Karen Kelly, MDProfessor of Medicine

UC Davis Cancer Center

Targeted Agents as Maintenance Therapy

Disclosures

• Genentech – Advisory Board

Maintenance Therapy

Drug TherapyDefined TreatmentNon-Progressing

PatientsUntil progression

Continuation

or

Switch

Molecularly Targeted Agents Are Ideal Candidates

• Majority have an oral route of administration

• Modest to low toxicity profile with potential for long term administration

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

NSCLC

n=1,949

Non-PD

n=889

4 cycles of

1st-line

platinum-

based doublet*

Placebo PD

Erlotinib

150mg/dayPD

Mandatory tumour

sampling

Co-Primary Endpoints:

PFS in all patients

PFS in patients with EGFR IHC+ tumours

Secondary Endpoints:

Overall survival (OS) in all patients and those with

EGFR IHC+ tumours, OS and PFS in EGFR IHC–

tumours; biomarker analyses; safety; time to symptom

progression; quality of life (QoL)

SATURNStudy Schema

ITT

EGFR Wild Type

Cappuzzo F et al. Lancet Oncol 11:521-529, 2010

SATURN – Primary EndpointProgression-Free Survival

SATURNOverall Survival

ITT

EGFR Wild Type

SATURN Progression-Free Survival

Cappuzzo F et al. Lancet Oncol 11:521-529, 2010

Overall Survival

SATURN – Primary Endpoint

Cappuzzo F et al. Lancet Oncol 11:521-529, 2010

EGFR mutated Patients

Progression-Free Survival

SATURNEfficacy by Response

Courdert B, et al. Ann Onc epublished May 24, 2011

SATURN Efficacy in Patients with Stable Disease

Overall Survival

SATURNEfficacy in Patients with Stable Disease

Courdert B, et al. Ann Onc epublished May 24, 2011

EGFR Wild Type

INFORM: Study Design

Gefitinib(250 mg/day)

Placebo(once daily)

1:1 randomization

Patients

Age ≥18 years

Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity

Life expectancy≥12 weeks

WHO PS 0-2

Measurable Stage IIIB/IV disease

Endpoints

Primary

Progression-free survival (PFS)

Secondary

Objective response rate (ORR)

Disease control rate (DCR)

Overall survival (OS)

Quality of life

Safety and tolerability

Exploratory

Biomarkers

EGFR mutation

Zhang L, et al. J Clin Oncol 29:478s, 2011

Progression-Free Survival (ITT population)

HR‡ (95% CI) = 0.42 (0.33, 0.55); p<0.0001

Gefitinib

(n=148)

Placebo

(n=148)

Median PFS,† months6-month PFS rate, %12-month PFS rate, %No. events, n (%)

4.847.333.2

124 (83.8)

2.615.02.9

144 (97.3)

0 16 40 56 72 96 112

0

10

40

60

80

100P

rob

ab

ilit

y o

f P

FS

(%

)

20

30

50

70

90

8 24 32 48 64 80 88 104

Time since randomization (weeks)

†Estimated using the Kaplan-Meier method‡Primary Cox analysis with covariates

HR <1 implies a lower risk of progression on Gefitinib

Gefitinib

Placebo

Patients at risk :

148 46 10 4 2 0 082 26 16 6 3 2 2 0

148 82 56 42 31 6 0109 70 65 49 38 20 15 1

Objective Response Rate and Disease Control Rate (RECIST; ITT population)

OR

R (

%)

(n=148) (n=148)

Odds ratio (95% CI)

= 54.1 (7.17, 408);

p=0.0001

(n=148) (n=148)

DC

R (

%)

Odds ratio (95% CI)

= 2.69 (1.62, 4.46);

p=0.0001

Overall Survival (ITT Population)

0 16 40 56 72 96 112

0

10

40

60

80

100O

ve

rall

su

rviv

al (%

)

20

30

50

70

90

8 24 32 48 64 80 88 104 120 128

Time (weeks)

Placebo

Patients at risk:

148 136 97 78 37 0 0147 115 107 91 66 13 6 0

148 129 102 84 39 0 0141 114 108 90 75 18 4 0

47

56

127

119Gefitinib

HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608

Gefitinib

(n=148)

Placebo

(n=148)

Median OS, months6-month survival rate, %

12-month OS rate, %No. events, n (%)

18.782.268.8

79 (53.4)

16.984.966.0

93 (62.8)

HR <1 implies a lower risk of death on Gefitinib

HR (95% CI) = 0.17 (0.07, 0.42)

Gefitinib (n=15) Median PFS†, 16.6 monthsNo. events, 9 (60.0%)

Placebo (n=15) Median PFS†, 2.8 monthsNo. events, 15 (100.0%)

EGFR Mutation-Positive

HR (95% CI) = 0.86 (0.48, 1.51)

Gefitinib (n=25) Median PFS†, 2.7 monthsNo. events, 25 (100.0%)

Placebo (n=24) Median PFS†, 1.5 monthsNo. events, 24 (100.0%)

EGFR Mutation-Negative

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

PF

S (

%)

Time (weeks)

15 9 5 3 3 2 1 1 1 1 1 1 0 0 0

15 15 14 14 13 11 10 18 7 7 5 3 1 0 0

Placebo

Gefitinib

No. of patients at risk

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

PF

S (

%)

Time (weeks)

24 9 5 3 2 0 0 0 0 0 0 0 0 0 0

25 14 6 3 3 1 0 0 0 0 0 0 0 0 0

Placebo

Gefitinib

No. of patients at risk

Progression-Free Survival by EGFRMutation Status

EGFR Mutations and Maintenance

• EGFR mutations predicts substantial and sustained PFS benefit from

EGFR TKI

INFORM SATURN

IFCT-GFPC 0502 Study Design

Observation

Progression:

2nd line

Primary endpoint: PFS

A

C

Maintenance

treatment

PD

N=155

N=154

N=155

PD: off

Objective

response or

stable disease

Cisplatin

Gemcitabine

x 4 cycles

N=834

NSCLC

Stage IIIB wet – IV

PS 0-1, 18-70 years

Asymptomatic brain

mets allowed

Tumor tissue

EGFR IHC

EGFR mutation

R*

N=464

BGemcitabine

Erlotinib

PD

PD

Pemetrexed

Pemetrexed

Pemetrexed

*Stratification factors:

– gender

– histology: adenocarcinoma vs other histology

– smoking status: non-smokers vs current/former smokers

– center

– response vs stabilization to induction chemotherapy

Induction Chemo: Cisplatin 80mg/m2 d1

+ Gemcitabine 1,250mg/m2 d1, d8

Arm B: Gemcitabine 1,250mg/m2 d1, d8 /3 wks

Arm C: Erlotinib 150mg daily

Perol, M, et al. J Clin Oncol 28:#7505, 2010

PFS is measured from time of randomisation

into the maintenance phase

Observation

Erlotinib

HR=0.82 (0.73–0.93)Log-rank test, p=0.002

Observation

N=152

Erlotinib

N=153

Median PFS, months 1.9 2.9

PFS at 3 months, % 30.3 35.3

PFS at 6 months, % 8.6 16.3

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40

Time (months)

Probability

PFS by Independent ReviewErlotinib versus Observation

0.2 0.4 0.6 0.8 1.0 1.2

Factor

Obsv.

NErlo.

N HR 95% CI

Stable disease 73 72 0.85 0.71 1.01

Objective response 79 81 0.80 0.68 0.95

Adenocarcinoma 100 98 0.79 0.67 0.92

No Adenocarcinoma 52 55 0.88 0.72 1.08

Smoker 94 94 0.79 0.68 0.92

Non-smoker 58 59 0.88 0.72 1.08

Male 111 112 0.83 0.72 0.95

Female 41 41 0.80 0.62 1.0

Pemetrexed 116 97 0.79 0.69 0.92

No Pemetrexed 36 56 0.94 0.73 1.20

PS 0 68 57 0.75 0.61 0.91

PS 1 79 84 0.86 0.73 1.02

PS 2–3 4 10 0.48 0.22 1.03

All 152 153 0.822 0.73 0.93

Erlotinib versus ObservationSubgroup analysis of PFS

Preliminary Overall Survival

Observation

Gemcitabine

Erlotinib

Gemcitabine vs observation

HR=0.86 (0.66–1.12)

Erlotinib vs observation

HR=0.91 (0.80–1.04)

Median follow-up: 21.6 months

324 deaths / 464 randomized patients (69.6%)

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30 35 40

Time (months)

Probability

Bevacizumab

+ Erlotinib

Bevacizumab

+ Placebo

PD

PD

Advanced NSCLC

patients

w/ no prior chemotherapy

N=1,160

Eligibility:

• Stage IIIB/IV NSCLC

• ECOG PS 0-1

Stratification factors:

• Gender

• Smoking history

• ECOG O vs ≥1

• Chemotherapy regimen

Primary endpoint Progression-free survival

Secondary endpoints Overall survival, safety

Exploratory endpoints Biomarker analyses (IHC, FISH, EGFR, K-Ras)

1:1

4 cycles of

1st-line

chemo +

Bevacizumab

Non-PD

n=768

Miller VA, et al. ASCO 2009. Abstract 8002.

ATLAS Study Design

No. of patients at risk:

373 142 58 27 15 6 3 0Bev + Placebo

370 178 81 43 20 6 3 1Bev + Erlotinib

ATLASProgression-Free Survival

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 E

ven

t

HR=0.722 (0.592-0.881)Log-rank P=0.0012

Progression-Free Survival (months)

Bev + Placebo (n=373)

Bev + Erlotinib (n=370)

Miller VA, et al. J Clin Oncol 27:407s, 2009

Median 4.8 months

Median 3.8 months

ATLAS: OS Results

Data cut-offPatients with

events, n/N (%)

Median OS

(months)

Bev + Erl vs Bev

HR (95% CI) p-value

July 18, 2008

(pre-specified)228/743 (31) 14.4 vs 13.3 0.92 (0.70-1.21) 0.5604

Jan 28, 2009 357/768 (46) 14.4 vs 13.6 0.90 (0.73-1.12) 03574

Jun 19, 2009 439/768 (57) 15.9 vs 13.9 0.90 (0.74-1.09) 0.2686

Evaluate Bev 15mg/kg + Erl 150 mg vs Bev + Placebo

following Bev + Platinum-based chemotherapy

Kabbinavar KK, et al, J Clin Oncol, 28:15s 2010 (suppl; abstr 7526)

Erlotinib Maintenance

4 cycles of

Platinum-based

Chemotherapy

(EGFR wild type)

R

A

N

D

O

M

I

Z

E

R

E

G

I

S

T

E

R

Erlotinib

ErlotinibPlacebo

NPD

NPD

Primary endpoint: OS

N = 610

Starting 11/11

The Role of Maintenance Therapy SWOG 0023

CDDP 50 mg/2

d 1,8,29,36

VP-16 50 mg/m2

d1-5, 29-33

XRT 1.8- 2 Gy/d

61 Gy

DOCETAXEL

75 mg/m2

x 3 cycles

1o Endpoint: Overall Survival;

20 Endpoint: PFS, toxicity and correlative scienceMaintenance therapy could continue for a maximum of 5 years

Stratification factors: IIIA vs IIIB; Measurable vs Non-measurable disease;

squamous vs nonsquamous

PLACEBO

GEFITINIB

500 mg/day

250 mg/day

(5-1-03)

Definitive TX Consolidation Maintenance

R

A

N

D

O

M

I

Z

E

SWOG 0023: Overall Survival From Randomization

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60

Months After RANDOMIZATION

Gefitinb

Placebo

N

118

125

Events

71

54

Median

in Months

23

35

P = .01

1 YR

OS

2 YR

OS

73% 46%

59%81%

Median FU time: 27 months

Kelly, K et al. J Clin Oncol. 26:2450-2460, 2008

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

Placebo

0 mg po

daily x 2 yrs

Randomized 1:1

*Protocol amended January 2003 to allow adjuvant chemotherapy

which became a stratification factorGoss, G. et al. J Clin Oncol 28: #7005, 2010

BR.19 - Overall Survival

Number at risk

Gefitinib

Placebo

HR : 1.23 (95% CI 0.94-1.64)

p=0.136*

Median survival: Gefitinib - 5.1 yrs

Placebo - N.E.

Placebo Gefitinib

Perc

en

tag

e

0

20

40

60

80

100

0

251252

1

217219

2

188198

3Time (Years)

163171

4

133138

5

4256

6

24

*Stratified Log Rank

BR.19 - Disease Free Survival

Number at Risk

Gefitinib

Placebo

Placebo Gefitinib

Perc

enta

ge

0

20

40

60

80

100

0

251

252

1

181

189

2

149

154

3Time (Years)

131

135

4

100

109

5

29

37

6

2

3

HR: 1.22 (95% CI 0.93-1.61)

p=0.152*

Median survival: Gefitinib - 4.2 yrs

Placebo - N.E.

*Stratified Log Rank

Overall Survival by EGFR Mutation

Status and Treatment

# at Risk

PlaceboGefitinib

Wild type

Placebo Gefitinib

Perc

enta

ge

0

20

40

60

80

100

0

145136

1

126121

2

118105

3Time (Years)

10189

4

7774

5

3421

6

22

# at Risk

Placebo

Gefitinib

Sensitizing mutation

Placebo Gefitinib

Perc

enta

ge

0

20

40

60

80

100

0

4036

1

3829

2

3226

3Time (Years)

3021

4

2617

5

67

6

10

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.)

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.)

Stage

IB-IIIASurgery

CTX4/

No CT

Erlotinib

Placebo

R*

* Selection

FISH + and/or IHC+

RADIANT

International Phase III Adjuvant Trial

Primary endpoint: Disease Free Survival

N = 945

Sunitinib as Maintenance Therapy

Multicenter Phase II Trial

Continue

until disease

progression†

Planned

follow-up:

1 year

Sunitinib

50 mg/day

4/2 weeks

Patients with

untreated

stage IIIB/IV

NSCLC and

ECOG PS 0–1 Four cycles

Paclitaxel / Carboplatin

10 Endpoint – Overall Survival at 1 YR – 55%

ITT

N= 84

Non-progressors

N =54

1 YR OS 40.5% 38.7%

Median OS 10.4 mos 8.7 mos

PFS 5.8 mos 3.9 mos

Grade 3/4 AEsFatigue 24%

Diarrhea 9%

Gervais R et al. Lung Cancer Epublished June 2011

CALGB 30607: Sunitinib as Maintenance

Therapy in Non-progressing Advanced NSCLC

Patients Following Chemotherapy

Phase III, randomized, placebo-controlled trial

Planned randomization: 250 patients

Continue

until disease

progression†

Planned

follow-up:

1 year

Sunitinib

37.5 mg/day

Placebo

Randomization

of responding

patients or

patients with

stable disease

stratified by

prior treatment

with/without

Bevacizumab

Patients with

untreated

stage IIIB/IV

NSCLC and

ECOG PS 0–1 Four cycles of

platinum-based

chemotherapy*

*Platinum-based regimen may include Carboplatin/Cisplatin plus Paclitaxel, Docetaxel,

Vinorelbine or Gemcitabine with or without Bevacizumab (Bevacizumab discontinued

after four cycles)†At progression, patients receiving placebo may cross over to the Sunitinib arm

10 Endpoint - PFS

Pazopanib Maintenance

Nonprogressors

after 4 cycles of

First line

Chemotherapy

For advanced

NSCLC

R

A

N

D

O

M

I

Z

E

Pazopanib

Placebo

Primary endpoint: OS

N = 587

Activated 7/11

Patients with EGFR mutated tumors are excluded

Summary

• Erlotinib is FDA approved for maintenance

treatment in nonprogressing patients treated with a

first line platinum-based regimen. Most of the

clinical benefit is seen in patients with EGFR

mutations and unselected patients with SD.

• No role for maintenance targeted therapy in early

stage disease (Stage I- III). Detrimental effects seen

with EGFR-TKIs.