maintenance therapy in advanced nsclc: state of the art or state of confusion
DESCRIPTION
Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion Corey J Langer MD, FACP Director Thoracic Oncology Abramson Cancer Center Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, PA 19104 [email protected]. - PowerPoint PPT PresentationTRANSCRIPT
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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]
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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
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Terminology: Maintenance
• Is it maintenance?
• Is it consolidation?
• Or is it early salvage?
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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
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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.
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Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression
Socinski et al. J Clin Oncol 20: 1335, 2002
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Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression
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
Socinski et al. J Clin Oncol 20: 1335, 2002
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Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression
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
Socinski et al. J Clin Oncol 20: 1335, 2002
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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
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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
Median survival 6.0 mos 7.0 mos 0.20
TTP 5.0 mos 5.0 mos ns
Smith et al. J Clin Oncol 19: 1336, 2001
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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
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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
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Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan
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%
Fidias et al, ASCO 2007
*Only 59% of patients randomized to delayed docetaxel received treatment.
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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%
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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%
Is this negative for survival benefit
or under-powered??
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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
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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)*
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Primary Objective Progression-free survival
Secondary Objectives
Overall survival
Objective response rate (CR+PR)
Disease control rate (CR+PR+SD)
Safety
Objectives
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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
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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
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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
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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
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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
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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)
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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)
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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*
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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
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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
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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
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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
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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?!
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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?!
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Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan
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%
Fidias et al, ASCO 2007
*Only 59% of patients randomized to delayed docetaxel received treatment.
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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)
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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
• 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?!
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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
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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
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Phase 3 Study of Immediate vs. Delayed Docetaxel After First Line
Gemcitabine/Carboplatin in Advanced NSCLC
Fidias et al. J Clin Oncol; 27:591-598 2009
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
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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
• Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment.
• Cost?!
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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)
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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)
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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
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• 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
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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?!
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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
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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
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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– Therapeutic holiday will do the pt (and the clinician) good
• Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment.
• Cost?!
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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
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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
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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– Therapeutic holiday will do the pt (and the clinician) good
• Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment.
– This trial may be “irrelevant to these two cohorts” and the robust PFS and OS advantage might be diluted
• Cost?!
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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.
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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• Klein cost-analysis: ~ $122,371 per life year gained in the
non-squamous population1
• Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts?
• Of course, the CEO of Lilly can change this endpoint with a keystroke on his laptop
1Klein R, et al. J Thorac Oncol. 2010;5:1263-1272.
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Why this Approach will Never Occur in the UK (or much of the ROW)
• Cost– $5400/cycle/3wks for pemetrexed
– $27,000/ maintenance pt for a median of 5 cycles– With a median improvement of 5.3 mos/pt, then cost per
life year gained = $ 61,132• Klein cost-analysis: ~ $122,371 per life year gained in the
non-squamous population1
• Can we afford to spend this much $$$$ on the palliative therapy of end-stage pts?
• Of course, the CEO of Lilly can change this endpoint with a keystroke on his laptop
1Klein R, et al. J Thorac Oncol. 2010;5:1263-1272.
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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– Therapeutic holiday will do the pt (and the clinician) good
• Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment.
– 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
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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
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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
1949889
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
4 cycles of 1st-line
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
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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)
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ATLAS: Additional PFS Outcome Measures
Bev + Placebo (n=370)
Bev + Erlotinib (n=373)
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)
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72
ATLAS: Additional PFS Outcome Measures
Bev + Placebo (n=370)
Bev + Erlotinib (n=373)
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
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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.
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Is there a role for Continuation Maintenance Tx in
NSCLC?
• Belani
• IFCT-GFPC 0502
• Paramount
• Avaperl
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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
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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%
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Favors Pemetrexed Favors Placebo
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
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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)
Favors Pemetrexed Favors Placebo
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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
Gemcitabine 1000 mg/m2 d 1,8
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
Gemcitabine 1000 mg/m2 d 1,8
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
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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
Gemcitabine 1000 mg/m2 d 1,8
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
Gemcitabine 1000 mg/m2 d 1,8
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
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How do we Combine Platinum and Pemetrexed
with Bevacizumab? Are there clinical insights? Should both Bevacizumab and Pemetrexed be continued beyond 6 cycles?
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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
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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)
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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)
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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.
Cont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)
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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
Cont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)
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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
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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
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Phase III First-Line Pem/Carbo/ Bevacizumab in Advanced Non-Sq NSCLC
POINT-BREAK
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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?
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
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
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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
Time from Induction (Months)
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
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
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
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
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
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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)
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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
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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
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Mr Debonnair strikes out