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ASCO Lung Cancer Review 2009
Mark A. Socinski, MD
Professor of Medicine
Multidisciplinary Thoracic Oncology Program
Lineberger Comprehensive Cancer Center
University of North Carolina
Abstracts
y g
• Early stage
Adjuvant therapy – BR10 Update (7501)
NATCH (7500)
• Stage III
ECOG 3598 – thalidomide (7503)
CALGB 30407 – cetuximab (7505)
• Stage IV NSCLC
“Maintenance” – Pemetrexed, SATURN, ATLAS (8000, 8001, 8002)
Biomarkers – FLEX, IPASS (8006, 8007)
Vandetinib trials – ZODIAC, ZEST, ZEAL (8003, 8009,8010)
2
JBR.10 Update - Study Design
Vincent M et al. ASCO 2009 abstr # 7501
Vi t t l 2009, b t
R
Stage IB/II
E T R Observation
G Stratified by A Only
I I N d l
Nodal
N
S * N0
S D
* N1
T S ras O
E U * Neg M Cisplatin
R E * Pos Vinorelbine
* UNK
I
S
E
Overall Survival: April 2004
5 yr: 61% vs 49% 5 yr: 69% vs 54%
HR: 0.60, p<0.001 HR: 0.69, p=0.009
Winton et al. NEJM 2005; 352: 2589-97
y g p
Overall Survival by Stage: April 2004
HR: 0.94, p=0.79 HR: 0.59, p= 0.004
Winton et al. NEJM 2005; 352: 2589-97
Updated Overall Survival by Treatment
Arm – ASCO 2009
A
'
100 Observation Vinorelbine
Stratified Log-Rank: p=0.04
HR: 0.780(0.613, 0.993)
80
e
Percentage
60
40 5 yr: 67% vs 56%
5 yr: 67% vs 56%
20 94 mo vs 72 mo
MST:MST 94m vs 72m
0
0 3 6 9 12 15
At Risk Time(Years)
Observation 240 155 117 58 9 0
Vinorelbine 242 182 135 67 12 0
Absolute improvement in 5 yr OS 11% (67%-56%)
Updated Survival by Stage
'
100 Observation Vinorelbine
Stratified Log-Rank: p=0.01
HR: 0.68(0.50, 0.92)
80
Interaction p=0.09
60
Percentage
40
6.8 3.6
MST 6 8 vs 3 6 yrs
20 St
Stage IB
5 yr: 59% vs 44% '
100 Observation Vinorelbine
0
0 3 6 9 12 15 Stratified Log-Rank: p=0.87
At Risk ( )
Time(Years)
Observation 1.03(0.70, 1.52)
HR: 1 03(0 70 1 52)
132 72 48 18 4 0 80
Vinorelbine 131 95 65 31 6 0 Stage IB
Stage II
centage
60
Perc
40
MST 9.8 vs 11 yrs
20
y
5 yr: 76% vs 69%
0
0 3 6 9 12 15
At Risk Time(Years)
Observation 108 83 69 40 5 0
Vinorelbine 111 87 70 36 6 0
Updated Stage IB Survival By T Size
'
100 Observation Vinorelbine
Stratified Log-Rank: p=0.07
HR: 1.73(0.98, 3.04)
80
0 02
Interaction p= 0.02
ge
60
Percentag
40 MST 7.6 yr vs 11.2 yr
5 yr 73% vs 79%
20
<4 cm, Observation vs chemo
0
0 3 6 9 12 15
At Risk Time(Years)
Observation 54 47 40 20 4 0
Vinorelbine 45 33 27 13 1 0 '
100 Observation Vinorelbine
Stratified Log-Rank: p=0.13
HR: 0.66(0.39, 1.14)
80
Percentage
e
60
MST NR vs 9.8 yr
40
5 yr 79% vs 59%
20 cm,
≥4 cm Observation vs chemo
0
0 3 6 9 12 15
At Risk Time(Years)
Observation 54 36 29 20 1 0
Vinorelbine 66 54 43 23 5 0
Cumulative Incidence Plots for Disease
Non-disease
and Non disease Related Deaths
1 .0
• Observation/Disease Related
Chemotherapy/Disease Related
Observation/Non-Disease Related
0 .8
Chemotherapy/Non-Disease Related
bility
Test for Disease Related Deaths Test for Non-Disease Related Deaths
tive P robab
======================== =============================
0 .6
Log-Rank Test p-value = 0.027 Log-Rank Test p-value = 0.660
Fine-Gray Test p-value = 0.023 Fine-Gray Test p-value = 0.622
-------------------------------------------- -----------------------------------------------------
C um ulat
0 .4
2
0 .2
0 .0
0 2 4 6 8 10 12 14
Time(Years)
Second Primary Malignancies
Observation Chemotherapy
N=239 N=243
N
No (91 2%)
218 (91.2%) 226 (93%)
Yes 21 (8.8%) 17 (7.9%)
Head & Neck 4 0
NSCLC 3 0
SCLC 1 1
Bladder 0 1
Kidney 1 1
Miscellaneous 12 14
NATCH Study Design
al 2009
Felip E et al. ASCO 2009, abstr # 7500
R g y
Surgery
A
N
g
Clinical stage
D
Paclitaxel /
IA(>2cm), IB, II, T3N1 O Surgery
Carboplatin
M
St tif by
Stratify b
I
─ Tumor size:
Z
(<3, 3-5 or > 5 cm)
E Paclitaxel /
─ Age: (≤ 60 or >60 y) Surgery
Carboplatin
Primary E d i t
Pi Endpoint: AUC 6
• Paclitaxel 200 mg/m2 /3h + Carboplatin AUC=6 q3wk for
a total of 3 cycles
5 yr DFS (∆ 15%) • Post-op thoracic RT allowed for p-N2 disease
11
(N 199)
Preop CT Arm: CT Compliance (N=199)
CT,
• Preop CT 193 pts (97%)
– 180 pts, 3 cycles (90%)
y
– 13 pts, < 3 cycles
Adverse events, 4 pts
Death, 2 pts
Progression, 1 pt
Other, 4 pts
No information, 2 pts
• Dose reductions 9% of pts / delays 11% of pts
12
(N=210)
Adj CT Arm: CT Compliance (N 210)
No adj CT, 71 pts (34%) Adj CT, 139 pts (66%)
• Post-operative mortality, 15 pts • 129 pts, 3 cycles
• Stage IIIB/IV at surgery, 12 pts
St t t
• 10 pts, < 3 cycles
• Surgical complications, 9 pts
– Adverse events, 4 pt
• Other histologies, 2 pts – Refusal, 2 pt
• CT,
Refused CT 11 pts – Progression 2 pt
Progression,
• PI’s decision, 4 pts – Death, 2 pt
• Progression, 3 pts • Dose reductions 11% of pts /
• Other, 5 pts delays 16% of pts
• Ineligible / cancelled at baseline, 10 pts
13
DFS in Preop CT Arm vs Surgery Arm
p
Median Follow-up 51 Months
Surgery Preop CT
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
(N=210) (N=199)
Events 132 117
Median DFS (mo) 25.1 31.5
3-year DFS 41.9% 48.4%
5-year DFS 34.1% 38.3%
0 92; (0 81 1.04); 0.176
HR = 0.92; 95% CI (0.81 to 1 04); P = 0 176
7
Probability
0
Preop CT
Surgery
At risk:
Preop CT 140 105 81 57 37 26
Surgery 130 98 77 53 34 23
0 1 2 3 4 5 6
Time (years)
14
DFS in Adj CT Arm vs Surgery Arm
p
Median Follow-up 51 Months
Surgery Adj CT
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
(N=210) (N=210)
Events 132 125
Median DFS (mo) 25.1 26.0
3-year DFS 41.9% 44.9%
5-year DFS 34.1% 36.6%
0 96; (0 75 1.22); 0.73
HR = 0.96; 95% CI (0.75 to 1 22); P = 0 73
7
Probability
0
Adj CT
Surgery
At risk:
Adj CT 131 95 71 54 37 25
Surgery 130 98 77 53 34 23
0 1 2 3 4 5 6
Time (years)
Ti ( )
15
Overall Survival by Arm
Surgery Adj CT Preop CT
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 (N=210) (N=210) (N=199)
Events 109 102 99
( )
Median OS (mo) 48.8 50.3 55.2
3-year OS 58.6% 58.4% 59.2%
5-year OS 44% 45.5% 46.6%
Surgery vs Adj CT: HR=0.99 (0.75 to 1.3); P=0.93
Surgery vs Preop CT: HR=0.96 (0.84 to 1.1); P=0.56
0
obability
Pro
At risk:
2
Preop CT 165 131 99 71 45 31
Adj CT 161 121 90 65 40 29
Surgery 168 131 105 72 40 27
0 1 2 3 4 5 6
Time (years)
16
Abstracts
y g
• Early stage
Adjuvant therapy – BR10 Update (7501)
NATCH (7500)
• Stage III
ECOG 3598 – thalidomide (7503)
CALGB 30407 – cetuximab (7505)
• Stage IV NSCLC
“Maintenance” – Pemetrexed, SATURN, ATLAS (8000, 8001, 8002)
Biomarkers – FLEX, IPASS (8006, 8007)
Vandetinib trials – ZODIAC, ZEST, ZEAL (8003, 8009,8010)
17
ECOG 3598: Rationale for Thalidomide
Diverse Properties
• Anti-angiogenic
– Inhibits expression of a number of angiogenic
cytokines: VEGF, bFGF, COX2, TGF beta
expression
• Immunomodulatory
– T cell/NK stimulation
p y
– Induces expression of immunomodulatory
cytokines (IL-12, gamma IFN)
• Anti-proliferative
18
E3598: Chemo/RT +/- Thalidomide
,
Schiller J et al. ASCO 2009, abstr # 7503
Amended Schema
R Carboplatin Wkly
Wkl
carbo/paclitaxel
A Paclitaxel
Stage N RT (60 Gy)
2 cycles
IIIA,
IIIA B D
NSCLC O
M Carboplatin Wkly
I P lit l
Paclitaxel carbo/paclitaxel
b / lit l PR, Thalidomide:
Z Thalidomide RT (60 Gy) + CR,
E 2 cycles Stable total of 2 years
Thalidomide
• Amended 6/04/2003 after 288 patients had been registered
• Weekly concurrent carboplatin/paclitaxel added
19
ECOG 3598: Outcomes
Carbo/paclitaxel +
Carbo/paclitaxel P (HR)
thalidomide
Response rate 35% 39% 0.36
0 36
Survival
0.84
14.9 mo 16.1 mo
Median (mo)
• M di ( ) (HR= 0.98;
(HR 0 98
(12.4-20.2) (14.5-18.5)
0.81 – 1.18)
57% 67%
• 1 year
(51-63%) (62-73%)
34% 33%
• 2 year
(29-41%) (28-40%)
0 99
0.99
PFS – median 7.4 mo 7.8 mo
(HR = 1.00;
(mo) (6.6 -8.7) (7.0-8.8)
0.84 – 1.20)
20
ECOG 3598: Outcomes
Progression Free Survival Survival
21
Conclusions
• Thalidomide did not improve the survival of
patients with locally advanced NSCLC when
administered with carbo/paclitaxel
• Thalidomide was associated with increased
thrombotic events, despite the addition of
low-dose aspirin.
• Lack of efficacy did not appear to be due to
inadequate thalidomide dosing, as patients
were titrated to their maximum tolerated
dose.
• Identifying effective anti-angiogenic drugs for
challenging
NSCLC is challenging.
22
Randomized Ph St d f P t d C b l ti d
R d i d Phase II Study of Pemetrexed, Carboplatin and
Thoracic Radiation with or without Cetuximab in
Stage III Non-small Cell Lung Cancer: CALGB 30407 Schema
Govindan R et al. ASCO 2009, abstr # 7505
R C b l ti AUC 5 q3week x 4 cycles
Carboplatin 3 k l
A Arm A Pemetrexed 500/mg² q3week x 4 cycles
N XRT – 70 Gy over 7 weeks Pemetrexed
D /
500 mg/m2
O
Carboplatin AUC 5 q3week x 4 cycles q 3 weekly x 4
M
Pemetrexed 500/mg² q3week x 4 cycles
I
XRT - 70 Gy over 7 weeks
Z
+
E Arm B Cetuximab 400mg/m² loading
and 250mg/m² weekly
Primary endpoint: OS (MST > 20.9 months)
23
g p
CALGB 30407 - Demographics
Characteristic Pemetrexed and Pemetrexed,
Carboplatin Carboplatin and
(n- 48)
(n (n 51)
Cetuximab (n-51)
Male 58% 65%
Median Age in Years (41 79)
62 (41-79) (32 81)
65 (32-81)
(Range)
Proportion over 70 years 25% 20%
Caucasians 77% 94%
Histology
Adenocarcinoma 46% 41%
Squamous 33% 35%
Poorly differentiated 19% 18%
Stage III A 58% 55%
Stage III B 40% 45%
24
CALGB 30407
Treatment Delivery (Post Chemoradiation)
Characteristic Pemetrexed and Pemetrexed,
Pemetrexed
Carboplatin Carboplatin and
(n- 48) Cetuximab (n-51)
ou cycles
All four cyc es 50% 9%
49%
Three cycles 8% 2%
Two cycles 19% 14%
One cycle 6% 6%
None 17% 27%
Missing 0 2%
90% and 80% of patients rec’d all four cycles of Cb/Pem on the Cb/Pem and
Cb/Pem/Cetuximab arms, respectively)
25
g
CALGB 30407 - Hematological
Toxicities (Grade III and IV)
Characteristic Pemetrexed and Pemetrexed,
Carboplatin Carboplatin and
n 48 (%)
n- Cetuximab
n-51 (%)
Anemia 18 14
Neutropenia 50 59
Thrombocytopenia 36 (22/14) 34(23/11)
(G3/G4)
Febrile Neutropenia 8 6
26
CALGB 30407 - Non-hematological
Toxicities (Grade III and IV)
Characteristic Pemetrexed and Pemetrexed,
p
Carboplatin p
Carboplatin and
n- 48 Cetuximab
(%) n-51 (%)
y p g
Dysphagia 32 24
Fatigue 22 17
Pneumonitis 12 8
Rash 2 21
Nausea/Vomiting 8 10
Hypersensitivity 2 8
Deaths
D th 4% 4%
27
CALGB 30407 - Overall Survival
CALGB 30407: Overall Survival
1.0
0
Median Overall Survival
0.8
Arm A 22 months (95% CI: 17-NA)
A
Arm B th CI 13-NA)
22 months (95% CI: 13 NA)
0.6
Probability
18 Month Overall Survival
0.4
Arm A (N=48)
Arm B (N=51)
0.2
p-value=0.669
Arm A 57% (95% CI 44-75)
Arm B 50% (95% CI 37-68)
0.0
0 10 20 30
Survival Time (Months)
p
Median follow up: 22 months
H0: p≤0.35 versus H1: p≥0.55
p = survival probability at 18 months
registration 28
CALGB 30407
Summary
Administration f t d b l ti
• Ad i i t ti of pemetrexed, carboplatin and d
thoracic radiation with or without cetuximab produced
a median survival of 22 months.
• Both regimens met the pre-defined threshold (median
survival of 20.9 months) to be considered worthy for
development
further development.
• Trends toward better outcomes observed with non-
q
squamous NSCLC in this study. y
• Toxicities related to concurrent chemoradiation are
similar to previous studies
29
Abstracts
y g
• Early stage
Adjuvant therapy – BR10 Update (7501)
NATCH (7500)
• Stage III
ECOG 3598 – thalidomide (7503)
CALGB 30407 – cetuximab (7505)
• Stage IV NSCLC
“Maintenance” – Pemetrexed, SATURN, ATLAS (8000, 8001, 8002)
Biomarkers – FLEX, IPASS (8006, 8007)
Vandetinib trials – ZODIAC, ZEST, ZEAL (8003, 8009,8010)
30
JMEN – “Maintenance” Pemetrexed Study Design
Belani CP et al. ASCO 2009, abstr #8000
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
Stage IIIB/IV NSCLC Pemetrexed 500 mg/m2
0 1
ECOG PS 0-1 (d1 q21d) + BSC (N=441)*
(d1,q21d) (N=441)
4 prior cycles of gem,
doc, or tax + cis or
carb, with CR, PR, or 2:1 Primary Endpoint = PFS
SD
Randomization Secondary = OS, RR, DCR, Tox
Randomization factors:
• gender
• PS
• stage Placebo (d1, q21d) + BSC
• best tumor (N=222)*
response
*B12, folate, and dexamethasone given in both
• non-platinum drug arms
• brain mets 31
Baseline Characteristics
Pemetrexed Placebo
N=441
N 441 N=222
N 222
% %
Median age, years 60.6 60.4
Male/Female 73/27 73/28
Caucasian/Asian/Other 63/32/4 67/30/3
Ever-smoker/Never-smoker 74/26 71/28
Disease stage (IIIB/IV) 18/82 21/79
ECOG PS 0/1 40/60 38/62
Histology
Non-squamous 74 70
Adenocarcinoma 50 48
Large cell carcinoma 2 5
Other or indeterminate 21 18
Squamous 26 30
32
Progression-free Survival
HR=0.60 (95% CI: 0.49–0.73)
1.0 P <0.00001
ability
0.9
0.8
ree Proba
0.7
0.6
0.5 Pemetrexed 4.0 mos
ession-fr
0.4
0.3
0.2
Progre
0.1 Placebo 2.0 mos
0.0
0 3 6 9 12 15 18 21 24
Time (months)
33
Overall Survival (Intent-to-treat Population)
( )
HR=0.79 (95% CI: 0.65–0.95)
1 .0 P =0.012
0 .9
ility
0 .8
Survival Probabi
0 .7
0 .6
0 .5 Pemetrexed 13.4 mos
0 .4
Placebo 10.6 mos
0 .3
0 .2
1
0 .1
0 .0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
34
Overall Survival by Histology
Non-
Non-squamous (n=481) Squamous (n=182)
HR=0.70 (95% CI: 0.56-0.88) HR=1.07 (95% CI: 0.49–1.73)
P =0.002 P =0.678
1.0 1.0
0.9
09 09
0.9
y
urvival Probability
0.8 0.8
0.7 0.7
0.6 0.6
0.5 Pemetrexed 15.5 mos 0.5 Pemetrexed 9.9 mos
0.4 0.4
0.3 0.3
Placebo Placebo
02
0.2 0.2
02
Su
10.3 mos 10.8 mos
0.1 0.1
0.0 0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months) Time (months)
35
Efficacy by Histologic Groups
Median OS, mos Median PFS, mos
Histology Groups
P-value P-value
Pem Plac Pem Plac
(HR) (HR)
Non-squamous
Non squamous 0.002 <0.00001
15.5 10.3 4.4 1.8
(n=481) (0.70) (0.47)
Adeno 0.026 <0.00001
16 8
16.8 11 5
11.5 4.6
46 27
2.7
(n=329) (0.73) (0.51)
Large cell 0.964 0.104
8.4 7.9 4.5 1.5
(n=20) (0.98) (0.40)
Other 0.025 0.0002
11.3 7.7 4.1 1.6
(n=133) (0.61) (0.44)
Squamous 0.678
0 678 0.896
0 896
9.9 10.8 2.4 2.5
(n=182) (1.07) (1.03)
There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·03
36
Systemic Post-study Therapy
Pemetrexed Placebo
(N=441) (N=222)
( )
% %
Patients with post-study therapy 52 67
Most common post-study therapies
p y p
Carboplatin 7 10
Cisplatin 5 6
Docetaxel 22 29
Erlotinib 22 21
Gefitinib 13 10
Gemcitabine
G it bi 9 14
Paclitaxel 4 6
Pemetrexed 1 19
Vinorelbine 13 17
Higher rate of follow-up treatment on the placebo arm
Balanced selection of therapies between arms and low rate of crossover 37
Systemic Post-study Therapy
Pemetrexed Placebo
(N=441) (N=222)
( )
% %
Patients with post-study therapy 52 67
Most common post-study therapies
p y p
Carboplatin 7 10
Cisplatin 5 6
Docetaxel 22 29
Erlotinib 22 21
Gefitinib 13 10
Gemcitabine
G it bi 9 14
Paclitaxel 4 6
Pemetrexed 1 19
Vinorelbine 13 17
Higher rate of follow-up treatment on the placebo arm
Balanced selection of therapies between arms and low rate of crossover 38
SATURN– Phase III double-blind, placebo-controlled trial of
Maintenance Erlotinib in Non-progressors following 1st Line Platinum-
based Chemotherapy
Cappuzzo F et al. ASCO 2009, abstr #8001 Erlotinib
PD
150mg/day
Chemonaïve 4 cycles of first-
advanced line platinum Non-PD
1:1
NSCLC doublet n=889
n=1,949 chemotherapy*
Placebo PD
Mandatory tumour
sampling
Stratification factors: Co primary
Co-primary endpoints:
• EGFR IHC (positive vs negative vs • PFS in all patients
indeterminate) • PFS in patients with EGFR IHC+ tumours
• Stage (IIIB vs IV)
Secondary endpoints:
• ECOG PS (0 vs 1)
• OS in all patients and those with EGFR IHC+
• CT regimen (cis/gem vs carbo/doc vs others)
tumours, OS and PFS in EGFR IHC–
• Smoking history (current vs former vs never) tumours; biomarker analyses; safety; time to
• Region symptom progression; QoL
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel
cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel
carboplatin/paclitaxel
39
Baseline characteristics
Erlotinib Placebo
(n=438) (n=451)
Age, median (range), years 60 (33–83) 60 (30–81)
Male / female, % 73 / 27 75 / 25
Stage IIIB / IV, % 26 / 74 24 / 76
Caucasian / Asian / Other, % 84 / 14 / 1 83 / 15 / 1
ECOG PS 0 / 1, % 31 / 69 32 / 68
Current / former / never smoker, % 55 / 28 / 18 56 / 27 /17
other,
Adenocarcinoma / squamous / other % 47 / 38 / 15 44 / 43 / 13
Response to prior chemotherapy, CR / PR/ SD, % <1 / 42 / 58 <1 / 47 / 52
CR = complete response; PR = partial response; SD = stable disease
40
PFS*: all patients (ITT)
PFS probability
1.0
Erlotinib Placebo
0.8
PFS at 12 wks (%) 53 40
PFS at 24 wks (%) 31 17
0.6
HR=0.71 (0.62–0.82)
Log-rank p<0.0001
0.4
04
Erlotinib (n=437)
Placebo (n=447)
0.2
0
0 8 16 24 32 40 48 56 64 72 80 88 96
(weeks)
Time ( eeks)
*PFS is measured from time of randomisation into the maintenance phase;
assessments were every 6 weeks; ITT = intent-to-treat population
41
PFS*: EGFR IHC+ tumours
(co-primary
(co primary endpoint)
PFS probability
1.0
Erlotinib Placebo
PFS at 12 wks (%) 54 40
0.8
PFS at 24 wks (%) 32 18
0.6
HR=0.69 (0.58–0.82)
Log-rank p<0.0001
0.4
04
Erlotinib (n=307)
0.2 Placebo (n=311)
0
0 8 16 24 32 40 48 56 64 72 80 88 96
(weeks)
Time ( eeks)
*PFS is measured from time of randomisation into the maintenance phase;
assessments were every 6 weeks
42
Disease control rate ≥12 weeks*
Patients (%)
50
p<0.0001
p<0 0001
40.8%
25 27.4%
0
Erlotinib Placebo
(n=436) (n=445)
*CR + PR + SD≥12 weeks
43
Subgroup analysis of PFS
HR (95% CI) n
All 0.71 (0.62–0.82) 884
Male 0.78 (0.66–0.92) 654
Female 0.56 (0.42–0.76) 230
C i
Caucasian 0.75 (0.64–0.88)
0 75 (0 64 0 88) 744
Asian 0.58 (0.38–0.87) 128
Adenocarcinoma 0.60 (0.48–0.75) 401
Squamous-cell 0.76 (0.60–0.95) 359
Never smoker 0.56 (0.38–0.81) 152
Former smoker 0.66 (0.50–0.88)
0 66 (0 50 0 88) 242
Current smoker 0.80 (0.67–0.97) 490
0.4 0.6 0.8 1.0 1.2
Favours HR Favours
erlotinib placebo
44
PFS in EGFR wild-type tumours
PFS probability
1.0
Erlotinib (n=199)
Placebo (n=189)
0.8
0.6
HR=0.78 (0.63–0.96)
Log-rank p=0.0185
0.4
04
0.2
0
0 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
45
PFS in EGFR mutation+ tumours*
PFS probability
1.0 Erlotinib (n=22)
Placebo (n=27)
0.8
( )
HR=0.10 (0.04–0.25)
0.6 Log-rank p<0.0001
0.4
04
0.2
0
0 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
*60% censored
46
Summary of safety data
Erlotinib Placebo
(n=433)
( ) ( )
(n=445)
Withdrawal due to any AE, % 5 2
Dose modification/interruption due to any AE, % 16 3
AEs i in f ti t
AE occurring i ≥10% of patients
Rash, % 60 9
grade 3/4* 9 0
Diarrhoea, % 20 4
grade 3/4* 2 0
• well characterised
Erlotinib has a well-characterised safety profile; no unexpected safety signals
were seen in this study
• No deterioration in QoL was seen in the erlotinib and placebo arms (FACT-L
questionnaire)
*no grade 4 events reported
47
ATLAS – Phase III Randomized, Double-Blind, Placebo-
controlled Trial of Maintenance Erlotinib in Non-Progressors
Platinum-based
Following 1st Line Platinum based Chemotherapy
Miller V et al. ASCO 2009, abstr # 8002
Bevacizumab (15mg/kg) +
erlotinib (150mg) to PD
Chemo-naïve 4 cycles of
advanced 1st-line Non-PD Unblind Post progression
chemotherapy* n=768 (66%) 1:1 therapy
NSCLC at PD
N=1,160 + bevacizumab
Bevacizumab +
placebo
to PD
Eligibility Primary endpoint
• Stage IIIB**/IV NSCLC • PFS in all randomized pts
• ECOG performance status 0-1 Secondary endpoints
Stratification factors • Overall survival
• Gender • Safety
• Smoking history (never vs Exploratory endpoints
former/current) • Biomarker analyses (
y (IHC, FISH, EGFR &
• ECOG performance status (0 v >1) K-Ras mutation)
• Chemotherapy regimen
*Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. **IIIB with pleural effusion 48
ATLAS: Baseline Characteristics
(ITT population)
Bevacizumab + Placebo Bevacizumab + Erlotinib
(n=373)* (n=370)*
Median age, years (range)
g ,y ( g ) 64 (23-83)
( ) ( )
64 (31-88)
Sex, %
Male 52.3 52.2
Female 47.7 47.8
Race, %
Caucasian 77.7 79.2
Asian 12.1 11.6
Other 10.2 9.2
Disease Stage, %
IIIB 10.2 8.7
IV 83.3 85.6
Recurrent 6.5 5.7
ECOG PS, %
0 46.1 48.1
1 53.6 51.9
*Patients randomized as of July 18 2008. 49
ATLAS: Baseline Characteristics (cont.)
Bevacizumab + Bevacizumab +
Placebo Erlotinib
(n=373) (n=370)
Smoking status, %
Current 34.6 34.9
Former 47.7 48.6
Never 17 7
17.7 16.5
16 5
Histology, %
Adenocarcinoma 82.5 81.3
Squamous (peripheral) 1.6 3.0
Other 15.9 15.7
Prior radiotherapy, yes, % 15.3 17.3
50
ATLAS: Progression-Free Survival
(ITT population, investigator assessment)
1.0
Bev + Placebo (n=373)
rtion Witho Event
0.8 Bev + Erlotinib (n=370)
out
0.6
HR=0.722 (0.592-0.881)
Log-rank P=0.0012
0.4
Propor
0.2
0.0
0 3 6 9 12 15 18 21
Progression-Free Survival (months)
p
No. of patients at risk:
Bev + Placebo 373 142 58 27 15 6 3 0
Bev + Erlotinib 370 178 81 43 20 6 3 1
51
ATLAS: Additional PFS Outcome Measures
Progression Free Survival: HR=0.722 (0.592-0.881) Log-rank P=0.0012
(ITT population, investigator assessment)
Bev + Placebo Bev + Erlotinib
(n=370) (n=373)
3.75 4.76
Median PFS, mos (95% CI)
(2.83, 4.04) (4.14, 5.52)
PFS rate, % (95% CI)
53.4 67.7
3 mos
(47.5, 58.9) (61.9, 72.7)
28.4 40.3
6 mos
(23.0, 34.1) (34.2, 46.3)
52
ATLAS: Grade 3-4 Adverse Events of Special Interest
(Cont.)
during the Post Chemotherapy Phase (Cont )
Bev + Placebo, n (%) Bev + Erlotinib, n (%)
(n=368) (n=367)
Grade 3–4 Grade 3–4
Rash 2 (0.5%) 38 (10.4%)
Diarrhea 3 (0.8%) 34 (9.3%)
Infection 17 (4.6%) 15 (4.1%)
ILD-like events 0 2 (0.5%)
Renal failure/ deficiency* 0 2 (0.5%)
Hepatic events* 1 (0.3%)
( ) ( )
1 (0.3%)
Grade 5 events: Bev + Placebo: 1 (0.3%) infection.
53
FLEX Phase III Trial: Cisplatin/Vinorelbine ±
Cetuximab in EGFR IHC–Positive
Advanced NSCLC – Biomarker Analysis
O’Byrne K et al. ASCO 2009, abstr # 8006
Cisplatin 80 mg/m2 d1
R
Vinorelbine 25 mg/m2 d1,8
A Cetuximab 400 mg/m2 d1, then
Stage IIIB or IV N
EGFR-expressing ( C)
G (IHC) 250 mg/m2 weekly
D N=557
chemotherapy-naïve
NSCLC
O
21-day cycle, up to 6 cycles
N=1125 M
I Cisplatin 80 mg/m2 d1
Z Vinorelbine 25 mg/m2 d1,8
E N=568
Primary endpoint: OS
Secondary endpoints: 1- and 2-year survival rates, 6-month and 12-
month PFS rates, RR, safety, QOL
Patient Selection Criteria: EGFR-expressing (IHC) stage IIIB/IV NSCLC,
PS 0-2, all histologies included; known brain metastases excluded
Pirker, R et al. Lancet 373:1525-33, 2009. 54
FLEX: Results
Median OS 1-Yr Surv.
CV + Cetuximab 11.3 mos 47%
CV 10.1 mos 42%
HR 0 871 P 0 044
HR: 0.871; P=0.044
OS (%)
Months
CV + Cetuximab CV P
RR 36% 29% 0.01
PFS 4.8 mos 4.8 mos NS
TTF 4 2 mos
4.2 3.7
3 7 mos 0.015
0 015
NS=not significant; TTF=time to treatment failure.
Pirker R et al. Lancet, 373:1525-33, 2009. 55
y
FLEX FISH analysis: OS
By FISH status
FISH status CT + cetuximab CT HR (95% CI) p-value
Median FISH - 10.6 mo 10.0 mo 0.91 (0.65–1.26) 0.56
OS FISH + 11.6 mo 9.9 mo 0.85 (0.56–1.29) 0.44
y
By treatment
Arm FISH - FISH + HR (95% CI) p-value
Median CT + cetuximab 10.6 mo 11.6 mo 1.09 (0.74–1.61) 0.66
OS CT 10.0 mo 9.9 mo 1.10 (0.76–1.58) 0.62
CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival
O’Byrne K et al. ASCO 2009, abstract #8007.
56
FLEX: FISH analysis: OS
FISH +
CT + cetuximab (n=49)
CT (n=53)
erall surviva (%)
FISH –
al
CT + cetuximab (n=82)
CT (n=95)
Ove
Months
CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival
O’Byrne et al. ASCO 2009, abstract #8007. 57
FLEX KRAS mutation analysis: OS
By mutation status
t t
KRAS status t i b
CT + cetuximab CT HR (95% CI) l
p-value
Median Wild type 11.4 mo 10.3 mo 0.96 (0.75–1.23) 0.75
OS Mutant 8.9 mo 11.1 mo 1.00 (0.60–1.66) 1.00
By treatment
Arm
A KRAS KRAS HR (95% CI) l
p-value
Wild type Mutant
Median CT + cetuximab 11.4 mo 8.9 mo 1.06 (0.72–1.56) 0.77
OS CT 10.3
10 3 mo 11 1 mo
11.1 1 02 (0 68 1 54)
1.02 (0.68–1.54) 0.91
0 91
CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival
58
FLEX KRAS mutation analysis: OS
KRAS wild type
CT + cetuximab (n=161)
verall surviv (%)
CT (n=159)
val
KRAS mutant
CT + cetuximab (n=38)
CT (n=37)
Ov
Months
CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival
O’Byrne K et al. ASCO 2009, abstract #8007.
59
FLEX: OS Early acne-like rash (1st cycle)
Pre-planned
Pre planned Analysis
Any grade: CT + Cetuximab
(N=290)
Overall Survival (%)
Grade 0: CT + Cetuximab
(
(N=228)
HR=0.631 (95% CI: 0.515-0.774)*
P<0.001
S
Patients at Risk Months
Grade 0 228 145 88 54 15 0
y
Any Grade 290 238 163 101 38 3
CV + Cetuximab Any grade Grade 0
OS 15.0 mos 8.8 mos
RR 44% 28%
PFS 5.4 mos 4.3 mos
*Landmark analysis.
Gatzemeier. 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology (abstr 8). 60
Iressa Pan Asian Study (IPASS) Phase III Trial:
Gefitinib vs Carboplatin/Paclitaxel in Selected Pts
With Advanced NSCLC – Biomarker Analysis
Fukouka et al. ASCO 2009, abstr # 8007
Never or light Gefitinib (250 mg/day)
ex-smoker* with R
adenocarcinoma A Offered carboplatin/paclitaxel
histology N on progression
D
PS 0-2 O
M
Stage IIIB or IV I p
Carboplatin ( )
(AUC 5 or 6)
chemotherapy-naïve Z +
NSCLC E Paclitaxel (200 mg/m2)
N=1217 3 times weekly up to 6 cycles
Primary endpoint: PFS (noninferiority)
Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerability
Exploratory: biomarkers – EGFR mutation, gene copy number, and protein expression
*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15 years ago and
smoked ≤10 pack-years.
Mok. ESMO. 2008 (abstr LBA2). 61
Progression-free survival in ITT population
Probability 1.0 Carboplatin /
of PFS Gefitinib
paclitaxel
N 609 608
0.8 Events 453 (74.4%) 497 (81.7%)
HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
06
0.6 Median
M di PFS ( (months)
th ) 57
5.7 58
5.8
4 months progression-free 61% 74%
6 months progression-free 48% 48%
12 months progression-free 25% 7%
0.4
Gefitinib demonstrated superiority relative to
carboplatin / paclitaxel in terms of PFS
0.2
0.0
At risk : 0 4 8 12 16 20 24 Months
Gefitinib 609 363 212 76 24 5 0
Carboplatin / 608 412 118 22 3 1 0
paclitaxel
Primary Cox analysis with covariates
HR <1 implies a lower risk of progression on gefitinib
62
Patients with evaluable (known)
biomarker data
N (% of total known)
Biomarker Status Gefitinib Carboplatin Overall
/ paclitaxel
EGFR mutation Positive 132 (59%) 129 (60%) 261 (60%)
Negative 91 (41%) 85 (40%) 176 (40%)
EGFR-gene-copy High 124 (60%) 125 (62%) 249 (61%)
number
Low 81 (40%) 76 (38%) 157 (39%)
EGFR expression Positive 132 (71%) 134 (74%) 266 (73%)
Negative 53 (29%) 46 (26%) 99 (27%)
63
p
Overlap of biomarkers
High EGFR- EGFR expression
25
gene-copy positive
51
number
13 N=242
N=198
Positive
for all 3
biomarkers
28
N=132
Negative for all
34
EGFR 15
3 biomarkers
mutation N=31
positive
N=209 N=329 with known biomarker
status for all 3 biomarkers
64
EGFR mutation status
N (% of all patients)
[% of patients with EGFR mutation positive]
EGFR mutation status Gefitinib Carboplatin/paclitaxel
(n=609) (n=608)
Negativea (14.9)
91 (14 9) (14.0)
85 (14 0)
Positiveb 132 (21.7) 129 (21.2)
Exon 19 deletions 66 [50.0] 74 [57.4]
Exon 21 L858R [48.8]
64 [48 8] [36.4]
47 [36 4]
Exon 20 T790M 5 [ 3.8] 6 [ 4.7]
Otherc 3 [ 2.3] 7 [ 5.4]
Unknownd (63.4)
386 (63 4) (64.8)
394 (64 8)
aNo mutation detected
bEleven patients had multiple mutations and are counted more than once
cIncludes 3 patients with exon 18 G719X, 5 with exon 20 S768I, and 2 with exon 21 L861Q
analysis,
d Patients without a tumour sample evaluable for EGFR mutation analysis and samples which were not
successfully analysed for EGFR mutation status were classified as unknown.
65
Progression-free survival by biomarkers
Treatment-by-subgroup
Known mutation status interaction test p-value
EGFR mutation positive p<0.0001
for EGFR
EGFR mutation negative mutation
Known EGFR-gene-copy number status
High EGFR
Hi h EGFR-gene-copy number
b p=0.0437
p=0 0437
for EGFR-
Low EGFR-gene-copy number gene-copy
number
o e p ess o
Known expression status
EGFR expression positive p=0.2135 for
EGFR expression
EGFR expression negative
0.25 0.5 1.0 2.0 4.0
HR (gefitinib vs carboplatin/paclitaxel) and 95% CI
Favors gefitinib Favors carboplatin/paclitaxel
ITT population; Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib
66
IPASS: PFS by EGFR Mutation Status
Gefitinib EGFR M+ (N=132)
Gefitinib EGFR M– (N=91)
1.0
Carboplatin/paclitaxel EGFR M+ (N=129)
Carboplatin/paclitaxel M– (N=85)
Carboplatin/paclita el EGFR M (N 85)
0.8 Gefitinib, HR=0.19; P<0.0001
Carboplatin/paclitaxel, HR=0.78; P=0.1103
obability of PFS
P
0.6
0.4
Pro
0.2
0.0
0 4 8 12 16 20 24
Time From Randomization (months)
H d ti implies lower risk of progression i th M+
Hazard ratio <1 i li a l i k f i in the
group than in the M– group
Mok. ESMO. 2008 (abstr LBA2). 67
Objective response rates by treatment
and biomarker status
OR (95% CI): 2.75 0.04 1.79 0.80 1.49 1.44
(1.65, 4.60) (0.01, 0.27) (1.08, 2.96) (0.38, 1.68) (0.92, 2.42) (0.60, 3,47)
p-value: 0.0001 0.0013 0.0243 0.5580 0.1093 0.4146
80
71.2
70 Gefitinib
58.9 Carboplatin/paclitaxel
60
51.5
50 47.3 44.8 41.8
ORR (%)
40 34
30 26.3 26.1
23.5 22 2
22.2
O
20
10
1.1
0
Positive Negative High Low Positive Negative
EGFR mutation EGFR-gene-copy number EGFR expression
n=132 n=129 n=91 n=85 n=124 n=125 n=81 n=76 n=132 n=134 n=53 n=46
p-values from logistic regression with covariates; OR >1 implies greater chance of response on gefitinib; ITT
population
68
IPASS: OS by EGFR Mutation Status
EGFR Mutation Positive EGFR Mutation Negative
Gefitinib (N=132) Gefitinib (N=91)
Carboplatin/paclitaxel (N=129) Carboplatin/paclitaxel (N=85)
Probability of OS
robability of OS
y
Months Pr Months
Patients at Risk
Gefitinib 132 126 114 73 41 17 0 0 91 69 44 25 13 5 0 0
Carboplatin/ 129 123 105 67 38 15 1 0 85 75 55 24 9 4 0 0
paclitaxel
• Cox analysis with covariates • ITT population
• HR<1 implies a lower risk of death on • Post-hoc analysis of OS by EGFR
gefitinib mutation status
Mok. 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology. 69
Summary
• EGFR mutation status
– In mutation positive patients, PFS was significantly longer with
gefitinib than with carboplatin/paclitaxel
– In EGFR mutation negative patients, PFS was significantly
shorter with gefitinib than with carboplatin/paclitaxel
EGFR-gene-copy number
• EGFR b
– A possibly related trend in PFS was observed. Post hoc
explorations suggest this effect was driven by the overlap of
high EGFR-gene-copy number with a positive EGFR mutation
status
• EGFR protein expression
– This was found to be less of a differentiator between the two
treatment arms in terms of PFS
• ORR results were consistent with PFS results
70
Vandetinib is a Selective Inhibitor of Key
Signaling Pathways in Cancer
Si li P th i C
Kinase IC50 (M)
VEGFR-2 (KDR) 0.04
F Br VEGFR-3 (Flt-4) 0.11
RET 0.13
N EGFR 0.50
O
N VEGFR-1 (Flt-1),
VEGFR 1 (Flt 1), 1
>1
PDGFR-Tie-2,
O N
FGFR1
N MEK, CDK2 >10
c-Kit, erbB2, FAK, >20
M Wt = 475 Da PDK1
Akt >100
IGF-1R >200
Adapted from Wedge SR et al. Cancer Res 2002;62:4645–4655
71
ZEAL
al. 2009,
de Boer RH et al ASCO 2009 abstr # 8010
• 534 2nd line pts randomized to pemetrexed + vandetinib
• Primary endpoint – PFS
• PFS HR – 0.86, p=0.108
• f i P d ti ib (p<0.001)
RR – 19% vs 8% favoring Pem + vandetinib ( 0 001)
• Delayed time to symptom progression (HR=0.61,
p=0.004)
p 0.004)
• No difference in overall survival
• Conclusion: Negative trial but largely consistent with the
ZODIAC results
• Issue: Inclusion of squamous cell carcinoma (21%)
72
ZEST
al. 2009,
Natale RB et al ASCO 2009 abstr # 8009
• 1240 2nd+ line pts randomized to erlotinib vs vandetinib
• Primary endpoint – PFS (superiority)
• PFS HR – 0.98, p=0.7
• l ti b d ti ib (p=ns)
RR – 12% vs 12% erlotinb vs vandetinib ( )
• Vandetinib was more toxic (diarrhea, QTc interval,
overall incidence of > grade 3 AEs)
• No difference in overall survival; planned non-inferiority
test for PFS and OS showed vandetinib was “not
inferior” l i ib
i f i ” to erlotinib
• Conclusion: Negative superiority trial; positive non-
inferiority trial (secondary)
73
Vandetinib
Trial Comparator #Pts PFS* RR (%) Comment
ZODIAC D t
Docetaxel +
l 1391 0.79
0 79 17 vs 10 TDS 0 78
0.78
(abstr # 8003) Vandetinib p<0.001 p<0.001 p=0.002
OS 0.91
p=0.196
ZEAL Pemetrexed + 534 0.86 19 vs 8 TDS 0.61
(abstr # 8010) Vandetinib p=0.108 p<0.001 p=0.004
OS 0.86
p=0.2
p
ZEST Vandetinib 1240 0.98 12 vs 12 OS 1.01
(abstr # 800^9) Vs p=0.7 p=ns p=0.83
Erlotinib
* PFS was primary endpoint in all three trials: RR, OS and TDS (time to
deterioration of symptoms) were secondary endpoints
74
Thank you
75
