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 (%)

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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

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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

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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

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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

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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)

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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

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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

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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)

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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?

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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

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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

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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

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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

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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: