)
OS of PCF improved at high Free IGF-1
levels in the Phase 3 Study (1016)
Median OS above
Free IGF-1 Criterion
Hazard Ratio above
Free IGF-1 Criterion
12
median OS (months)
Hazard Ratio PCF/PC
1.4
1.2
1.0
0.8
0.6
0.7
0.8
0.9
1.0
1.1
Free IGF-1 Criterion (ng/mL)
(pre-treatment)
1.2
PCF
10
8
PC
6
0.4
0.6
0.8
1.0
1.2
Free IGF-1 Criterion (ng/mL)
(pre-treatment)
Median OS at Free IGF-1 1.0 ng/ml
Favored PCF
Survival probability
1.0
PCF
mOS = 10.2 mo
0.8
Event
Total
PCF
44
86
PC
19
39
Censored
0.6
HR (95% CI): 0.97 (0.6, 1.7) *
PC
0.4
mOS = 7.0 mo
0.2
N=125 (Provision of samples for pharmacodynamics was optional)
0.0
0
5
10
Time (months)
15
* Additional follow up is necessary
20
Median OS at Free IGF-1 <1.0 ng/ml
Favored PC
1.0
Survival probability
PC
0.8
mOS = 10.3 mo
Event
Total
PCF
109
185
PC
75
139
Censored
0.6
HR (95% CI): 1.40 (1.0, 1.9)
PCF
0.4
mOS = 7.0 mo
0.2
N=324 (Provision of samples for pharmacodynamics was optional)
0.0
0
5
10
Time (months)
15
20
Conclusions
•
•
•
•
Addition of figitumumab to standard chemotherapy
did not increase overall survival in advanced
non-adenocarcinoma NSCLC
Potential benefit of figitumumab may be
compromised by its side effects
Risk/benefit of figitumumab in addition to standard
chemotherapy appears related to the levels
of circulating free IGF-1
Additional research is necessary to verify the
potential of benefit in patients with high free IGF-1
Paclitaxel (qw) + Carbo (q4w) vs Single agent Gem or
Vinorelbine as frontline therapy in patients 70-89
Quoix et al. (plenary Session)



French multicentric randomized Phase III trial; endpoint
survival; erlotinib as fixed second line therapy; PS 0-2;
451 patients
Significant improvement in survival, PFS, and RR with
the combination:
Survival: 10.4 mo vs 6.2 mo, HR: 0.60, p=0.0001
PFS: 6.3 mo vs 3.2 mo, HR 0.44, p<0.0001
RR: 29% vs 11%,
Grade 3-4 hematological toxicity greater in combination
arm, 54% vs 14%, (gem 5%) with significant increase in
toxic deaths (9 vs 3, p=0.03)
Abstract #LBA7511
Results of a Randomized, Phase III Trial of nabPaclitaxel and Carboplatin Compared With
Cremophor-based Paclitaxel and Carboplatin as
First-line Therapy in Advanced Non-small Cell
Lung Cancer
MA Socinski,1 I Bondarenko,2 NA Karaseva,3 AM Makhson,4 IO Vynnychenko,5
I Okamoto,6 J Hon,7 V Hirsh,8 P Bhar,9 J Iglesias9
1Lineberger
Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA; 2City Hosp #4, Dnepropetrovsk, Ukraine; 3City
Oncology Center, St. Petersburg, Russia; 4City Oncology Hospital #62, Moscow, Russia; 5Regional Oncology Center, Sumy, Ukraine; 6Kinki
University School of Medicine, Osaka-Sayama, Japan; 7Clearview Cancer Inst Onc Specialties, P.C, Huntsville, AL, USA; 8McGill University,
Montreal, Quebec, Canada; 9Abraxis BioScience, Los Angeles, CA
Biologic Rationale for nab-P
 nab-P leverages the gp60 / caveolin-1 / SPARC
transcytosis pathway to establish a portal to the
tumor microenvironment resulting in high intratumoral drug concentration (Desai 2008)
 Overexpression of caveolin-1 and SPARC occurs
in NSCLC and is associated with poor prognosis
(Yoo, 2002; Chin 2005; Koukorakis, 2003)
Phase III nab-P/C vs P/C
Study Design
Chemo-naive
PS 0-1
Stage IIIb/IV
NSCLC
N = 1,050
nab-Paclitaxel 100 mg/m2 d1, 8 15
Carboplatin AUC 6 d1
No Premedication
n = 525
1:1
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
With Premedication of
Dexamethasone + Antihistamines
n = 525
Stratification factors:
 Stage (IIIb vs IV)
 Age (<70 vs >70)
 Sex
 Histology (squamous vs nonsquamous)
 Geographic region
Objective Responses by Histology*
Squamous
P < 0.001
Nonsquamous
P = 0.060
P = 0.808
P = 0.069
50%
Percent Responses
40%
nab-P/C
P/C
41%
37%
37%
30%
29%
20%
24%
30%
26%
25%
10%
0%
Independent
Radiologic
Review
Investigator
Assessment
n = 228
* Not a pre-specified endpoint
n = 221
Independent
Radiologic
Review
n = 292
Investigator
Assessment
n = 310
Conclusions

In this phase 3 randomized trial, nab-P/C demonstrated a
statistically significant higher response rate than P/C (33% vs
25 %, P < 0.001).

The response rate in the squamous cell subset was 41% in the
nab-P/C arm vs 24% in the P/C arm (P < 0.001).

nab-P/C was well tolerated and associated with less sensory
neuropathy, myalgia, and neutropenia than P/C.

nab-P/C was associated with more anemia and
thrombocytopenia than P/C.

Progression-free survival analysis is planned for later this year.
TOPICAL
Tumour type: NSCLC
Data: Oral Abstract Session
Title: TOPICAL: Randomized phase III trial of erlotinib compared
with placebo in chemotherapy-naive patients with advanced non–
small cell lung cancer (NSCLC) and unsuitable for first-line
chemotherapy.
Author: Lee SM
Regimen
Design
• Erlotinib (150
mg/d) plus BSC
(n=350) or placebo
plus BSC (n=320)
Disease
Setting
•
•
Data/Results
Chemo-naïve,
poor PS
advanced
NSCLC
patients.
• 670 patients were randomized to either erlotinib (350) or
placebo (320)
ECOG PS 2/3
or PS 0/1 unfit
for platinum
chemotherapy;
stage IIIB/IV
• Pre-specified subgroup analyses showed significant longer
OS and PFS for females only: HR of 0.75 [0.57-0.99,
P=0.04] and 0.64 [0.49-0.83, P=<0.001] respectively. PFS
HR for adenocarcinoma was 0.74 [0.57-0.97, P=0.03]. PFS
HR according to gender and histology were: 0.68 [0.460.99, P=0.046] females with adenocarcinoma; 0.62 [0.430.89, P=0.01] females with non-adenocarcinoma; 0.85
[0.59-1.22, P=0.37] males with adenocarcinoma; and 1.14
[0.89-1.45, P=0.31] male with non-adenocarcinoma.
• Hazard ratio (HR; erlotinib vs placebo) for OS was 0.98
[95% CI 0.82-1.15; P=0.77]. PFS HR was 0.86 [0.74-1.01,
P=0.07].
Impact: High
Abs.# 7504
Details of the
presentation:
Monday, June 7, 3:00
PM - 6:00 PM, E Hall D2
Author Conclusions
• Overall, erlotinib plus BSC did
not improve OS, but there was
some evidence of benefit for
PFS.
• However, there was a clear effect
on both OS and PFS for females,
and PFS for adenocarcinoma.
• However, the effect in
adenocarcinoma was largely
driven by female patients.
• Final analyses, including EGFR
mutation, VeriStrat serum tests
and QoL will be presented.
• As expected, increased Grade 3/4 rash and diarrhea were
observed in patients receiving erlotinib.
⇒
Key takeaway: For patients ineligible for platinum-based 1L chemo, vs BSC, Tarceva offers a clear
PFS benefit for adenocarcinomas
TORCH
Tumour type: NSCLC
Data: Oral Abstract Session
Title: International multicenter randomized phase III study of firstline erlotinib (E) followed by second-line cisplatin + gemcitabine (CG)
versus first-line CG followed by second-line E in advanced non small
cell lung cancer (aNSCLC). The TORCH trial.
Author: Gridelli C
Regimen
Design
• First-line E (150
mg/d po) followed at
progression by CG (C
80 mg/m² d1 + G
1200 mg/m² dd1&8,
q3w), versus standard
first-line CG followed
at progression by E
Disease
Setting
•
1st-line
Advanced
NSCLC
•
Stage IV/IIIb
(with
supraclavicula
r nodes or
pleural
effusion); PS
0-1, were
eligible
Data/Results
• 760 pts were randomized, 380 in each arm, 612 in Italy,
148 in Canada
• At the planned interim analysis done after 340 deaths
(half of the events required for final analysis), 151 and
189 in the standard and experimental arms, HR of death
in the experimental arm was 1.40 (95% CI 1.13-1.73),
p=0.002; the boundary of study interruption for inferiority
was crossed.
Impact: Medium
Abs.# 7508
Details of the
presentation:
Monday, June 7, 3:00
PM - 6:00 PM, E Hall
D2
Author Conclusions
• A strategy based on first-line E
followed by CG at progression
is inferior than the reverse
standard one, in unselected
patients with aNSCLC.
• Data on compliance and
selected secondary endpoints will also be presented.
• Median survival was 10.8 months in the standard and
7.7 in the experimental arm. There was no heterogeneity
of the HR across gender, smoking habit, and histotype
subgroups.
• The IDMC recommended early study termination and
cross-over to CG was offered to pts receiving first-line E.
⇒
Key takeaway: In unselected patients, first-line Tarceva followed by CG was inferior to the reverse
sequence
Results from ARQ 197-209:
A Global Randomized Placebo-Controlled Phase 2
Clinical Trial Comparing Erlotinib Plus ARQ 197 to
Erlotinib Plus Placebo in Previously Treated EGFRInhibitor Naïve Patients with Locally Advanced or
Metastatic Non-Small Cell Lung Cancer
J. H. Schiller, W. L. Akerley, W. Brugger, D. Ferrari,
E. G. Garmey, D. E. Gerber, S. V. Orlov, R. Ramlau,
J. Von Pawel, L. V. Sequist
For the ARQ 197-209 Clinical Trial Group
c-MET Receptor Tyrosine Kinase
•
•
Implicated in tumor cell
migration, invasion,
proliferation, and angio-
genesis1
Only known high-affinity
receptor for hepatocyte
growth factor (HGF)1
• c-MET amplification associated with:
• Poor prognosis in NSCLC2
• Resistance to EGFR kinase inhibitors in NSCLC cells3,4
1.
2.
3.
4.
Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–10
Cappuzzo F et al. JCO 2009;27:1667–74
Engelman JA et al. Science 2007;316:1039–43
Bean J et al. PNAS 2007;104:20932–7
Schiller54
ARQ 197: a Novel and Selective
Tyrosine Kinase Inhibitor


Non-ATP competitive inhibitor of cMET
Novel mechanism of binding
stabilizes inactive conformation of
c-MET1
• Compound demonstrates broad-spectrum, anti-tumor activity
in a number of tumor xenograft models (including NSCLC)
• In vivo anti-tumor activity of ARQ 197 + EGFR inhibitor greater
than either drug alone2
• Demonstration of safety and linear PK in phase I combination
with EGFR inhibitor erlotinib3,4
1.
2.
3.
4.
Munshi N et al. Mol Cancer Ther 2010;Epub ahead of print
Unpublished; courtesy of ArQule, Inc. and Kyowa Hakko Kirin Co., Ltd
Laux I et al. ASCO 2009
Goldman J et al. IASLC 2009
Schiller 55
ARQ 197-209: Study Objectives
Primary objective:

Compare progression-free survival* (PFS) of patients treated
with erlotinib plus ARQ 197 vs erlotinib plus placebo
Secondary/exploratory objectives:




Evaluate PFS in predefined patient subsets including histology,
molecular profile, and other prognostic characteristics
Evaluate overall survival (OS)
Evaluate objective response rate (ORR)
Further characterize safety of ARQ 197 in combination with
erlotinib
* PFS primary endpoint based on investigator assessment
Schiller 56
ARQ 197-209: Study Design
Randomized, placebo-controlled,
double-blind clinical trial
NSCLC
• Inoperable locally
adv/ metastatic dz.
• ≥1 prior chemo
(no prior EGFR TKI)
Endpoints
• 1° PFS
• 2° ORR, OS
• Subset analyses
• Crossover: ORR
R
A
N
D
O
M
I
Z
E
Erlotinib 150 mg PO QD
+ ARQ 197 360 mg PO BID
28-day cycle
PD
Erlotinib 150 mg PO QD
+ Placebo
28-day cycle
• 33 sites in 6 countries
• Study accrual over 11 months (10/08-9/09)
• Randomization stratified by prognostic factors
incl. sex, age, smoking, histology, performance
status, prior therapy and best response, and
geography (U.S. vs. ex-U.S.)
Schiller 57
ARQ 197-209: Progression-Free Survival
(ITT Population)
• HR=0.81 (95% CI: 0.57, 1.15); p=0.24
• Adjusted HR=0.68 (95% CI: 0.47, 0.98); p<0.05*
Proportion of patients progression-free
1.0
0.9
0.8
0.7
Erlotinib + ARQ 197 16.1 wks
(n=84)
0.6
0.5
0.4
0.3
0.2
Erlotinib + Placebo 9.7 wks
(n=83)
0.1
0
0
10
20
30
40
50
Time from randomization (weeks)
*
•
Cox regression model
PFS also measured by independent radiographic review:
- median 15.6 vs. 8.4 wks
- unadjusted/adjusted HR= 0.74/0.51
58
ARQ 197-209: Overall Survival
(ITT Population)
1.0
• HR=0.88 (95% CI: 0.60, 1.3); p=0.50
• Adjusted HR=0.88 (95% CI: 0.6, 1.3); p=0.52*
Proportion of patients surviving
0.9
0.8
Erlotinib + ARQ 197: 36.6 wks
(n=84)
0.7
0.6
0.5
0.4
Erlotinib + Placebo: 29.4 wks
(n=83)
0.3
0.2
0.1
0.0
0
10
20
30
40
50
60
70
Survival time (weeks)
* Cox regression model
Schiller 59
PFS (Investigator Assessed)
Overall survival
• HR=0.71 (95% CI: 0.46, 1.10) P=0.12
• Adjusted HR=0.61 (95% CI: 0.47, 0.98) P<0.05*
• HR=0.72 (95% CI: 0.6, 1.3) P=0.18
• Adjusted HR=0.58 (95% CI: 0.34, 0.99) P<0.05*
1.0
1.0
0.9
0.8
Erlotinib + ARQ 197 18.9 wks
(n=58)
0.7
0.6
0.5
0.4
0.3
0.2
Erlotinib + Placebo 9.7 wks
(n=59)
0.1
0.0
Proportion of patients surviving
Proportion of patients progression-free
ARQ 197-209: PFS and OS in Non-Squamous Cell
Histology Patients (n=117)
0.9
0.8
Erlotinib + ARQ 197 43.1 wks
(n=58)
0.7
0.6
0.5
0.4
0.3
0.2
Erlotinib + Placebo 29.4 wks
(n=59)
0.1
0.0
0
10
20
30
40
Time from randomization (weeks)
50
0
10
20
30
40
50
60
70
Time from randomization (weeks)
* Cox regression model
Schiller 60
ARQ 197-209: PFS in Histologic
and Molecular Subgroups
ARQ197/erlotinib
N
Placebo/erlotinib
Unadjusted HR (95% CI)
Median PFS (95% CI, weeks)
Squamous Cell
26 / 24
13.7 (8.0‒18.1)
8.4 (7.9‒21.0)
HR=1.05
Non-Squamous Cell
58 / 59
18.9 (15.0‒31.1)
9.7 (8.0‒16.0)
HR=0.71
c-MET FISH >4
19 / 18
15.4 (8.1‒24.4)
15.3 (7.1‒16.3)
HR=0.71
c-MET FISH >5
8 / 11
24.1 (16.3‒NE)
15.6 (7.9‒31.4)
HR=0.45
EGFR mutant
6 / 11
24.1 (8.0‒32.1)
21.0 (8.1‒36.0)
HR=1.23
EGFR wt
51 / 48
13.7 (8.1‒18.1)
8.1 (7.9‒9.9)
HR=0.70
KRAS mutant
10 / 5
9.7 (7.9‒NE)
4.3 (1.1‒8.0)
HR=0.18
KRAS wt
49 / 45
15.4 (8.1‒18.1)
9.9 (8.0‒16.0)
HR=1.01
0
0.5
1.0
1.5
2.0 5.0
Favors
FavorsSchiller
ARQ 197/Erlotinib Erlotinib/placebo
ARQ 197-209: PFS in Histologic
and Molecular Subgroups
ARQ197/erlotinib
N
Placebo/erlotinib
Unadjusted HR (95% CI)
Median PFS (95% CI, weeks)
Squamous Cell
26 / 24
13.7 (8.0‒18.1)
8.4 (7.9‒21.0)
HR=1.05
Non-Squamous Cell
58 / 59
18.9 (15.0‒31.1)
9.7 (8.0‒16.0)
HR=0.71
c-MET FISH >4
19 / 18
15.4 (8.1‒24.4)
15.3 (7.1‒16.3)
HR=0.71
c-MET FISH >5
8 / 11
24.1 (16.3‒NE)
15.6 (7.9‒31.4)
HR=0.45
EGFR mutant
6 / 11
24.1 (8.0‒32.1)
21.0 (8.1‒36.0)
HR=1.23
EGFR wt
51 / 48
13.7 (8.1‒18.1)
8.1 (7.9‒9.9)
HR=0.70
KRAS mutant
10 / 5
9.7 (7.9‒NE)
4.3 (1.1‒8.0)
HR=0.18
KRAS wt
49 / 45
15.4 (8.1‒18.1)
9.9 (8.0‒16.0)
HR=1.01
0
0.5
1.0
1.5
2.0 5.0
Favors
Favors
62
ARQ 197/Erlotinib Erlotinib/placebo
ARQ 197-209: PFS in Histologic
and Molecular Subgroups
ARQ197/erlotinib
N
Placebo/erlotinib
Unadjusted HR (95% CI)
Median PFS (95% CI, weeks)
Squamous Cell
26 / 24
13.7 (8.0‒18.1)
8.4 (7.9‒21.0)
HR=1.05
Non-Squamous Cell
58 / 59
18.9 (15.0‒31.1)
9.7 (8.0‒16.0)
HR=0.71
c-MET FISH >4
19 / 18
15.4 (8.1‒24.4)
15.3 (7.1‒16.3)
HR=0.71
c-MET FISH >5
8 / 11
24.1 (16.3‒NE)
15.6 (7.9‒31.4)
HR=0.45
EGFR mutant
6 / 11
24.1 (8.0‒32.1)
21.0 (8.1‒36.0)
HR=1.23
EGFR wt
51 / 48
13.7 (8.1‒18.1)
8.1 (7.9‒9.9)
HR=0.70
KRAS mutant
10 / 5
9.7 (7.9‒NE)
4.3 (1.1‒8.0)
HR=0.18
KRAS wt
49 / 45
15.4 (8.1‒18.1)
9.9 (8.0‒16.0)
HR=1.01
0
0.5
1.0
1.5
2.0 5.0
Favors
Favors
63
ARQ 197/Erlotinib Erlotinib/placebo
ARQ 197-209: Overall Response Rate*
(RECIST 1.0)
ARQ 197/erlotinib
n=73
Partial Response**
Placebo/erlotinib
n=72
7 (10%)
5 (7%)
Stable Disease
41 (56%)
34 (47%)
Disease Control Rate
48 (66%)
39 (54%)
* Among patients evaluable for RECIST response
** EGFR status:
• Combination arm: 3 mutants; 1 WT; 3 IND
• Erlotinib arm: 4 mutants; 1 IND
Schiller 64
Historic Context of ARQ 197-209
Placebo Arm (BR.21)
BR.21
Placebo arm
(placebo)
(n=243)
BR.21
Active arm
(erlotinib)
(n=488)
ARQ 197-209
Placebo arm
(placebo/erlotinib)
(n=83)
ARQ 197-209
Active arm
(ARQ 197/erlotinib)
(n=84)
Progression-free
survival
(mos.)
1.8
2.2
2.3
3.7
Overall survival
(mos.)
4.7
6.7
6.9
8.5
Objective
response rate
<1%
8.9%
6.9%
10%
Schiller 65
Historic Context of ARQ 197-209
Placebo Arm (BR.21)
BR.21
Placebo arm
(placebo)
(n=243)
BR.21
Active arm
(erlotinib)
(n=488)
ARQ 197-209
Placebo arm
(placebo/erlotinib)
(n=83)
ARQ 197-209
Active arm
(ARQ 197/erlotinib)
(n=84)
Progression-free
survival
(mos.)
1.8
2.2
2.3
3.7
Overall survival
(mos.)
4.7
6.7
6.9
8.5
Objective
response rate
<1%
8.9%
6.9%
10%
Schiller 66
ARQ 197-209: Crossover Patients
2 PR2
34
Crossover
Patients
23 Evaluable for
Response1
9 SD3
12 PD
1
Baseline + ≥1 post-baseline scan.
Reasons for non-evaluable incl:
- Clinical progression (n=4)
- Active but haven’t received 1st post-progression scan (n=2)
- Death (n=1)
- Dosing delay (n=1)
- Withdrew consent (n=1)
- Investigator decision (n=1)
2
Pt # 24:
EGFR IND
KRAS WT
c-MET > 4
Pt # 58:
EGFR MUT
KRAS WT
c-MET > 5
3
3‒18+ weeks
Schiller 67
ARQ 197-209: Conclusions

ARQ 197-erlotinib combination well-tolerated with side-effect
profile similar to individual agents

RECIST responses observed in both primary double blind analysis
and following crossover from placebo to combination therapy

Median PFS prolonged with ARQ 197 plus erlotinib vs. erlotinib
alone (16.1 weeks vs. 9.7 weeks)
– Statistically significant HR when adjusting for key prognostic
factors in Cox regression analysis (0.68 [0.47, 0.98]; p 0.05)

Improvements in median OS parallel PFS:
–


7.2 weeks in ITT population (36.6 wks vs. 29.4 wks)
PFS and OS benefits most pronounced in non-squamous patients:
–
9.2 week improvement in median PFS (18.9 wks vs. 9.7 wks)
–
13.7 week improvement in median OS (43.1 wks vs. 29.4 wks)
Benefits in EGFR wild-type and KRAS mutation positive patients
intriguing and merit further investigation
68 Schiller
Efficacy and Safety of PF299804 vs Erlotinib:
Randomized Phase II
Trial after Chemotherapy Failure
Boyer et al. (Poster Discussion)

Irreversible, oral, pan-HER inhibitor

More potent and active than erlotinib in
preclinical models

Randomized Phase II: 94 patients per arm
Efficacy and Safety of PF299804 vs Erlotinib:
Randomized Phase II
Trial after Chemotherapy Failure
Boyer et al. (Poster Discussion)
Results



RR: 17% for PF vs 4% for erlotinib (p=009)
PFS: 0.681 (p=0.019)
Benefit across all subgroups including wt EGFR
and mut K-Ras
Common EGFR TKI treatment-related AE’s
more frequent with PF
A Phase III Prospective,
Randomized, Double-Blind, PlaceboControlled Trial of the Epidermal
Growth Factor Receptor Inhibitor,
Gefitinib in Completely Resected
Stage IB-IIIA Non Small Cell Lung
Cancer, NCIC CTG BR.19
G.D.Goss, I. Lorimer, M-S. Tsao, C. O’Callaghan, K. Ding, G. Masters,
P. Roberts, J. Jett, M. J. Edelman, F. A. Shepherd
On behalf of NCIC CTG, ACOSOG, CALGB, ECOG, NCCTG, RTOG,
SWOG
BR.19 - Schema
Pts with completely
resected stage
IB,II, and IIIA
NSCLC
Stratified by
- stage
- histology
post-op RT
sex
adjuvant
chemotherapy*
Gefitinib
250 mg po
daily x 2 yrs
Randomized 1:1
Placebo
0 mg po
daily x 2 yrs
*Protocol amended January 2003 to allow adjuvant chemotherapy
which became a stratification factor
BR.19 - Objectives
Primary: Overall survival
Secondary:
• Disease-free survival
• Toxicity
• Establish a tumor bank
• Confirm the prognostic and predictive
significance of:
KRAS mutation status
EGFR gene expression by FISH
EGFR mutation status
BR.19 - Overall Survival
100
Percentage
80
60
HR : 1.23 (95% CI 0.94-1.64)
p=0.136*
Median survival: Gefitinib - 5.1 yrs
Placebo - N.E.
40
20
Placebo
Gefitinib
0
Number at risk
Gefitinib
Placebo
0
1
2
3
Time (Years)
4
5
6
251
252
217
219
188
198
163
171
133
138
42
56
2
4
*Stratified Log Rank
Overall Survival by EGFR Mutation
Status - Placebo Arm Patients
EGFR mutation
100
Wild type
Percentage
80
60
HR EGFR mutation/wild type: 1.06 ( 95%CI
0.62,1.83)
Log Rank p=0.830
40
20
Median (95%C.I.)
- Wild type: Not reached (5.1,inf.)
- EGFR mutation: 5.1 years (4.4,inf.)
0
Number at Risk
Wild type
EGFR class mutation
0
1
2
3
Time (Years)
4
5
6
145
40
126
38
118
32
101
30
77
26
34
6
2
1
Overall Survival by EGFR Mutation
Status and Treatment
Wild type
100
Placebo
Sensitizing mutation
Gefitinib
100
Gefitinib
80
Percentage
80
Percentage
Placebo
60
40
60
40
20
20
0
0
# at Risk 0
Placebo 145
Gefitinib 136
1
126
121
2
3
4
Time (Years)
118
101
77
105
89
74
5
6
34
21
2
2
HR (95% C.I.)
Gefitinib/Placebo: 1.21 (0.84, 1.73)
Log Rank: p=0.301
Median (95% C.I.)
-Placebo: Not reached (5.1, inf.)
-Gefitinib: 5.0 (4.3, inf.)
# at Risk 0
Placebo 40
Gefitinib 36
1
2
38
29
32
26
3
4
Time (Years)
30
26
21
17
5
6
6
7
1
0
HR (95% C.I.)
Gefitinib/Placebo: 1.58 (0.83, 3.00)
Log Rank: p=0.160
Median (95% C.I.)
- Placebo: 5.1 (4.4, inf.)
- Gefitinib: 3.7 (2.6, inf.)
Conclusions





Gefitinib was well tolerated
In this under-powered study, gefitinib did not improve
disease free and overall survival in patients with completely
resected early stage NSCLC
In exploratory analyses, KRAS mutation status, EGFR by
FISH or EGFR sensitizing mutation status were neither
prognostic nor predictive of survival
It is yet to be demonstrated that a targeted agent improves
overall survival in NSCLC in the adjuvant setting and, for
the present, chemotherapy in good performance patients
remains the treatment of choice
The results of the RADIANT trial of adjuvant erlotinib
are awaited
Randomized Trial of Gemcitabine-Carboplatin (G-Cb)
Therapy Followed by Gemcitabine (G)
Maintenance or Best Supportive Care (BSC)
in Advanced NSCLC
C.P. Belani1, D.M. Waterhouse2, H.H. Ghazal3, S. Ramalingam 4 ,
J.M. Waples5, R.E. Bordoni6, G.A. Reznikoff7, C.P. Curran8, R. H.
Greenberg9
1Penn
2Oncology
State Hershey Cancer Institute, Hershey, PA, USA;
Hematology Care, Cincinnati, OH; 3Kentucky Cancer Clinic, Hazard, KY);
4Emory University Winship Cancer Institute, Atlanta, GA, 5 Clearview Cancer Institute,
6Georgia Cancer Specialists, Atlanta, GA; 7Medical
Huntsville, AL;
8 Palmetto Hematology Oncology,
Specialists of Fairfield, Fairfield, CT;
9The Center for
Spartanburg, SC;
Cancer and Hematologic Disease, Cherry Hill, NJ
Abstract # 7507
Study Design

Chemonaïve Stage IIIB/IV
NSCLC
Arm A

Randomization factors:
Gemcitabine 1000 mg/m2 d 1,8
• PS
q 21 days
+
• stage
Best supportive care (BSC)
• best tumor response CR
PR
Gemcitabine 1000 mg/m2 d
SD
1,8
1:1
Primary Endpoint = OS
Carboplatin AUC 5 d 1
Randomization
q 21 days X 4 cycles
Arm B
PD
Off
study
Best supportive care (BSC)
Overall Survival
(Intent-to-treat Population)
1.0
HR=0.97 (95% CI:0.72,
1.30)
P =0.838
0.9
0.8
0.7
0.6
BSC 9.3 mos.
0.5
0.4
0.3
0.2
0.1
Gemcitabine 8.0 mos.
0.0
0
6
12
18
24
30
36
42
Overall Survival (months)
48
54
60
Progression-free Survival
(Intent-to-treat Population)
1.0
HR=1.09 (95% CI:0.81,
1.45)
P =0.575
0.9
0.8
0.7
0.6
0.5
BSC 7.7
months
0.4
0.3
0.2
0.1
0.0
0
Gemcitabine 7.4
months
6
12
18
24
30
36
42
48
Progression-free Survival (months)
54
60
Conclusions

This study failed to show a survival benefit for
maintenance Gemcitabine in non-progressors following
standard treatment of G-Cb for patients with advanced
NSCLC
 Nearly two thirds of patients were ECOG PS 2 at study
entry

Gemcitabine in the maintenance setting was well
tolerated

Few patients received post-study therapy likely due to
poor PS
IFCT-GFPC 0502 (Perol)
Tumour type: NSCLC
Data: Oral Abstract Session
Title: Maintenance with either gemcitabine or erlotinib versus observation with
predefined second-line treatment after cisplatin-gemcitabine induction
chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study.
Author: Perol M
Regimen
Design
• Maintenance
gemcitabine (G) or E vs
observation (O),
following induction CT
with a predefined
second-line therapy in
all arms (pemetrexed
[P]).
• Randomized to O, or
to receive as
maintenance therapy
either G (1250mg/m2,
days 1 and 8 of a 3
week cycle) or E
150mg/day until
disease progression.
⇒
Disease
Setting
•
NSCLC
patients (pts)
whose tumors
have not
progressed
following
platinumbased
chemotherapy
(CT).
Data/Results
• 464 were randomized to either O (155), G (154) or E
(155).
• Median PFS by investigator assessment was 2.1, 3.7
and 2.8 months for O, G and E respectively.
• PFS by independent review (83% pts assessed) was
significantly prolonged by G (HR [95% CI] 0.51
[0.39 0.66]) and E (HR 0.83 [0.73 0.94]) vs O.
• Second-line P was received by 72/55/60% of pts,
respectively.
Impact: High
Abs.# 7507
Details of the
presentation:
Monday, June 7, 3:00 PM 6:00 PM, E Hall D2 (4:00)
Author Conclusions
• Maintenance with G or E
significantly delays disease
progression after cisplatingemcitabine induction.
• The impact on OS with a
predefined second-line
therapy will be discussed in
the May 2010 update.
• Grade 3 /4 treatment-related AEs were more common
with G (27%) and E (14%) than with O (2%).
• Final results of the independent review will be available
for the meeting, and will include mature OS data,
subgroup analyses by stratification factors and EGFR
mutation status.
Key takeaway: 3rd Phase III trial to show PFS benefit with Tarceva; OS results immature
Prevention of erlotinib-induced folliculitis with
Doxycycline (D) in NSCLC
Deplanque et al. (poster discussion)




Randomized, open label, multicentric Phase II study vs standard of
care (73 pts per arm)
No difference in the overall incidence of folliculitis
No difference in RR and PFS
Decrease in the severity of folliculitis and improved quality of life
with D
D
Control
Grade 1
61%
18%
Grade 2
35%
p=0.06
62%
Grade 3
4%
18%
Grade 4
0%
2%
No significant difference in the incidence of dose reductions
Other Negative Trials



Randomized Phase II of mapatumumab, a TRAIL-R1
agonist MoAb in combination with carboplatin and
paclitaxel Von Pawel et al
Randomized Phase III trial of NOV-002 in combination
with carboplatin and paclitaxel Fidias et al.
Randomized Phase III chemoprevention trial with
selenium in resected stage I NSCLC Karp et al.
Take Home Messages









Patients with EGFR mutations and ALK translocations represent distinct subgroups
for which targeted therapies are available and expected to be approved in the near
future
Guidelines for testing need to be developed
Expanded use program for Crizotinib necessary
In EGFR mutated patients, combinations do not enhance erlotinib efficacy as
frontline therapy
In EGFR wt patients, erlotinib combinations with other signal transduction inhibitors
or second generation EGFR TKI’s appear to broaden the spectrum of activity of
erlotinib (Kras mutant tumors)
Switch maintenance more promising than maintenance with an agent used frontline
Single agents (paclitaxel, erlotinib) inferior to doublets as frontline therapy
Erlotinib a reasonable option as frontline therapy in patients not candidates for
chemotherapy
Too early to assess the potential use of nab-paclitaxel
Figitumumab can only be rescued by strict patient selection
Results of gefitinib adjuvant study worrisome