Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion

Maintenance Therapy in Advanced NSCLC:

State of the Art or State of Confusion

Corey J Langer MD, FACPDirector Thoracic Oncology

Abramson Cancer CenterProfessor of Medicine

Hematology-Oncology DivisionUniversity of Pennsylvania

Philadelphia, PA [email protected]

Disclosures: Past 5 yrs• Grant/Research Support:

– Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering Plough Research Institute, SanofiAventis, Amgen, Cell Therapeutics Inc., Celgene, Genentech, OSI, Astra Zeneca, Active Biothech,

• Scientific Advisor:– Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer-Pharmacia,

GlaxoSmithKline, Abbott, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Bayer/Onyx, Abraxis; Biodesix; Clarient; Agennix; Vertex

• Speakers Bureau: curtailed as of 12/2010– Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly,

Genentech, OSI

Terminology: Maintenance

• Is it maintenance?

• Is it consolidation?

• Or is it early salvage?

Terminology: Maintenance• Prolonged Therapy: continuing the original regimen

indefinitely until PD or toxicity– Full dose: Identical regimen (Prolonged Chemo)– Attenuated dose: usually to mitigate cumulative toxicity

• Continuation Maintenance: continuing Rx with the non-platinum component of Tx (single agent instead of combination)

• Switch Maintenance: alternative cytotoxic or targeted agent– AKA: Early Second Line Tx

Phase III: 4 Cycles Chemo vs. Continuous Chemo Followed by Second Line Therapy in Adv NSCLC

At Progression:Weekly Paclitaxel 80 mg/m2/wk until PD

Eligibility• NSCLC IIIb/IV• PS ≥ 70• Chemonaive• Treated Brain Mets• No neuropathy

Endpoints: Survival and Quality of Life

Carboplatin AUC 6 + Paclitaxel 200 mg/m2

every 21 days until PD

Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 21 days x 4 cyc

RANDOMIZE

Socinski M, et al. J Clin Onc 2005; 20(5).Hensing TA, et al. Lung Cancer 2005; 47:253.

Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression

Socinski et al. J Clin Oncol 20: 1335, 2002

http://jco.ascopubs.org/content/vol20/issue5/images/large/29ff3.jpeg


PC x 4 n=114

PC to PD n=116

P value

Number of cycles 4 ( 0-6) 4 (0-19)

ORR 22% 24% ns

Median survival 6.6 mos 8.5 mos 0.63

1-yr survival 28% 34%

2nd-line therapy 42% 47% 0.42

Grade 2-4 neuro toxicity

14% 27% 0.02



PC x 4 n=114

PC to PD n=116

P value

Number of cycles 4 ( 0-6) 4 (0-19)

ORR 22% 24% ns


1-yr survival 28% 34%

2nd-line therapy 42% 47% 0.42

Grade 2-4 neuro toxicity

14% 27% 0.02


Smith, JCO 19: 1336, 2001

Prolonged Chemotherapy

Stage IIIB/IVNSCLCPS 0-2

R

MVP: mitomycin, vinblastine, cisplatinMVP: mitomycin, vinblastine, cisplatin

All patients could receive MVP at progression

MVP x 3 Cycles versus MVP x 6 Cycles

MVP x 3 n=155

MVP x 6 n=153

P value

Received full treatment

113 (72%) 48 (31%)

ORR 31% 38% 0.20


TTP 5.0 mos 5.0 mos ns

Smith et al. J Clin Oncol 19: 1336, 2001

MVP x 3 Cycles versus MVP x 6 Cycles

Survival, all patients Survival, patients who Survival, PS 0-1 patients received at least 3 cycles

Smith et al. J Clin Oncol 19: 1336, 2001

http://jco.ascopubs.org/content/vol19/issue5/images/large/g0783f1.jpeg



Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan

Patient Eligibility• NSCLC Stage

IIIb/IV

• Chemonaïve

• ECOG PS = 0-2

• CNS Mets allowed

GC Phase Gemcitabine, 1000 mg/m2, D 1, 8 Carboplatin AUC 5, Day 1 Every 21 d 4 cycles

RANDOMIZE

ImmediateDocetaxel

75mg/m2 day 1, every 21 days until PD or

maximum of 6 cycles

DelayedDocetaxel

Best Supportive Care, then start therapy at PD

75mg/m2 on day 1, every 21 days, until PD or maximum of 6 cycles

CR, PR, SD

Primary endpoint: Overall Survival, HR: 1.43

Fidias et al, ASCO 2007


ChemonaϊveStage IIIb/IV NSCLC

N = 562

GCb PhaseN = 552(388 (69%) received 4 cycles)

Off StudyN = 245

RandomizedSD, PR, CRN = 307

(56%)

Immediate Docetaxel

N = 153

DelayedDocetaxel

N = 154

ImmediateTreated

N = 142

DelayedTreatedN = 91*

Treated

ORR 29%


*Only 59% of patients randomized to delayed docetaxel received treatment.

Immediate (n=153)

Delayed (n=154)

LR

p-Value

Median PFS (mo) 5.7 2.7 <0.0001

12-month PFS, % 20% 9%

Fidias et al. J Clin Oncol; 27:591-598 2009

Immediate (n=153)

Delayed (n=154)

LR

p-Value

Med OS (mo) 12.3 9.7 0.085

12-mo OS 51.1% 43.5%

Immediate (n=153)

Delayed (n=154)

LR

p-Value

Median PFS (mo) 5.7 2.7 <0.0001

12-month PFS, % 20% 9%


Immediate (n=153)

Delayed (n=154)

LR

p-Value

Med OS (mo) 12.3 9.7 0.085

12-mo OS 51.1% 43.5%

Is this negative for survival benefit

or under-powered??

C.P. Belani1, T. Brodowicz2, 3, T. Ciuleanu3, 4, J.H. Kim5,

M. Krzakowski3, 6*, E. Laack7, Y.L. Wu8, P. Peterson9,

K.Krejcy10, C. Zielinski2, 3

1Penn State Hershey Cancer Institute, Hershey, PA, USA; 2Medical University, Vienna, Austria; 3Central European Cooperative Oncology Group (CECOG); 4Institutul

Oncologic I Chiricuta, Cluj, Romania; 5Yonsei Cancer Center, Seoul, Korea; 6 Maria Sklodowska-Curie Memorial Cancer Center & Institute Of Oncology, Warsaw, Poland; 7Cancer Center, University Hospital

Hamburg-Eppendorf, Germany; 8Guangdong General Hospital, Guangzhou, China; 9Eli Lilly and Co. IN, USA; 10Lilly Regional Operations, Vienna, Austria

Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus

BSC: A Phase III Study in NSCLC

Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of

gem, doc, or tax + cis or carb, with CR, PR, or SD

Randomization factors:

• gender• PS• stage• best tumor

response• non-platinum

drug• brain mets

*B12, folate, and dexamethasone given in both arms

Double-blind, Placebo-controlled, Multicenter, Phase III Trial

Study Design

Primary Endpoint = PFS2:1

Randomization

Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*

Placebo (d1, q21d) + BSC (N=222)*

Primary Objective Progression-free survival

Secondary Objectives

Overall survival

Objective response rate (CR+PR)

Disease control rate (CR+PR+SD)

Safety

Objectives

PemetrexedN=441

%

PlaceboN=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

Baseline Characteristics

PemetrexedN=441

%

PlaceboN=222

%

Docetaxel-carboplatin 5 3

Docetaxel-cisplatin 2 2

Paclitaxel-carboplatin 30 27

Paclitaxel-cisplatin 6 9

Gemcitabine-carboplatin 24 22

Gemcitabine-cisplatin 33 38

Best response to initial therapy

CR + PR/SD 48/52 52/48

Initial Therapy

0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0

Pemetrexed 4.0 mos

Placebo 2.0 mos

Progression-free Survival

Pro

gre

ssio

n-f

ree P

rob

ab

ilit

y

Time (months)

HR=0.60 (95% CI: 0.49 0.73) P <0.00001

Progression-free Survival by Histology

0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0

0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0

Pemetrexed 4.4 mos Pemetrexed 2.4 mos

Placebo 1.8 mos

Placebo 2.5 mos

Non-Non-squamous squamous

SquamouSquamous s

Time (months) Time (months)

Pro

gre

ssio

n-f

ree P

rob

ab

ilit

y HR=0.47 (95% CI: 0.37-0.6) P <0.00001

HR=1.03 (95% CI: 0.77-1.5) P =0.896

Overall Survival (Intent-to-treat Population)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pemetrexed 13.4 mos

Placebo 10.6 mos

Su

rviv

al P

rob

ab

ilit

y

Time (months)

HR=0.79 (95% CI: 0.65–0.95) P =0.012

Overall Survival by Histology

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pemetrexed 15.5 mos Pemetrexed 9.9 mos

Placebo 10.3 mos

Placebo 10.8 mos

Non-squamous (n=481)Non-squamous (n=481) Squamous (n=182)Squamous (n=182)

HR=0.70 (95% CI: 0.56-0.88) P =0.002

HR=1.07 (95% CI: 0.49–0.73) P =0.678

Su

rviv

al P

rob

ab

ilit

y

Time (months) Time (months)

Histology GroupsMedian OS, mos Median PFS, mos

Pem PlacP-value

(HR)Pem Plac

P-value

(HR)

Non-squamous (n=481)

15.5 10.30.002

(0.70)4.4 1.8

<0.00001

(0.47)

Adeno (n=329)

16.8 11.50.026

(0.73)4.6 2.7

<0.00001

(0.51)

Large cell (n=20)

8.4 7.90.964

(0.98)4.5 1.5

0.104

(0.40)

Other (n=133)

11.3 7.70.025

(0.61)4.1 1.6

0.0002

(0.44)

Squamous (n=182)

9.9 10.80.678

(1.07)2.4 2.5

0.896

(1.03)

Efficacy by Histologic Groups

There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·033)

Pemetrexed (N = 441)

%

Placebo (N = 222)

%

Grade 3/4 Grade 3/4

Neutropenia‡ 3 0

Anemia 3 1

Leukopenia 2 1

Fatigue‡ 5 1

Anorexia 2 0

Infection 1 0

Diarrhea 1 0

Nausea 1 1

Vomiting <1 0

Sensory neuropathy 1 0

Mucositis/Stomatitis 1 0

*NCI CTC version 3.0‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

Treatment-related Toxicities*

Favors placebo

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0

Stage IV (n=536)Stage IIIB (n=126)

Induction Response SD (n=337)Induction Response CR/PR (n=322)

Induction Carboplatin (n=374)Induction Cisplatin (n=288)

ECOG PS 1 (n=400)ECOG PS 0 (n=261)

Never-smoker (n=176)Ever-smoker (n=482)

Other Ethnic Origin (n=81)East Asian (n=154)Caucasian (n=428)

Male (n=483)Female (n=180)

Age >= 65 (n=220)Age < 65 (n=443)

Squamous Cell Carcinoma (n=182)Other Histology* (n=133)

Large Cell Carcinoma (n=20)Adenocarcinoma (n=328)

Overall ITT Population (n=663)

Hazard Ratio

0.800.760.680.900.700.890.860.680.640.830.461.050.770.780.830.880.741.070.610.980.730.79

Favors pemetrexed

Treatment HRs for Overall Survival in Subgroups of the ITT Population

First randomized, double-blind, placebo-controlled study to demonstrate a significant overall survival benefit for maintenance treatment with in patients with advanced NSCLC

Non-squamous histology: predictive of the improved efficacy of pemetrexed in patients with advanced NSCLC

Administration of pemetrexed in the maintenance setting is fairly well tolerated and is devoid of any cumulative toxicity

Conclusions

Switch MaintenanceAgent/Control Arm N PFS Salvage

treatment % OS

Fidias DocetaxelDelayed Docetaxel

309 5.7 m HR 0.632.7 m p<.001

63 12.3 HR 0.809.7 p.085

Ciuleanu PemetrexedPlacebo

663 4.0 m HR 0.602.0 m p<.001

67 13.4 HR 0.7910.6 p .012

Capuzzo ErlotinibPlacebo

889 12.3 w HR 0.7111.1 w p<.001

72 12.0 HR 0.8111.0 p .0088

Miller Erlotinib + BevacizumabPlacebo + Bevacizumab

768 4.8 m HR 0.723.8 m p.0012

55.5 15.9 HR 0.913.9 p .2686

Perol ErlotinibObservation

310 2.9 m HR 0.821.9 m p.002

81.9 NA HR .91NA

Zhang GefitinibPlacebo

296 4.8 m HR 0.422.6 m p<0.0001

58.8 18.7 HR .8316.9 p 0.2109

Fidias, J Clinc Oncol 28:5116-5123Zhang et al [INFORM] ASCO 2011

Switch MaintenanceAgent/Control Arm N PFS Salvage

treatment % OS

Fidias DocetaxelDelayed Docetaxel

309 5.7 m HR 0.632.7 m p<.001

63 12.3 HR 0.809.7 p.085

Ciuleanu PemetrexedPlacebo

663 4.0 m HR 0.602.0 m p<.001

67 13.4 HR 0.7910.6 p .012

Capuzzo ErlotinibPlacebo

889 12.3 w HR 0.7111.1 w p<.001

72 12.0 HR 0.8111.0 p .0088

Miller Erlotinib + BevacizumabPlacebo + Bevacizumab

768 4.8 m HR 0.723.8 m p.0012

55.5 15.9 HR 0.913.9 p .2686

Perol ErlotinibObservation

310 2.9 m HR 0.821.9 m p.002

81.9 NA HR .91NA

Zhang GefitinibPlacebo

296 4.8 m HR 0.422.6 m p<0.0001

58.8 18.7 HR .8316.9 p 0.2109

Fidias, J Clinc Oncol 28:5116-5123

Potential Criticisms

• Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted

• Toxicity of pemetrexed, though mild, is not entirely trivial• Early institution of 2nd line Tx unnecessary in sizable

proportion of pts• Result of this trial do not apply to those who receive

pemetrexed or bevacizumab as part of first-line treatment.• Cost?!

Potential Criticisms

• Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed


• Toxicity of pemetrexed, though mild, is not entirely trivial• Early institution of 2nd line Tx unnecessary in sizable

proportion of pts• Result of this trial do not apply to those who receive

pemetrexed or bevacizumab as part of first-line treatment.• Cost?!


ChemonaϊveStage IIIb/IV NSCLC

N = 562

GCb PhaseN = 552(388 (69%) received 4 cycles)

Off StudyN = 245

RandomizedSD, PR, CRN = 307

(56%)

Immediate Docetaxel

N = 153

DelayedDocetaxel

N = 154

ImmediateTreated

N = 142

DelayedTreatedN = 91*

Treated

ORR 29%


*Only 59% of patients randomized to delayed docetaxel received treatment.

Limited Applicability• If we look at the Fidias trial, only 56% of those started on

first-line Tx were randomized to maintenance • Reasons: Therapeutic reality

– Disease progression

– Intercurrent Co-moribidities

– Pt opt-out

• Benefits of Pemetrexed are confined to the non-squamous population, ~ 2/3 of the remainder

• So the benefits of pemetrexed maintenance apply to only 38% of the entire advanced stage good PS NSCLC population (if we use Fidias as our reference)

Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits

of maintenance” pemetrexed– Benefits confined to <50% of those who start first-line therapy,

maybe < 40%


• Toxicity of pemetrexed, though mild, is not entirely trivial

• Early institution of 2nd line Tx unnecessary in sizable proportion of pts

• Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment.

• Cost?!

Pemetrexed (N=441) %

Placebo

(N=222) %

Patients with post-study therapy 52 67Most common post-study therapies

Carboplatin 7 10

Cisplatin 5 6

Docetaxel 22 29

Erlotinib 22 21

Gefitinib 13 10

Gemcitabine 9 14

Paclitaxel 4 6

Pemetrexed 1 19

Vinorelbine 13 17

Total Validated 2nd Line Tx 58 79

Systemic Post-study Therapy

Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover

Pemetrexed (N=441) %

Placebo

(N=222) %

Patients with post-study therapy 52 67Most common post-study therapies

Carboplatin 7 10

Cisplatin 5 6

Docetaxel 22 29

Erlotinib 22 21

Gefitinib 13 10

Gemcitabine 9 14

Paclitaxel 4 6

Pemetrexed 1 19

Vinorelbine 13 17

Total Validated 2nd Line Tx 58 79

Systemic Post-study Therapy

Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover

Phase 3 Study of Immediate vs. Delayed Docetaxel After First Line

Gemcitabine/Carboplatin in Advanced NSCLC


Median SurvivalNumber Randomized Pts

Pts Who Actually Received docetaxel

Delayed Docetaxel 91 (59%) 9.7 mo 12.5 mo

Immediate Docetaxel 142 (93%) 12.3 mo NA

• Analysis of those who went onto Docetaxel as “salvage” therapy suggests no compromise in longterm survival

Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits of

maintenance” pemetrexed– Benefits confined to <50% of those who start first-line therapy, maybe < 40%

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted– Would have inoculated this study from critique if the OS advantage had been

maintained

• Toxicity of pemetrexed, though mild, is not entirely trivial

• Early institution of 2nd line Tx unnecessary in sizable proportion of pts


• Cost?!

Pemetrexed (N = 441) %

Placebo (N = 222) %

Grade 3/4 All grades Grade 3/4 All grades

Neutropenia‡ 3 3 6 00 0

Anemia 33 15 11 5

Leukopenia 2 2 6 11 2

Fatigue‡ 5 5 24 1 1 10

Anorexia 2 2 19 0 0 5

Infection 1 1 5 0 0 2

Diarrhea 1 1 5 00 3

Nausea 1 1 19 11 5

Vomiting <1 <1 9 0 0 1

Sensory neuropathy 11 9 00 4

Mucositis/Stomatitis 11 7 0 0 2

Early Discontinuation for Toxicity 5 1

*NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

Maintenance Pemetrexed: Tx-related Toxicities*Maintenance Pemetrexed: Tx-related Toxicities*

Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Pemetrexed (N = 441) %

Placebo (N = 222) %

Grade 3/4 All grades Grade 3/4 All grades

Neutropenia‡ 3 3 6 00 0

Anemia 33 15 11 5

Leukopenia 2 2 6 11 2

Fatigue‡ 5 5 24 1 1 10

Anorexia 2 2 19 0 0 5

Infection 1 1 5 0 0 2

Diarrhea 1 1 5 00 3

Nausea 1 1 19 11 5

Vomiting <1 <1 9 0 0 1

Sensory neuropathy 11 9 00 4

Mucositis/Stomatitis 11 7 0 0 2

Early Discontinuation for Toxicity 5 1

*NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

Maintenance Pemetrexed: Tx-related Toxicities*Maintenance Pemetrexed: Tx-related Toxicities*

Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Perspectives on ToxicityMaintenance Pemetrexed

• Incidence of grade 3+4 toxicity was low

• Only 5% dropped out b/o side effects

• But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted

• Incidence of grade 3+4 toxicity was low

• Only 5% dropped out b/o side effects

• But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted– Particularly in the Palliative Care Setting– Many pts will stay on maintenance Tx far

longer than their original “induction” regimens

Perspectives on ToxicityMaintenance Pemetrexed

Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits of

maintenance” pemetrexed– Benefits confined to <50% of those who start first-line therapy, maybe <

40%

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted– Would have inoculated this study from critique if the OS advantage had

been maintained

• Toxicity of pemetrexed, though mild, is not entirely trivial– Cumulative effects of fatigue and aesthenia

• Early institution of 2nd line Tx unnecessary in sizable proportion of pts• Result of this trial do not apply to those who receive pemetrexed or

bevacizumab as part of first-line treatment.• Cost?!

0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0

Pemetrexed 4.0 mos

Placebo 2.0 mos

Progression-free Survival Pro

gre

ssio

n-f

ree

Pro

babili

ty

Time (months)

HR=0.60 (95% CI: 0.49–0.73) P <0.00001

Benefits of Therapeutic Holiday

• Recovery from platinum-based toxicities• 50% or more will have at least a two month window

– Time to travel, participate in family events– “Reconstitute the immune system”

• Many will remain asymptomatic at the time of PD– Sufficient time to judiciously implement second line Tx– Unethical if 2nd line Tx is not available

Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits of maintenance”

pemetrexed– Benefits confined to <50% of those who start first-line therapy, maybe < 40%

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted– Would have inoculated this study from critique if the OS advantage had been

maintained


• Early institution of 2nd line Tx unnecessary in sizable proportion of pts– Therapeutic holiday will do the pt (and the clinician) good


• Cost?!

Relevance in the setting of First-line Therapy with Bevacizumab and

Pemetrexed

• 25 to 40% of US pts with newly diagnosed Non-Sq NSCLC are treated with Bevacizumab upfront

• An increasing percentage of chemo-naïve pts (~30 to 50%) receive pemetrexed as part of their first-line therapy

• Neither of these two groups were included in this trial (probably >50% of potentially eligible pts)

• Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted

Relevance in the setting of First-line Therapy with Bevacizumab and

Pemetrexed

• 25 to 40% of US pts with newly diagnosed Non-Sq NSCLC are treated with Bevacizumab upfront

• An increasing percentage of chemo-naïve pts (~30 to 50%) receive pemetrexed as part of their first-line therapy

• Neither of these two groups were included in this trial (probably >50% of potentially eligible pts)

• Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted

• Concerns since addressed by Paramount and AvaPERL trials

Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits of maintenance”

pemetrexed– Benefits confined to <50% of those who start first-line therapy, maybe < 40%

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted– Would have inoculated this study from critique if the OS advantage had been maintained




– This trial may be “irrelevant to these two cohorts” and the robust PFS and OS advantage might be diluted

• Cost?!

Why this Approach will Never Occur in the UK (or much of the ROW)

• Cost– $5400/cycle/3wks for pemetrexed

– $27,000/ maintenance pt for a median of 5 cycles– With a median improvement of 5.3 mos/pt, then cost per

life year gained = $ 61,132

1Klein R, et al. J Thorac Oncol. 2010;5:1263-1272.




life year gained = $ 61,132• Klein cost-analysis: ~ $122,371 per life year gained in the

non-squamous population1

• Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts?

• Of course, the CEO of Lilly can change this endpoint with a keystroke on his laptop





life year gained = $ 61,132• Klein cost-analysis: ~ $122,371 per life year gained in the

non-squamous population1

• Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts?

• Of course, the CEO of Lilly can change this endpoint with a keystroke on his laptop


Potential Criticisms• Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed

– Benefits confined to <50% of those who start first-line therapy, maybe < 40%

• Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted– Would have inoculated this study from critique if the OS advantage had been maintained




– This trial may be “irrelevant to these two cohorts” and the robust PFS and OS advantage might be diluted

• Cost?!– Fungible endpoint, but highly relevant in these tight financial times

SATURN: phase III trial of sequentialTarceva (Erlotinib) in unresectable NSCLC

1:1

Chemonaïve advanced

NSCLCn~1,700

Non-PDn~850

4 cycles of 1st-line

platinum-based doublet

Placebo PD

Erlotinib150mg/day

PD

Tumour samples

(mandatory)

Stratify by EGFR IHC

results

Completed: 152 centers participated in 29 countries

Primary endpoint: PFS (25% improvment)

Stratifications• EGFR protein expression by IHC

– positive vs negative vs indeterminate• Stage at randomisation

– IIIb vs IV• ECOG PS

– 0 vs 1• CT regimen

– cisplatin-gemcitabine vs carboplatin-docetaxel vs others• Smoking status

– smoking vs former vs never• Region

SATURN: phase III trial of sequentialTarceva (Erlotinib) in unresectable NSCLC

1:1

Chemonaïve advanced

NSCLCn~1,700

Non-PDn~850


platinum-based doublet

Placebo PD

Erlotinib150mg/day

PD

Tumour samples

(mandatory)

Stratify by EGFR IHC

results

Completed: 152 centers participated in 29 countries

Primary endpoint: PFS (25% improvment)

Stratifications• EGFR protein expression by IHC

– positive vs negative vs indeterminate• Stage at randomisation

– IIIb vs IV• ECOG PS

– 0 vs 1• CT regimen

– cisplatin-gemcitabine vs carboplatin-docetaxel vs others• Smoking status

– smoking vs former vs never• Region

1949889

SATURN: PFS* all patients (ITT)P

FS

pro

bab

ilit

y

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)

HR=0.71 (0.62–0.82) Log-rank p<0.0001

Erlotinib (n=437)

Placebo (n=447)

*investigator results corroborated by independent review

Erlotinib Placebo

PFS at 12 wks (%) 53 40

PFS at 24 wks (%) 31 17

Subgroup analysis of PFS All

Male

Female

Caucasian

Asian

Adenocarcinoma

Squamous-cell

Never smoker

Former smoker

Current smoker

HR (95% CI) n

0.71 (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

PFS in EGFR Mutation + Tumors*

HR=0.10 (0.04–0.25)Log-rank p<0.0001

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)

Erlotinib (n=22)

Placebo (n=27)

PFS probability

*60% censoredCappuzzo F, et al. J Clin Oncol 27:407s, 2009

SATURN

SATURN: Summary of QoL Data

HR (95% CI) P value

Time to Deterioration in QoL (FACT-L) 0.96 (0.79-1.16) 0.6530

Time to Pain 0.61 (0.42-0.88) 0.0080

Time to Cough 0.77 (0.49-1.21) 0.2546

Time to Dyspnea 0.75 (0.48-1.17) 0.2054

Time to Analgesic Use 0.66 (0.46-0.94) 0.0199

OS*: all patients (ITT)

0 3 6 9 12 15 18 21 24 27 30 33 36

OS

pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=438)

Placebo (n=451)

11.0 12.0

*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

Outcome MS 1 yr OS (%) 2 yr OS (%)

Erlotinib 12 mos 50 26

Placebo 11 mos 45 19

Criticisms of SATURN• Fewer than 50% of those enrolled actually made it to the

maintenance randomization• Toxicity of longterm erlotinib (diarrhea and skin rash in the

majority of pts) is not trivial• PFS improvement, while statistically signifiicant, may be clinically

irrelevant– 1 month advantage

• Survival improvement, similarly, was “clinically underwhelming: 12 vs 11 mos

• Mandatory crossover to EGFR TKI at the time of PD was not included

Saturn: ToxicityErlotinib (N=433) Placebo (N=445)

Grade ≥ 3 All grades Grade ≥ 3 All grades

One or more AE 12% 65% 1% 20%

Skin issue 9% 62% 0 10%

Rash 9% 60% 0 8%

Pruritis <1% 6% 0 2%

GI issue 2% 23% <1% 8%

Diarrhea 2% 18% 0 3%

General 1% 9% <1% 2%

Nutritional <1% 5% <1% 2%

Anorexia <1% 5% <1% 2%

Infection 1% 5% 0 <1%

Cappuzzo et al. Lancet Oncol online as of May 20

Saturn: ToxicityErlotinib (N=433) Placebo (N=445)

Grade ≥ 3 All grades Grade ≥ 3 All grades

One or more AE 12% 65% 1% 20%

Skin issue 9% 62% 0 10%

Rash 9% 60% 0 8%

Pruritis <1% 6% 0 2%

GI issue 2% 23% <1% 8%

Diarrhea 2% 18% 0 3%

General 1% 9% <1% 2%

Nutritional <1% 5% <1% 2%

Anorexia <1% 5% <1% 2%

Infection 1% 5% 0 <1%

Cappuzzo et al. Lancet Oncol online as of May 20

Criticisms of SATURN• Fewer than 50% of those enrolled actually made it to the

maintenance randomization• Toxicity of longterm erlotinib (diarrhea and skin rash in the

majority of pts) is not trivial• PFS improvement, while statistically signifiicant, may be clinically

irrelevant– 1 month advantage

• Survival improvement, similarly, was “clinically underwhelming: 12 vs 11 mos

• Mandatory crossover to EGFR TKI at the time of PD was not included (only 21% in the placebo group received Erl at PD)

Erlotinib Placebo

PFS at 12 wks (%) 53 40

PFS at 24 wks (%) 31 17

SATURN: Survival Subgroup Analyses

Demographic HR No.

All 0.81 (0.70-0.95) 889

Male 0.88 (0.74-1.05) 659

Female 0.64 (0.46-0.91) 230

Caucasian 0.86 (0.73-1.01) 746

Asian 0.66 (0.42-1.05) 131

Adenoca 0.77 (0.61-0.97) 403

Squamous cell 0.86 (0.68-1.10) 360

Never smoker 0.69 (0.45-1.05) 152

Former smoker 0.75 (0.56-1.00) 244

Current smoker 0.88 (0.72-1.08) 493

Cappuzzo F, et al. J Clin Oncol 27:407s, 2009

Maintenance TrialsRecently Reported

• ATLAS: Bev/Erl vs Bev• Belani: Gem vs BSC• IFCT-GFPC 0502: Gem vs Erl vs Obs [BSC]• INFORM: Gefitinib vs Placebo• PARAMOUNT: Cont Pem vs IV Placebo• AVAPERL: Bev vs Bev/PEM [ESMO 2011]• POINT-BREAK: E4599 v Patel/Hensing

Ongoing• E5508: Cont Bev vs Switch Pem vs Both

Randomized, Double Blind, Placebo Controlled, Phase IIIb Trial (ATLAS) Comparing

Bevacizumab Therapy with or without Erlotinib, after Completion of Chemotherapy with

Bevacizumab for 1st-line Treatment of Locally-advanced, Recurrent, or Metastatic Non-small

Cell Lung Cancer (NSCLC)

Vincent A. Miller, MD,1 Paula O’Connor, MD,2 Chang-Heok Soh, PhD,2 and Fairooz Kabbinavar, MD,3 for the ATLAS Investigators

1Memorial Sloan-Kettering Cancer Center, New York, NY, 2Genentech, Inc, South San Francisco, CA, 3University of California Los Angeles –

Translational Oncology Research International, Los Angeles, CA

69

ATLAS Study Design

1:1

*Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel.

Unblind at PD

Bevacizumab (15mg/kg) +erlotinib (150mg) to PD

Chemo-naïveadvanced

NSCLCN=1,160


chemotherapy* + bevacizumab

Non-PDn=768 (66%)

Post progressiontherapy

Bevacizumab +placebo

to PD

Primary endpoint

• PFS in all randomized pts (26% improvement)

Secondary endpoints

• Overall survival

• Safety

Exploratory endpoints

• Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation)

Eligibility

• Stage IIIB**/IV NSCLC

• ECOG performance status 0-1

Stratification factors

• Gender

• Smoking history (never vs former/current)

• ECOG performance status (0 v >1)

• Chemotherapy regimen

**IIIB with pleural effusion

70373 142 58 27 15 6 3 0

370 178 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 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)

71

ATLAS: Additional PFS Outcome Measures



Median PFS, mos (95% CI)3.75

(2.83, 4.04)4.76

(4.14, 5.52)

PFS rate, % (95% CI)

3 mos53.4

(47.5, 58.9)67.7

(61.9, 72.7)

6 mos28.4

(23.0, 34.1)40.3

(34.2, 46.3)

Progression Free Survival: HR=0.722 (0.592-0.881) Log-rank P=0.0012(ITT population, investigator assessment)

72

ATLAS: Additional PFS Outcome Measures



Median PFS, mos (95% CI)3.75

(2.83, 4.04)4.76

(4.14, 5.52)

PFS rate, % (95% CI)

3 mos53.4

(47.5, 58.9)67.7

(61.9, 72.7)

6 mos28.4

(23.0, 34.1)40.3

(34.2, 46.3)

Overall Survival* 13.93 15.93

Progression Free Survival: HR=0.722 (0.592-0.881) Log-rank P=0.0012(ITT population, investigator assessment)

*HR = 0.897 (0.74-1.088) Log rank p=0.2686

73

ATLAS: Grade 3-4 Adverse Events of Special Interest during the Post Chemotherapy Phase (Cont.)

Bev + Placebo, n (%)

(n=368)

Bev + Erlotinib, n (%)

(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.

Is there a role for Continuation Maintenance Tx in

NSCLC?

• Belani

• IFCT-GFPC 0502

• Paramount

• Avaperl

Gemcitabine Maintenance + BSC vs BSC Alone

Chemotherapy-naive patients

with stage IIIB/IV NSCLC

(N = 519)

Gemcitabine + BSC(n = 128)

BSC(n = 127)

Belani CP, et al. ASCO 2010. Abstract 7506.

Patients stratified by PS, stage, best tumor responsePrimary endpoint: OS Other endpoints: PFS, ORR, safety

Gemcitabine/Carboplatinfor 4 cycles

Patients without disease progression randomized 1:1

Gemcitabine + BSC vs BSC: Treatment Outcomes

OutcomeGemcitabine

+ BSC(n = 128)

BSC(n = 127)

HR (95% CI) P Value

Median OS, mo 8.0 9.3 0.97 (0.72-1.30) .838

Median PFS, mo 7.4 7.7 1.09 (0.81-1.45) .575

ORR, % 28 6 -- NR

Belani CP, et al. ASCO 2010. Abstract 7506.

Benefits of gemcitabine maintenance may have been nullified by patient population studied

Median patient age: 66.6 years

ECOG PS 2: 64%

Observation

IFCT-GFPC 0502 study design

*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

Progression:2nd line

Primary endpoint: PFS

A

C

Maintenancetreatment

PD

N=155

N=154

N=155

EGFR = epidermal growth factor receptorIHC = immunohistochemistry; PD = progressive disease

PD: off

Objectiveresponse or

stable disease

Cisplatingemcitabine

x 4 cyclesN=834

NSCLCStage IIIB wet – IVPS 0-1, 18-70 yearsAsymptomatic brain

mets allowed

Tumor tissueEGFR IHC

EGFR mutation

R*N=464

BGemcitabine

Erlotinib

PD

PD

Pemetrexed

Pemetrexed

Pemetrexed

Perol et al ASCO 2010

PFS by independent reviewGemcitabine versus observation

ObservationGemcitabine

HR=0.55 (0.43–0.70)Log-rank test, p<0.0001

ObservationN=152

GemcitabineN=149

Median PFS, months 1.9 3.8

PFS at 3 months, % 30.3 55.0

PFS at 6 months, % 8.6 22.1

PFS is measured from time of randomizationinto the maintenance phase

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

PFS is measured from time of randomisationinto the maintenance phase

ObservationErlotinib

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

ObservationN=152

ErlotinibN=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

Preliminary overall survival

ObservationGemcitabineErlotinib

Gemcitabine vs observationHR=0.86 (0.66–1.12)

Erlotinib vs observationHR=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

00 5 10 15 20 25 30 35 40

Time (months)

Probability

PARAMOUNT: Study DesignPARAMOUNT: Study Design

Study Treatment PeriodProgression

Induction Therapy (4 cycles)

Maintenance Therapy (Until PD)

21 to 42 Days

500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d

CR, PR, SD

PD

Placebo + BSC, d1, q21d

500 mg/m2 Pemetrexed + BSC, d1, q21d

2:1 Randomization

Patients enrolled if:•Nonsquamous NSCLC•No prior systemic treatment for lung cancer•ECOG PS 0/1

Stratified for: •PS (0 vs 1) •Disease stage (IIIB vs IV) prior to induction•Response to induction (CR/PR vs SD)

Primary objective: progression-free survival

Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events

PARAMOUNT: Study Design

Study Treatment PeriodProgression

Induction Therapy (4 cycles)

Maintenance Therapy (Until PD)

21 to 42 Days

500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d

CR, PR, SD

PD

Placebo + BSC, d1, q21d

500 mg/m2 Pemetrexed + BSC, d1, q21d

2:1 Randomization

Patients enrolled if:•Nonsquamous NSCLC•No prior systemic treatment for lung cancer•ECOG PS 0/1

Stratified for: •PS (0 vs 1) •Disease stage (IIIB vs IV) prior to induction•Response to induction (CR/PR vs SD)

Primary objective: progression-free survival

Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events

N=939

N=359

N=180

N=539 57%

Paz-Ares et al, ASCO 2011, abstract CRA7510

Time (Months)

0 3 6 9 12 15

Su

rviv

al

Pro

ba

bil

ity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PARAMOUNT: Investigator Assessed PFS (from Maintenance)

Pemetrexed: median =4.1 mos (3.2-4.6)Placebo: median =2.8 mos (2.6-3.1)Log-rank P=0.00006Unadjusted HR: 0.62 (0.49-0.79)

Pem + BSC

Placebo + BSC

PFS results were internally consistent; benefit was seen across all subgroups

Favors Pemetrexed Favors Placebo

Treatment Hazard Ratio (95% CI)

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

─0.62

─0.62

─0.55

─0.48

─0.74

─0.67

─0.53

─0.41

─0.70

─0.74

─0.49

─0.69

─0.34

─0.70

─0.64

─0.39

─0.62

All Randomized Patients (N=539)

Stage IV (n=489)

Stage IIIB (n=50)Induction Response CR/PR

(n=242)Induction Response SD (n=280)

Pre-randomization PS 1 (n=366)

Pre-randomization PS 0 (n=170)

Non-smoker (n=116)

Smoker (n=419)

Male (n=313)

Female (n=226)

Age <70 (n=447)

Age ≥70 (n=92)

Age <65 (n=350)

Age > 65 (n=189) Other Histologic Diagnosis

(n=32)Large Cell Carcinoma (n=36)

Adenocarcinoma (n=471)

PARAMOUNT: Subgroup PFS Hazard Ratios

PARAMOUNT: Final OS from InductionS

urv

iva

l Pro

ba

bili

ty

Time from Induction (Months)

0 3 6 9 12 15 18 21 24 27 30 33 36

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pemetrexed Median OS =16.9 mos (95% CI: 15.8–19.0)

Placebo Median OS =14.0 mos (95% CI: 12.9–15.5)Log-rank P=0.0191HR=0.78 (95% CI: 0.64–0.96)

Patients at RiskPem + BSC 359 335 276 234 200 164 138 106 77 42 15 2 0Placebo + BSC 180 168 132 103 78 63 49 35 23 12 8 3 0


Hazard Ratio

0.780.790.820.810.760.82

0.700.750.830.820.730.750.89

0.820.710.810.440.80

Treatment Hazard Ratio (95% CI)

0.0 0.5 1.0 1.5 2.0 2.5

Adenocarcinoma (n=471)Large Cell Carcinoma (n=36)

Other Histologic Diagnosis (n=32)Age 65 (n=189)Age < 65 (n=350)

Age 70 (n=92)Age < 70 (n=447)

Female (n=226)Male (n=313)

Smoker (n=418)Non-smoker (n=117)

Pre-randomization ECOG PS 0 (n=173)Pre-randomization ECOG PS 1 (n=363)

Induction Response SD (n=285)Induction Response CR/PR (n=234)

Stage IIIB (n=49)Stage IV (n=490)

All Randomized Patients (N=539)

PARAMOUNT: Subgroup OS Hazard Ratios

♦ The survival results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: Induction Response SubgroupsOS Hazard Ratios

♦ The survival results were consistent across both induction response subgroups

CR/PRHR = 0.81

SDHR = 0.76

Time from Randomization (Months)

0 9 18 27 36

0 9 18 27 36 0.700.750.830.820.730.750.89

0.820.710.810.440.80

0.0 0.5 1.0 1.5 2.0

All Randomized Patients (N=539)Stage IV (n=490)Stage IIIB (n=49)

Induction Response CR/PR (n=234)Induction Response SD (n=285)

Pre-randomization ECOG PS 1 (n=363)Pre-randomization ECOG PS 0 (n=173)

Non-smoker (n=117)Smoker )n=418)

Male (n=313)Female (n=226)

Age < 70 (n=447)Age > 70 (n=92)

Age < 65 (n=350)Age > 65 (n=189(

Other Histologic Diagnosis (n=32)Large Cell Carcinoma (n=36)

Adenocarcinoma (n=471)

0.780.790.820.810.760.82

Hazard Ratio

Treatment Hazard Ratio (95%% CI)


Continuation Maintenance

Study Year Induction Therapy Maintenance Therapy Median PFS

Median OS

Main grade 3/4 toxicities

Brodowicz

2006 Gemcitabine 1250 mg/m2 d 1, 8 + cisplatin 80 mg/m2 d 1 x 4

Gemcitabine 1250 mg/m2 d 1,8

BSC

6.6 months

5.0 months(p<.001)

13.0 months

11.0 months

Maintenance Gem: ANC14.9%, Plts 1.7%; blood transfusion 20% gemcitabine vs. 6.3% BSC

Belani 2010 Gemcitabine 1000 mg/m2 d 1,8 + carboplatin AUC 5 d1 x 4


BSC

7.4 months

7.7 months(p=.575)

8.0 months

9.3 months(p=.838)

ANC 15% chemo, 2% BSC; Plts 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC

Perol 2010 Gemcitabine 1250 mg/m2 d 1, 8 + cisplatin 80 mg/m2 d 1 x 4


BSC

3.3 months

1.9 months(p<.001)

NR

NR

At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6%

Paz Ares 2011 Pemetrexed 500 mg/m2 d 1 + cisplatin 75 mg/m2 d 1 x 4

Pemetrexed 500 mg/m2 d 1

BSC

4.1 months

2.8 months(p=.0006)

13.9 months

11.1 months(p=0.034)

Fatigue:4.2% pem, 0.6% BSC, Anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC

Continuation Maintenance

Study Year Induction Therapy Maintenance Therapy Median PFS

Median OS

Main grade 3/4 toxicities

Brodowicz

2006 Gemcitabine 1250 mg/m2 d 1, 8 + cisplatin 80 mg/m2 d 1 x 4


BSC

6.6 months

5.0 months(p<.001)

13.0 months

11.0 months

Maintenance Gem: ANC14.9%, Plts 1.7%; blood transfusion 20% gemcitabine vs. 6.3% BSC

Belani 2010 Gemcitabine 1000 mg/m2 d 1,8 + carboplatin AUC 5 d1 x 4


BSC

7.4 months

7.7 months(p=.575)

8.0 months

9.3 months(p=.838)

ANC 15% chemo, 2% BSC; Plts 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC

Perol 2010 Gemcitabine 1250 mg/m2 d 1, 8 + cisplatin 80 mg/m2 d 1 x 4


BSC

3.3 months

1.9 months(p<.001)

NR

NR

At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6%

Paz Ares 2011 Pemetrexed 500 mg/m2 d 1 + cisplatin 75 mg/m2 d 1 x 4

Pemetrexed 500 mg/m2 d 1

BSC

4.1 months

2.8 months(p=.0006)

13.9 months

11.1 months(p=0.034)

Fatigue:4.2% pem, 0.6% BSC, Anemia: 4.5%, 0.6% BSC, ANC: 3.6% pem, 0 BSC

How do we Combine Platinum and Pemetrexed

with Bevacizumab? Are there clinical insights? Should both Bevacizumab and Pemetrexed be continued beyond 6 cycles?

91

AVAPERL: Patient disposition

a RECIST-related end points measured from the preinduction phase.b Intent-to-treat population

First-line induction withBev-cis-pem(n=376)

Arm A:Bevacizumab

(n= 125)CR/PR/SD by RECIST

PD

Not eligible for randomization(n=123)

Patients randomized to maintenancea

(n=253)b

Patients screened(n=414)

Arm B:bevacizumab + pemetrexed (n=128)

5 patients not treated

3 patients not treated

123 patients not randomized• 50 discontinued due to AEs• 49 discontinued due to PD• 9 patients died• 7 withdrew consent• 5 discontinued for other reasons• 3 did not start treatment

Median follow-up time for this analysis: 11 months

92

AVAPERL: Patient characteristics: maintenance population

Bevacizumab

(n=125)Bevacizumab + pemetrexed

(n=128)

Median age, y

<65 y, no. (%)

60

88 (70)

60

88 (69)

Male, no. (%) 70 (56) 74(58)

ECOG PS, no. (%)

0

1

52 (43)

67 (55)

66 (52)

59 (46)

Current stage IV, no. (%) 110 (88) 121 (94)

Histology, no. (%)

Adenocarcinoma

Large cell

Other

115 (92)

9 (7)

1 (1)

110 (86)

12 (9)

6 (5)

Smoking status, no. (%)

Current smoker

Past smoker

Never smoker

31 (25)

60 (48)

33 (27)

30 (23)

67 (52)

31 (24)

93

AVAPERL: PFS from inductiona Bev+pem 10.2 months (81 events) Bev 6.6 months (104 events)HR, 0.50 (0.37–0.69); P <.001

Pro

gre

ssio

n -f

ree

surv

ival

(%

)

Time (months)

128 126 103 66 25 4 0125 122 73 38 12 2 0

100

75

50

25

00 3 6 9 12 15 18

Pts at risk Bev+pem Bev

Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients.

a Randomized pts, Intent-to-treat population

Cont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)

94

AVAPERL: PFS from randomizationa

Bev+pem 7.4 months (81 events)Bev 3.7 months (104 events)HR, 0.48 (0.35–0.66); P <.001

Pro

gre

ssio

n -f

ree

surv

ival

fr

om

date

of

rand

omiz

atio

n(%

)

Time (months)

128 104 67 25 4 0 125 73 36 13 2 0

100

75

50

25

00 3 6 9 12 15

Pts at risk Bev+pem Bev

a Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm)bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients.


95

AVAPERL: OS from inductiona O

vera

ll su

rviv

al (

% o

f p

atie

nts)

100

75

50

25

00 3 6 9 12 15 18 21

128 127 120 103 56 20 3 0125 123 110 96 45 17 2 0

Time (months)

Bev+pem NR (34 events)Bev 15.7 months (42 events)HR: 0.75 (0.47–1.20); P=0.23

Pts at risk Bev+pemBev

Median follow-up time: 11 months (8 months, excluding induction).30% of events at the time of analysis for overall survival.bev, bevacizumab; HR, hazard ratio; NR, not reached; pem, pemetrexed; pts, patients.

a Randomized pts, Intent-to-treat population


Phase II study of Carboplatin + Pemetrexed + Bevacizumab

Patel et al, ASCO 2008, Abst 8044, JCO 2009

Chemotherapy-naïve

Stage IIIB/IV

ECOG PS 0-1

Non-squamous histology

No CNS mets

Carboplatin AUC 6 i.v. day 1

Pemetrexed 500 mg/m2 i.v. day 1

Bevacizumab 15 mg/kg i.v. day 1

Cycles q3 weeks X 6

PD

Off Study

Non-PD

Pemetrexed 500 mg/m2

Bevacizumab 15 mg/kg

Cycles q3 weeks until PD

Phase II study of Carboplatin + Pemetrexed + Bevacizumab

Patel et al, ASCO 2008, Abst 8044

• 51 patients enrolled

• ORR 55% (41-69%)

• MPFS 7.8 months (5.2 – 11.5)

• MST 14.1 months (10.8 – 19.6)

• 0% inc. of FN; 2% inc of TRDs

Patel JD. Hensing T et al. JCO 2009

Phase III First-Line Pem/Carbo/ Bevacizumab in Advanced Non-Sq NSCLC

POINT-BREAK

Two POINT-BREAK Questions:

• Would it POINT the way to a new treatment paradigm?

• If Pemetrexed/Bevacizumab became a new standard during induction and maintenance, would the combination BREAK the bank?

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Su

rviv

al

Pro

ba

bil

ity

PointBreak: KM OS from Randomization (ITT)

Pem+Cb+Bev Pac+Cb+Bev

OS median (mo) 12.6 13.4

HR (95% CI); P value 1.0 (0.86, 1.16); P=0.949

Censoring (%) 27.8 27.2

Survival rate (%)

1-year 52.7 54.1

2-year 24.4 21.2

0 3 6 9 12 15 18 21 24 27 30 33 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Su

rviv

al P

rob

abil

ity

PointBreak: Kaplan-Meier (KM) PFS from Randomization (ITT)

Pem+Cb+Bev Pac+Cb+Bev

PFS median (mo) 6.0 5.6

HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012

G4 PFS median (mo) 4.3 3.0HR (95% CI); P value 0.74 (0.64, 0.86) P<.001

TTPD (mo) 7.0 6.0HR (95% CI); P value 0.79 (0.67, 0.94); P=0.006

ORR (%) 34.1 33.0

Censoring rate for Pem+Cb+Bev was 26.9; for Pac+Cb+Bev was 23.3

0 3 6 9 12 15 18 21 24 27 30 33 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Su

rviv

al P

rob

ab

ilit

y PointBreak: Prespecified Analysis of KM PFS from

Randomization for the Maint. Population

Pem+Cb+Bev

(n=292)Pac+Cb+Bev

(n=298)

PFS median (mo) 8.6 6.9

Censoring (%) 24.7 14.1

Prespecified exploratory non-comparative subgroup analyses

Pem-Bev

Bev

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Su

rviv

al P

rob

ab

ilit

y

PointBreak: Prespecified Analysis of KM OS from Randomization for the Maintenance Population

Pem+Cb+Bev

(n=292)Pac+Cb+Bev

(n=298)

OS median (mo) 17.7 15.7

Censoring (%) 36.0 30.2

Prespecified exploratory non-comparative subgroup analyses

Bev

Pem-Bev

Eligibility Stage IIIB/IV Bev

eligible NSCLC PS 0-1 Tx Brain mets OK 4 prior cycles of

CarbTax +Bev

(1236) , with CR, PR, SD (864)

Randomization factors: Gender PS Stage Best tumor response

to induction

Pemetrexed 500 mg/m2 (q21d)Primary Endpoint = OS

*B12, folate, and dexamethasone given in Pem. arms

ECOG 5508 Phase III Study Design ECOG 5508 Phase III Study Design ““Cont” Bev. vs “Switch” Pem. vs “Hybrid” Bev.+Pem.

RANDOMIZE

Bevacizumab 15mg/kg (q21d)

Pemetrexed 500 mg/m2 (q21d)Bevacizumab 15mg/kg (q21d)

Total 1236 patients with 864 randomized (288/arm)

Maintenance Tx: Conclusions (1)• Reasonable option in fit, motivated pts who have stabilized or

responded to initial plaintum-based chemotherapy• Bevacizumab maintenance is part of the E4599 paradigm, though

not proven vs observation in randomized phase III trials• Pemetrexed is well tolerated and convenient

– PFS and Overall Survival benefits seen • Both “continuation” and “switch” settings• Confined to non-squamous histology

• Striking survival advantage seen with pemetrexed in this setting would have been more credible had it been observed in the context of mandatory crossover in the control group at the time of PD

• Cost may ultimately constitute the 800lb gorilla

Maintenance Tx: Conclusions (2)• Maintenance therapy with erlotinib after cytotoxic chemotherapy

offers a clinically modest, but statistically significant advantage wrt PFS and OS

• Survival benefits are a bit more robust in the phenotypically favored subgroups (Asians, women, adenoca, never smokers), but not secure in the mutation (+) cohorts

• The (not so) striking survival advantage seen with erlotinib in this setting would have been far more credible had it been observed in the context of mandatory crossover in the control group

• Inclusion of QoL and TOI enhances the clinical credibility of maintenance trials

• No survival advantage as yet for Pem-Bev or Erl-Bev combinations over Bev alone

Mr Debonnair strikes out

Documents

Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion