3/23/2010
1
Federico Cappuzzo
Livorno Hospital
Livorno-Italy
MAINTENANCE THERAPY WITH TARGETED AGENTS IN
NSCLC
Why do we need maintenance therapy in NSCLC?
In recent studies, approximately 50% of patients did not receive second-line therapy
0 25 50 75 100
Fidias et al. 2009
Scagliotti et al. 2008
Pirker et al. 2008
Ciuleanu et al. 2008
Park et al. 2007
Barata et al. 2007
von Plessen et al. 2006
Brodowicz et al. 2006
Belani et al. 2003
Socinski et al. 2002
Patients receiving 2nd-line therapy (%)
3/23/2010
2
Recent studies with maintenance therapy
• Studies with cytotoxic agents not used in first-line combinations:– Docetaxel– Pemetrexed
• Studies with targeted agents used in first-line combinations: – Cetuximab– Bevacizumab– Bevacizumab ± erlotinib
• Studies with targeted agents not used in first-line combinations:– Erlotinib– Gefitinib
SATURN study design
Stratification factors:• EGFR IHC (positive vs negative vs
indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs
others)• Smoking history (current vs former vs
never)• Region
1:1
Chemonaïve advanced NSCLCn=1,949
Non-PDn=889
4 cycles of 1st-line
platinum-based doublet*
Placebo PD
Erlotinib150mg/day
PD
Mandatory tumor sampling
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel
Co-primary endpoints:• PFS in all patients• PFS in patients with EGFR IHC+ tumors
Secondary endpoints:• OS in all patients and those with EGFR
IHC+ tumors, OS and PFS in EGFR IHC–tumors; biomarker analyses; safety; time to symptom progression; QoL
3/23/2010
3
PFS*: all patients (ITT)
PFS probability1.0
0.8
0.6
0.4
0.2
00 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
HR=0.71 (0.62–0.82)Log-rank p<0.0001
Erlotinib (n=437)
Placebo (n=447)
Erlotinib Placebo
PFS at 12 wks (%) 53 40
PFS at 24 wks (%) 31 17
*PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks
Subgroup analysis of PFS
All
Male
Female
Caucasian
Asian
Adenocarcinoma
Squamous-cell
Never smoker
Former smoker
Current smoker
HR (95% CI) n0.71 (0.62–0.82) 884
0.78 (0.66–0.92) 654
0.56 (0.42–0.76) 230
0.75 (0.64–0.88) 744
0.58 (0.38–0.87) 128
0.60 (0.48–0.75) 401
0.76 (0.60–0.95) 359
0.56 (0.38–0.81) 152
0.66 (0.50–0.88) 242
0.80 (0.67–0.97) 490
0.4 0.6 0.8 1.0 1.2
Favourserlotinib
Favoursplacebo
HR
3/23/2010
4
Log-rank p<0.0001
HR=0.60 (0.48–0.75)
PFS according to histology
PFS probability
1.0
0.8
0.6
0.4
0.2
0
Time (weeks)0 8 16 24 32 40 48 56 64 72 80 88
Erlotinib (n=204)
Placebo (n=197)
Adenocarcinoma
Log-rank p=0.0148
HR=0.76 (0.60–0.95)
Squamous-cell carcinoma
1.0
0.8
0.6
0.4
0.2
0
Time (weeks)0 8 16 24 32 40 48 56 64 72 80 88
Erlotinib (n=166)
Placebo (n=193)
PFS probability
With at least one treatment (%)
Erlotinib(n=438)
Placebo(n=451)
All classes 71 72
Taxanes (including docetaxel) 30 31
Antimetabolites (including pemetrexed) 24 23
Antineoplastic agents 16 18
Tyrosine-kinase inhibitors (TKIs) 11 21
Platinum compounds 9 12
Documented post-study treatments
3/23/2010
5
SATURN: OS in all patients (ITT)
0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)
OS
pro
ba
bili
ty
1.0
0.8
0.6
0.4
0.2
0
Erlotinib (n=438)
Placebo (n=451)
*OS is measured from time of randomisation into the maintenance phase;ITT = intent-to-treat population
HR=0.81 (0.70–0.95)Log-rank p=0.0088
0.4 0.6 0.8 1.0 1.2
Favourserlotinib
Favoursplacebo
HR
All
Male
Female
Caucasian
Asian
Adenocarcinoma
Squamous-cell
Never smoker
Former smoker
Current smoker
HR (95% CI) n0.81 (0.70–0.95) 889
0.88 (0.74–1.05) 659
0.64 (0.46–0.91) 230
0.86 (0.73–1.01) 746
0.66 (0.42–1.05) 131
0.77 (0.61–0.97) 403
0.86 (0.68–1.10) 360
0.69 (0.45–1.05) 152
0.75 (0.56–1.00) 244
0.88 (0.72–1.08) 493
OS: subgroup analyses by clinical characteristics
3/23/2010
6
OS in patients with non-squamous disease
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36
OS
pro
ba
bili
ty
Time (months)
10.5 13.7
HR=0.79 (0.64–0.96)Log-rank p=0.0194
Erlotinib (n=272)
Placebo (n=257)
PFS according to response to first-line chemotherapy
PF
S p
rob
abili
ty
1.0
0.8
0.6
0.4
0.2
00 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
Log-rank p<0.0001
HR=0.68 (0.56–0.83)
Erlotinib (n=252)
Placebo (n=235)
11.1 12.4
SD
Log-rank p=0.0059
HR=0.74 (0.60–0.92)
Erlotinib (n=184)
Placebo (n=210)
11.3 12.1
CR/PR
1.0
0.8
0.6
0.4
0.2
00 8 16 24 32 40 48 56 64 72 80 88 96
Time (weeks)
3/23/2010
7
OS according to response to first-line chemotherapy*
OS
pro
bab
ility
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
9.6 11.9
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
12.0 12.5
Log-rank p=0.0019
HR=0.72 (0.59–0.89)
Erlotinib (n=252)
Placebo (n=235)
Log-rank p=0.6181
HR=0.94 (0.74–1.20)
Erlotinib (n=184)
Placebo (n=210)
SD CR/PR
*OS is measured from time of randomisation into the maintenance phase
SATURN: Summary of tumor biomarker
analyses
11
89
18
82
Results among evaluable samples (%)
49555583
% of total study population (n=889)
437493488742Evaluable samples
EGFRmutationd
KRASmutationcEGFR FISHbEGFR IHCa
48
52
84
16
+
–
+
–
Mut
WT
Mut = mutation positive; WT = wild-typea. IHC+ status: ≥10% tumour cells with any membranous stainingb. Scored according to Cappuzzo et al. (J Natl Cancer Inst 2005;97:643) c. Codons 12, 13 and/or 61 versus confirmed wild-typed. Exon 19 deletion and/or L858R versus confirmed wild-type
Mut
WT
84 48 18 11
16 52 82 89
3/23/2010
8
Largest PFS benefit with erlotinib in patients with EGFR mutated tumours
Log-rank p<0.0001
HR=0.10 (0.04–0.25)1.0
0.8
0.6
0.4
0.2
0
Time (weeks)
Erlotinib (n=22)
Placebo (n=27)
Log-rank p=0.0185
HR=0.78 (0.63–0.96)1.0
0.8
0.6
0.4
0.2
0
Time (weeks)
Erlotinib (n=199)
Placebo (n=189)
0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96
EGFRmutation+ EGFRwild-type
Interaction p<0.001
PF
S p
rob
abili
ty
OS according to EGFR mutation status
0 3 6 9 12 15 18 21 24 27 30 33 36
OS
pro
bab
ility
1.0
0.8
0.6
0.4
0.2
0
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
1.0
0.8
0.6
0.4
0.2
0
Time (months)
EGFRmutation+ EGFR wild-type
Log-rank p=0.6810 HR=0.83 (0.34–2.02)
Erlotinib (n=199)
Placebo (n=189)
Erlotinib (n=22)
Placebo (n=27)*
Log-rank p=0.0243HR=0.77 (0.61–0.97)
*Note that 67% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI
3/23/2010
9
ATLAS Study Design
1:1
Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel.
Unblind at PD
Bevacizumab +Erlotinib
to PDChemo-naïve
Advanced NSCLCN=1,160
4 cycles of 1st-line
chemotherapy* + bevacizumab
Non-PDn=768 (66%)
Post progressiontherapy
Bevacizumab +Placebo
to PD
Primary endpoint
• PFS in all randomized pts
Secondary endpoints
• Overall survival
• Safety
Exploratory endpoints
• Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation)
Eligibility
• Stage III/IV NSCLC
• ECOG performance status 0-1
Stratification factors
• Gender
• Smoking history (never vs former/current)
• ECOG performance status (0 v >1)
• Chemotherapy regimen
373 142 58 27 15 6 3 0370 178 81 43 20 6 3 1
No. of patients at risk:
Bev + Placebo
Bev + Erlotinib
ATLAS: Progression-Free Survival(ITT population, investigator assessment)
0 3 6 9 12 15 18 21
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n W
ith
ou
t Eve
nt
HR=0.722 (0.592-0.881)Log-rank P=0.0012
Progression-Free Survival (months)
Bev + Placebo (n=373)
Bev + Erlotinib (n=370)
3/23/2010
10
ATLAS: Progression-Free Survival in Subgroups
* Includes <1% patients with ECOG PS 2.
Bev + Placebo Bev + Erlotinib
Total (n)
Pts with an Event
(n)Total (n)
Pts with an Event
(n) HRa 95% CI
Age<65 years≥65 years
189184
119119
201169
10696
0.660.69
0.51–0.860.53–0.90
Race/ethnicityWhiteBlackAsian or Pacific IslanderOther
29029459
19321195
293224312
1791454
0.750.810.180.43
0.61–0.920.41–1.600.06–0.550.11–1.64
GenderMaleFemale
195178
122116
193177
10597
0.750.63
0.58–0.980.48–0.83
Smoking historyNeverCurrent/former
66307
36202
61309
20182
0.340.76
0.19–0.610.62–0.93
ECOG PS at randomization
0≥1*
125245
77160
126241
66136
0.650.72
0.47–0.910.57–0.91
1 20.5Favors placebo
Favors erlotinib
0.2
Should we prefer EGFR-TKIs or chemotherapy as maintenance
treatment?
3/23/2010
11
Maintenance Chemotherapy – PFS:Curves Separate Early and Come Together by
12-18 Months
Immediate D
(N = 153)
Delayed D(N = 156)
Log-rankP-v alue
Median PFS (months)
5.7 2.70.0001
(95% CI) (4.4-6.9) (2.6-2.9)
Months
Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598.
PemetrexedPlacebo
Months 24% censored
Pemetrexed: 4.04 mos(95% CI: 3.06-4.44)
PFS HR = 0.599(95% CI: 0.49-0.73)
0.8
1
0.6
0.4
0.2
00 3 6 9 12151821242730333639424548
Placebo: 1.97 mos(95% CI: 1.54-2.76)
0.8
1
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24
Pro
bab
ility
Immediate DocetaxelDelayed Docetaxel
Ciuleanu T et al. The Lancet 2009;374(9699):1432-1440.
Pemetrexed vs. Placebo Docetaxel(Immediate vs. Delayed)
Pro
bab
ility
Maintenance Chemotherapy – OS:Curves Separate Early and Come Together
by 20 Months
0.8
1
0.6
0.4
0.2
0
Placebo: 10.18 mos(95% CI: 8.57-13.17)
Pemetrexed: 13.01 mos(95% CI: 11.40-14.42)
0.8
1
0.6
0.4
0.2
0
Months 55% censored
OS HR = 0.798(95% CI: 0.63-1.01)
0 3 6 9 12 15 18 21 24 27 30 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Pro
bab
ility
Immediate D(N = 153)
Delayed D(N = 156)
Median OS, months(95% CI)
12.3 9.7
12-month survival, % (95% CI)
51.1% 43.5
Months
Pemetrexed vs. Placebo Docetaxel vs. Placebo
Ciuleanu T et al. The Lancet 2009;374(9699):1432-1440. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598.
Pro
bab
ility
PemetrexedPlacebo
Immediate DocetaxelDelayed Docetaxel
3/23/2010
12
Maintenance Erlotinib – SATURN PFS:Curves Separate Near 6 Weeks and Stay
Separated
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
0 16 32 48 64 80 88
Weeks
Erlotinib (N = 437)Placebo (N = 447)
968 24 40 56 72
HR = 0.71 (95% CI: 0.62-0.82);Log-rank p <0.0001
Maintenance Erlotinib – SATURN OS:Curves Separate Late and Stay Separated for
Many Months
1.0
0.8
0.6
0.4
0.2
06 12 18 24 30 33 363 9 15 21 270
Erlotinib (N = 438)Placebo (N = 451)
Months
HR = 0.81 (95% CI: 0.70-0.95);Log-rank p = 0.0088
Pro
bab
ility
3/23/2010
13
Maintenance Gefitinib:Both PFS and OS Curves Separate Late
and Stay Separated for Many Months
Takeda K et al. (JCO 2010)
PFS HR = 0.68(95% CI: 0.57-0.80)
OS HR = 0.86(95% CI: 0.72-1.03)
80
100
60
40
20
00 10 20 30 40 50 60
80
100
60
40
20
00 10 20 30 40 50 60
Chemotherapy followed by gefitinib (Arm B)Chemotherapy alone (Arm A)
Chemotherapy followed by gefitinib (Arm B)Chemotherapy alone (Arm A)
Pro
bab
ility
Months Months
Pro
bab
ility
Ciuleanu T et al. The Lancet 2009;374(9699):1432-1440.
Pemetrexed Maintenance:Survival by Histology
Benefit Confined to Non-squamous Histology
PemetrexedPlacebo
Non-squamous (N = 481)HR = 0.70 (95% CI: 0.56-0.88)P = 0.002
Squamous (N = 182)HR = 1.07 (95% CI: 0.77-1.50)P = 0.678
Months
Pro
bab
ility
0.8
1
0.6
0.4
0.2
00 3 6 9 12151821242730333639424548
Months
0.8
1
0.6
0.4
0.2
00 3 6 9 12151821242730333639424548
Placebo:10.3 months
Pemetrexed:15.5 months
Placebo:10.8 months
Pemetrexed:9.9 months
Ciuleanu T et al. The Lancet 2009;374(9699):1432-1440.
Pro
bab
ility
3/23/2010
14
BR.21 and SATURN:Effect of Histology on OS and PFS
OSAdenocarcinomaSquamous-cell
PFSAdenocarcinomaSquamous-cell
OSAdenocarcinomaSquamous-cell
PFSAdenocarcinomaSquamous-cell
NHR (95% CI)
Favors erlotinib Favors placeboHR
10.8 20.60.4
0.71 (0.56-0.92)0.67 (0.50-0.90)
0.60 (0.47-0.75)0.53 (0.39-0.70)
0.77 (0.61-0.97)0.86 (0.68-1.10)
0.60 (0.48-0.75)0.76 (0.60-0.95)
365222
365222
403360
401359
10.8 20.60.4
SATURN
BR.21
Maintenance Therapy:Grade 3/4 Toxicity by Study
Agent Neutropenia Fatigue Rash Diarrhea
Docetaxel^ 28% 10% NR 1%
Pemetrexed† 3% 5% 1% <1%
Gefitinib 0% 2% 2% 0%
Erlotinib* 0% <1% 6% 2%
*No Grade 4^All patients received decadron and anti-emetics; 28% had Grade 3/4 thromobcytopenia†10% received an RBC transfusion; 6% received epo and 4% were hospitalizedfor Grade 3/4 toxicity; all patients received oral decadron, anti-emetics, B12 injectionsand daily folic acid supplementation
Toxicity acceptable in all studiesbut greater with chemotherapy and more
supportive care required with chemotherapy
3/23/2010
15
Conclusions
• Easy:– Orally available
– Favorable toxicity profile
• Effective:– Dramatic and prolonged efficacy in
specific subgroups (EGFR Mut+)
– Some benefit in all subgoups irrespective of clinical or biological characteristics: no biomarker for “negative” selection
In the maintenance setting targeted agents are: