Transcript Highlights of the Day II

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]
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, PfizerPharmacia, 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
Eligibility
• NSCLC IIIb/IV
• PS ≥ 70
• Chemonaive
• Treated Brain Mets
• No neuropathy
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 6 +
Paclitaxel 200 mg/m2
every 21 days x 4 cyc
At Progression:
Weekly Paclitaxel
80 mg/m2/wk until PD
Carboplatin AUC 6 +
Paclitaxel 200 mg/m2
every 21 days until PD
Endpoints: Survival and Quality of Life
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
Paclitaxel Carboplatin x 4 Cycles vs
Paclitaxel Carboplatin to Progression
PC x 4
n=114
PC to PD
n=116
4 ( 0-6)
4 (0-19)
22%
24%
ns
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
Number of cycles
ORR
Median survival
P value
Socinski et al. J Clin Oncol 20: 1335, 2002
Paclitaxel Carboplatin x 4 Cycles vs
Paclitaxel Carboplatin to Progression
PC x 4
n=114
PC to PD
n=116
4 ( 0-6)
4 (0-19)
22%
24%
ns
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
Number of cycles
ORR
Median survival
P value
Socinski et al. J Clin Oncol 20: 1335, 2002
Prolonged Chemotherapy
MVP x 3 cycles
Stage IIIB/IV
NSCLC
PS 0-2
R
All patients could receive MVP at progression
MVP x 6 cycles
MVP: mitomycin, vinblastine, cisplatin
Smith, JCO 19: 1336, 2001
MVP x 3 Cycles versus
MVP x 6 Cycles
MVP x 3
n=155
Received full
treatment
ORR
MVP x 6
P value
n=153
113 (72%) 48 (31%)
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
MVP x 3 Cycles versus
MVP x 6 Cycles
Survival, all patients
patients
Survival, patients who
received at least 3 cycles
Survival, PS 0-1
Smith et al. J Clin Oncol 19: 1336, 2001
Immediate Versus Delayed Docetaxel After Induction
Eligibility & Treatment Plan
CR, PR, SD
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
Primary endpoint:
Overall Survival, HR: 1.43
R
A
N
D
O
M
I
Z
E
Immediate
Docetaxel
75mg/m2 day 1,
every 21 days until PD or
maximum of 6 cycles
Delayed
Docetaxel
Best Supportive Care,
then start therapy at PD
75mg/m2 on day 1,
every 21 days, until PD
or maximum of 6 cycles
Fidias et al, ASCO 2007
Immediate Versus Delayed Docetaxel After
Induction Eligibility & Treatment Plan
Chemonaϊve
Stage
IIIb/IV
NSCLC
N = 562
GCb Phase
N = 552
(388 (69%)
received 4 cycles)
Off Study
N = 245
ORR
29%
SD, PR, CR
N = 307
Immediate
Docetaxel
Immediate
Treated
N = 142
Randomized
Treated
N = 153
(56%)
Delayed
Docetaxel
N = 154
Delayed
Treated
N = 91*
*Only 59% of patients randomized to delayed docetaxel received treatment.
Fidias et al, ASCO 2007
Immediate Delayed
(n=153)
(n=154)
Median PFS (mo)
5.7
2.7
12-month PFS, %
20%
9%
LR
p-Value
<0.0001
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%
Fidias et al. J Clin Oncol; 27:591-598 2009
Immediate Delayed
(n=153)
(n=154)
Median PFS (mo)
5.7
2.7
12-month PFS, %
20%
9%
LR
p-Value
<0.0001
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%
Fidias et al. J Clin Oncol; 27:591-598 2009
Maintenance Pemetrexed Plus Best Supportive Care
(BSC) Versus Placebo Plus BSC: A Phase III Study
in NSCLC
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
Study Design
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
 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
Pemetrexed 500 mg/m2
(d1,q21d) + BSC (N=441)*
2:1
Randomization
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC
(N=222)*
*B12, folate, and dexamethasone given in both arms
Objectives
Primary Objective
 Progression-free survival
Secondary Objectives
 Overall survival
 Objective response rate (CR+PR)
 Disease control rate (CR+PR+SD)
 Safety
Baseline Characteristics
Pemetrexed
N=441
%
Placebo
N=222
%
60.6
60.4
73/27
73/28
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
74
70
50
48
2
5
21
18
26
30
Median age, years
Male/Female
Caucasian/Asian/Other
Histology
Non-squamous
Adenocarcinoma
Large cell carcinoma
Other or indeterminate
Squamous
Initial Therapy
Pemetrexed
N=441
%
Placebo
N=222
%
Docetaxel-carboplatin
5
3
Docetaxel-cisplatin
2
2
30
27
6
9
Gemcitabine-carboplatin
24
22
Gemcitabine-cisplatin
33
38
48/52
52/48
Paclitaxel-carboplatin
Paclitaxel-cisplatin
Best response to initial therapy
CR + PR/SD
Progression-free Probability
Progression-free Survival
HR=0.60 (95% CI: 0.49 0.73)
P <0.00001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pemetrexed 4.0 mos
Placebo 2.0 mos
0
3
6
9
12
Time (months)
15
18
21
24
Progression-free Survival by Histology
Progression-free Probability
Non-squamous
Squamous
HR=1.03 (95% CI: 0.77-1.5)
P =0.896
HR=0.47 (95% CI: 0.37-0.6)
P <0.00001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pemetrexed 4.4 mos
Placebo
1.8 mos
0
3
6
9
12
15
Time (months)
18
21
24
Pemetrexed 2.4 mos
Placebo
2.5 mos
0
3
6
9
12
15
Time (months)
18
21
24
Overall Survival
(Intent-to-treat Population)
HR=0.79 (95% CI: 0.65–0.95)
P =0.012
Survival Probability
1.0
0.9
0.8
0.7
0.6
Pemetrexed 13.4 mos
0.5
0.4
Placebo 10.6 mos
0.3
0.2
0.1
0.0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Overall Survival by Histology
Non-squamous (n=481)
Squamous (n=182)
HR=1.07 (95% CI: 0.49–0.73)
P =0.678
HR=0.70 (95% CI: 0.56-0.88)
P =0.002
Survival Probability
1.0
0.9
1.0
0.8
0.9
0.7
0.8
0.7
0.6
Pemetrexed 15.5 mos
0.5
0.6
Pemetrexed 9.9 mos
0.5
0.4
0.4
0.3
Placebo
10.3 mos
0.2
0.1
0.3 Placebo
0.2 10.8 mos
0.1
0.0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
0.0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Efficacy by Histologic Groups
Median OS, mos
Histology Groups
Pem
Non-squamous
(n=481)
15.5
Plac
10.3
Adeno
(n=329)
16.8
11.5
Large cell
(n=20)
8.4
7.9
Other
(n=133)
Squamous
(n=182)
11.3
9.9
7.7
10.8
P-value
(HR)
0.002
(0.70)
0.026
(0.73)
0.964
(0.98)
0.025
(0.61)
0.678
(1.07)
Median PFS, mos
Pem
4.4
Plac
1.8
4.6
2.7
4.5
1.5
4.1
2.4
1.6
2.5
P-value
(HR)
<0.00001
(0.47)
<0.00001
(0.51)
0.104
(0.40)
0.0002
(0.44)
0.896
(1.03)
There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·033)
Treatment-related Toxicities*
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
<1
0
Sensory neuropathy
1
0
Mucositis/Stomatitis
1
0
Vomiting
*NCI CTC version 3.0
‡P <0.05 for grade 3/4 rates of neutropenia and fatigue
Treatment HRs for Overall Survival in
Subgroups of the ITT Population
Hazard Ratio
Overall ITT Population (n=663)
Adenocarcinoma (n=328)
Large Cell Carcinoma (n=20)
Other Histology* (n=133)
Squamous Cell Carcinoma (n=182)
Age < 65 (n=443)
Age >= 65 (n=220)
Female (n=180)
Male (n=483)
Caucasian (n=428)
East Asian (n=154)
Other Ethnic Origin (n=81)
Ever-smoker (n=482)
Never-smoker (n=176)
ECOG PS 0 (n=261)
ECOG PS 1 (n=400)
Induction Cisplatin (n=288)
Induction Carboplatin (n=374)
Induction Response CR/PR (n=322)
Induction Response SD (n=337)
Stage IIIB (n=126)
Stage IV (n=536)
0.79
0.73
0.98
0.61
1.07
0.74
0.88
0.83
0.78
0.77
1.05
0.46
0.83
0.64
0.68
0.86
0.89
0.70
0.90
0.68
0.76
0.80
0.0
0.2
0.4
0.6
0.8
1.0
Favors pemetrexed
1.2
1.4
1.6
1.8
Favors placebo
2.0
2.2
2.4
2.6
2.8
3.0
Conclusions

First randomized, double-blind, placebocontrolled 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
Switch Maintenance
Agent/Control Arm
N
PFS
Salvage
treatment %
OS
Fidias
Docetaxel
Delayed Docetaxel
309
5.7 m HR 0.63
2.7 m p<.001
63
12.3 HR 0.80
9.7 p.085
Ciuleanu
Pemetrexed
Placebo
663
4.0 m HR 0.60
2.0 m p<.001
67
13.4 HR 0.79
10.6 p .012
Capuzzo
Erlotinib
Placebo
889
12.3 w HR 0.71
11.1 w p<.001
72
12.0 HR 0.81
11.0 p .0088
Miller
Erlotinib + Bevacizumab
Placebo + Bevacizumab
768
4.8 m HR 0.72
3.8 m p.0012
55.5
15.9 HR 0.9
13.9 p .2686
Perol
Erlotinib
Observation
310
2.9 m HR 0.82
1.9 m p.002
81.9
NA
NA
Zhang
Gefitinib
Placebo
296
4.8 m HR 0.42
2.6 m p<0.0001
58.8
18.7
16.9
Fidias, J Clinc Oncol 28:5116-5123
Zhang et al [INFORM] ASCO 2011
HR .91
HR .83
p 0.2109
Switch Maintenance
Agent/Control Arm
N
PFS
Salvage
treatment %
OS
Fidias
Docetaxel
Delayed Docetaxel
309
5.7 m HR 0.63
2.7 m p<.001
63
12.3 HR 0.80
9.7 p.085
Ciuleanu
Pemetrexed
Placebo
663
4.0 m HR 0.60
2.0 m p<.001
67
13.4 HR 0.79
10.6 p .012
Capuzzo
Erlotinib
Placebo
889
12.3 w HR 0.71
11.1 w p<.001
72
12.0 HR 0.81
11.0 p .0088
Miller
Erlotinib + Bevacizumab
Placebo + Bevacizumab
768
4.8 m HR 0.72
3.8 m p.0012
55.5
15.9 HR 0.9
13.9 p .2686
Perol
Erlotinib
Observation
310
2.9 m HR 0.82
1.9 m p.002
81.9
NA
NA
Zhang
Gefitinib
Placebo
296
4.8 m HR 0.42
2.6 m p<0.0001
58.8
18.7
16.9
Fidias, J Clinc Oncol 28:5116-5123
HR .91
HR .83
p 0.2109
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
• 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?!
Immediate Versus Delayed Docetaxel After
Induction Eligibility & Treatment Plan
Chemonaϊve
Stage
IIIb/IV
NSCLC
N = 562
GCb Phase
N = 552
(388 (69%)
received 4 cycles)
Off Study
N = 245
ORR
29%
SD, PR, CR
N = 307
Immediate
Docetaxel
Immediate
Treated
N = 142
Randomized
Treated
N = 153
(56%)
Delayed
Docetaxel
N = 154
Delayed
Treated
N = 91*
*Only 59% of patients randomized to delayed docetaxel received treatment.
Fidias et al, ASCO 2007
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 nonsquamous 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%
• 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?!
Systemic Post-study Therapy
Pemetrexed
(N=441) %
Placebo
(N=222) %
52
67
7
10
Cisplatin
Docetaxel
Erlotinib
5
22
22
6
29
21
Gefitinib
13
10
Gemcitabine
9
14
Paclitaxel
Pemetrexed
Vinorelbine
4
1
13
6
19
17
Total Validated 2nd Line Tx
58
79
Patients with post-study therapy
Most common post-study therapies
Carboplatin
 Higher rate of follow-up treatment on the placebo arm
 Balanced selection of therapies between arms and low rate of crossover
Systemic Post-study Therapy
Pemetrexed
(N=441) %
Placebo
(N=222) %
52
67
7
10
Cisplatin
Docetaxel
Erlotinib
5
22
22
6
29
21
Gefitinib
13
10
Gemcitabine
9
14
Paclitaxel
Pemetrexed
Vinorelbine
4
1
13
6
19
17
Total Validated 2nd Line Tx
58
79
Patients with post-study therapy
Most common post-study therapies
Carboplatin
 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
Fidias et al. J Clin Oncol; 27:591-598 2009
Median Survival
Number
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
• Result of this trial do not apply to those who receive
pemetrexed or bevacizumab as part of first-line treatment.
• Cost?!
Maintenance Pemetrexed: Tx-related Toxicities*
Pemetrexed
(N = 441) %
Placebo
(N = 222) %
Grade 3/4
All grades
Grade 3/4
All
grades
Neutropenia‡
3
6
0
0
Anemia
3
15
1
5
Leukopenia
2
6
1
2
Fatigue‡
5
24
1
10
Anorexia
2
19
0
5
Infection
1
5
0
2
Diarrhea
1
5
0
3
Nausea
1
19
1
5
Vomiting
<1
9
0
1
Sensory neuropathy
1
9
0
4
Mucositis/Stomatitis
1
7
0
2
Early Discontinuation for Toxicity
*NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue
5
1
Ciuleanu et al. Lancet 374: 1432-1440 (2009)
Maintenance Pemetrexed: Tx-related Toxicities*
Pemetrexed
(N = 441) %
Placebo
(N = 222) %
Grade 3/4
All grades
Grade 3/4
All
grades
Neutropenia‡
3
6
0
0
Anemia
3
15
1
5
Leukopenia
2
6
1
2
Fatigue‡
5
24
1
10
Anorexia
2
19
0
5
Infection
1
5
0
2
Diarrhea
1
5
0
3
Nausea
1
19
1
5
Vomiting
<1
9
0
1
Sensory neuropathy
1
9
0
4
Mucositis/Stomatitis
1
7
0
2
Early Discontinuation for Toxicity
*NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue
5
1
Ciuleanu et al. Lancet 374: 1432-1440 (2009)
Perspectives on Toxicity
Maintenance 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
Perspectives on Toxicity
Maintenance 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
– Particularly in the Palliative Care Setting
– Many pts will stay on maintenance Tx far
longer than their original “induction” regimens
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?!
Progression-free Probability
Progression-free Survival
HR=0.60 (95% CI: 0.49–0.73)
P <0.00001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pemetrexed 4.0 mos
Placebo 2.0 mos
0
3
6
9
12
Time (months)
15
18
21
24
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
• 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?!
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
• 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?!
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.
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 $$$$ on the palliative
therapy of end-stage pts?
• Of course, the CEO of Lilly can change this endpoint
with a keystroke on his laptop
1Klein
R, et al. J Thorac Oncol. 2010;5:1263-1272.
Why this Approach will Never Occur in
the UK (or much of the ROW)
• Cost
– $5400/cycle/3wks for pemetrexed
– $27,000/ maintenance pt for a median of 5 cycles
– With a median improvement of 5.3 mos/pt, then cost per
life year gained = $ 61,132
• Klein cost-analysis: ~ $122,371 per life year gained in the
non-squamous population1
• Can we afford to spend this much $$$$ 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.
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
SATURN: phase III trial of sequential
Tarceva (Erlotinib) in unresectable NSCLC
Tumour
samples
(mandatory)
Chemonaïve
advanced
NSCLC
n~1,700
Stratify by
EGFR IHC
results
4 cycles of
1st-line
platinumbased doublet
Non-PD
n~850
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
Erlotinib
150mg/day
PD
Placebo
PD
1:1
Completed: 152 centers
participated in 29 countries
Primary endpoint: PFS (25%
improvment)
SATURN: phase III trial of sequential
Tarceva (Erlotinib) in unresectable NSCLC
Tumour
samples
(mandatory)
Chemonaïve
advanced
NSCLC
n~1,700
1949
Stratify by
EGFR IHC
results
4 cycles of
1st-line
platinumbased doublet
Non-PD
n~850
889
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
Erlotinib
150mg/day
PD
Placebo
PD
1:1
Completed: 152 centers
participated in 29 countries
Primary endpoint: PFS (25%
improvment)
SATURN: PFS* all patients (ITT)
1.0
PFS probability
0.8
Erlotinib
Placebo
PFS at 12 wks (%)
53
40
PFS at 24 wks (%)
31
17
0.6
HR=0.71 (0.62–0.82)
Log-rank p<0.0001
0.4
Erlotinib (n=437)
0.2
Placebo (n=447)
0
0
8
16
24
32
40 48 56
Time (weeks)
*investigator results corroborated by independent review
64
72
80
88
96
Subgroup analysis of PFS
All
HR (95% CI)
0.71 (0.62–0.82)
n
884
Male
0.78 (0.66–0.92)
654
Female
0.56 (0.42–0.76)
230
Caucasian
0.75 (0.64–0.88)
744
Asian
0.58 (0.38–0.87)
128
Adenocarcinoma
0.60 (0.48–0.75)
401
Squamous-cell
0.76 (0.60–0.95)
359
Never smoker
0.56 (0.38–0.81)
152
Former smoker
0.66 (0.50–0.88)
242
Current smoker
0.80 (0.67–0.97)
490
0.4
0.6
0.8
1.0
Favours
erlotinib
HR
1.2
Favours
placebo
SATURN
PFS in EGFR Mutation + Tumors*
PFS probability
1.0
Erlotinib (n=22)
Placebo (n=27)
0.8
HR=0.10 (0.04–0.25)
Log-rank p<0.0001
0.6
0.4
0.2
0
0
88
8
96
16
24
Cappuzzo F, et al. J Clin Oncol 27:407s, 2009
32
40
48
Time (weeks)
56
64
72
80
*60% censored
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)
1.0
HR=0.81 (0.70–0.95)
OS probability
0.8
Log-rank p=0.0088
0.6
Erlotinib (n=438)
Placebo (n=451)
0.4
0.2
11.0
0
0
3
6
Outcome
9
12.0
12
15
18
21
24
27
30
MS
1 yr OS (%)
2 yr OS (%)
Erlotinib
12 mos
50
26
Placebo
11 mos
45
19
*OS is measured from time of randomisation into the maintenance phase;
ITT = intent-to-treat population
33
36
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: Toxicity
Erlotinib (N=433)
Placebo (N=445)
Grade ≥ 3
Grade ≥ 3
All grades
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%
2%
23%
<1%
8%
2%
18%
0
3%
General
1%
9%
<1%
2%
Nutritional
<1%
5%
<1%
2%
Anorexia
<1%
5%
<1%
2%
1%
5%
0
<1%
GI issue
Diarrhea
Infection
Cappuzzo et al. Lancet Oncol online as of May 20
Saturn: Toxicity
Erlotinib (N=433)
Placebo (N=445)
Grade ≥ 3
Grade ≥ 3
All grades
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%
2%
23%
<1%
8%
2%
18%
0
3%
General
1%
9%
<1%
2%
Nutritional
<1%
5%
<1%
2%
Anorexia
<1%
5%
<1%
2%
1%
5%
0
<1%
GI issue
Diarrhea
Infection
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
Erlotinib
Placebo
PFS at 12 wks (%)
53
40
PFS at 24 wks (%)
31
17
• 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)
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 Trials
Recently 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 Locallyadvanced, 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
ATLAS Study Design
Bevacizumab (15mg/kg) +
erlotinib (150mg) to PD
Chemo-naïve
advanced
NSCLC
N=1,160
4 cycles of
1st-line
chemotherapy*
+ bevacizumab
Non-PD
n=768 (66%)
1:1
Unblind
at PD
Post progression
therapy
Bevacizumab +
placebo
to PD
Eligibility
Primary endpoint
• Stage IIIB**/IV NSCLC
• PFS in all randomized pts (26% improvement)
• ECOG performance status 0-1
Secondary endpoints
Stratification factors
• Overall survival
• Gender
• Safety
• Smoking history (never vs
former/current)
Exploratory endpoints
• ECOG performance status (0 v >1)
• Biomarker analyses (IHC, FISH, EGFR &
K-Ras mutation)
• Chemotherapy regimen
*Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel.
**IIIB with pleural69
effusion
ATLAS: Progression-Free Survival
(ITT population, investigator assessment)
Proportion Without Event
1.0
Bev + Placebo (n=373)
Bev + Erlotinib (n=370)
0.8
0.6
HR=0.722 (0.592-0.881)
Log-rank P=0.0012
0.4
0.2
0.0
0
3
6
9
12
15
18
21
3
3
0
1
Progression-Free Survival (months)
No. of patients at risk:
Bev + Placebo 373
70
Bev + Erlotinib 370
142
178
58
81
27
43
15
20
6
6
ATLAS: Additional PFS Outcome
Measures
Progression Free Survival: HR=0.722 (0.592-0.881) Log-rank P=0.0012
(ITT population, investigator assessment)
Bev + Placebo
(n=370)
Bev + Erlotinib
(n=373)
3.75
(2.83, 4.04)
4.76
(4.14, 5.52)
3 mos
53.4
(47.5, 58.9)
67.7
(61.9, 72.7)
6 mos
28.4
(23.0, 34.1)
40.3
(34.2, 46.3)
Median PFS, mos (95% CI)
PFS rate, % (95% CI)
71
ATLAS: Additional PFS Outcome
Measures
Progression Free Survival: HR=0.722 (0.592-0.881) Log-rank P=0.0012
(ITT population, investigator assessment)
Bev + Placebo
(n=370)
Bev + Erlotinib
(n=373)
3.75
(2.83, 4.04)
4.76
(4.14, 5.52)
3 mos
53.4
(47.5, 58.9)
67.7
(61.9, 72.7)
6 mos
28.4
(23.0, 34.1)
40.3
(34.2, 46.3)
13.93
15.93
Median PFS, mos (95% CI)
PFS rate, % (95% CI)
Overall Survival*
*HR = 0.897 (0.74-1.088) Log rank p=0.2686
72
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%)
1 (0.3%)
1 (0.3%)
Hepatic events*
Grade 5 events:
73
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
Patients without disease
progression randomized 1:1
Chemotherapynaive patients
with stage
IIIB/IV NSCLC
(N = 519)
Gemcitabine + BSC
(n = 128)
Gemcitabine/Carboplatin
for 4 cycles
Patients stratified by PS, stage, best tumor response
Primary endpoint: OS
Other endpoints: PFS, ORR, safety
Belani CP, et al. ASCO 2010. Abstract 7506.
BSC
(n = 127)
Gemcitabine + BSC vs BSC:
Treatment Outcomes
Gemcitabine
+ 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
Outcome
 Benefits of gemcitabine maintenance may have been
nullified by patient population studied
 Median patient age: 66.6 years
 ECOG PS 2: 64%
Belani CP, et al. ASCO 2010. Abstract 7506.
IFCT-GFPC 0502 study design
Maintenance
treatment
PD: off
A
Cisplatin
gemcitabine
x 4 cycles
N=834
Objective
response or
stable disease
Tumor tissue
EGFR IHC
EGFR mutation
Induction chemo: cisplatin 80mg/m2 d1
+ gemcitabine
1,250mg/m2
PD
Pemetrexed
PD
Pemetrexed
PD
Pemetrexed
N=155
R*
N=464
B
d1, d8
Gemcitabine
N=154
C
NSCLC
Stage IIIB wet – IV
PS 0-1, 18-70 years
Asymptomatic brain
mets allowed
Observation
Progression:
2nd line
Erlotinib
N=155
Primary endpoint: PFS
*Stratification factors:
– gender
Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks
– histology: adenocarcinoma vs other histology
Arm C: erlotinib 150mg daily
– smoking status: non-smokers vs current/former smokers
– center
– response vs stabilization to induction chemotherapy
Perol et al ASCO 2010
EGFR = epidermal growth factor receptor
IHC = immunohistochemistry; PD = progressive disease
PFS by independent review
Gemcitabine versus observation
Probability
Observation
N=152
Gemcitabine
N=149
Median PFS, months
1.9
3.8
PFS at 3 months, %
30.3
55.0
PFS at 6 months, %
8.6
22.1
1.0
0.8
0.6
HR=0.55 (0.43–0.70)
0.4
Log-rank test, p<0.0001
Observation
Gemcitabine
0.2
0
0
5
10
15
20
25
30
35
40
Time (months)
PFS is measured from time of randomization
into the maintenance phase
PFS by independent review
Erlotinib versus observation
Probability
Observation
N=152
Erlotinib
N=153
Median PFS, months
1.9
2.9
PFS at 3 months, %
30.3
35.3
PFS at 6 months, %
8.6
16.3
1.0
0.8
0.6
HR=0.82 (0.73–0.93)
0.4
Log-rank test, p=0.002
Observation
Erlotinib
0.2
0
0
5
10
15
20
25
30
35
40
Time (months)
PFS is measured from time of randomisation
into the maintenance phase
Preliminary overall survival
Probability
1.0
Observation
Gemcitabine
Erlotinib
0.8
Gemcitabine vs observation
HR=0.86 (0.66–1.12)
0.6
Erlotinib vs observation
HR=0.91 (0.80–1.04)
0.4
0.2
0
0
5
10
15
20
25
30
35
40
Time (months)
Median follow-up: 21.6 months
324 deaths / 464 randomized patients (69.6%)
PARAMOUNT: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
Maintenance Therapy (Until PD)
21 to 42 Days
Patients enrolled if:
• Nonsquamous NSCLC
• No prior systemic treatment for
lung cancer
• ECOG PS 0/1
500 mg/m2 Pemetrexed +
75 mg/m2 Cisplatin, d1, q21d
500 mg/m2 Pemetrexed + BSC, d1, q21d
CR,
PR, SD
2:1 Randomization
Placebo + BSC, d1, q21d
Stratified for:
• PS (0 vs 1)
• Disease stage (IIIB vs IV) prior to induction
• Response to induction (CR/PR vs SD)
PD
Primary objective: progression-free survival
Secondary objectives: Overall survival, response rate,
pt reported outcomes, resource utilization, adverse
events
PARAMOUNT: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
Maintenance Therapy (Until PD)
21 to 42 Days
Patients enrolled if:
• Nonsquamous NSCLC
• No prior systemic treatment for
lung cancer
• ECOG PS 0/1
500 mg/m2 Pemetrexed +
75 mg/m2 Cisplatin, d1, q21d
N=939
N=359
N=539
57%
CR,
PR, SD
500 mg/m2 Pemetrexed + BSC, d1, q21d
2:1 Randomization
Placebo + BSC, d1, q21d
Stratified for:
N=180
• PS (0 vs 1)
• Disease stage (IIIB vs IV) prior to induction
• Response to induction (CR/PR vs SD)
PD
Primary objective: progression-free survival
Secondary objectives: Overall survival, response rate,
pt reported outcomes, resource utilization, adverse
events
Paz-Ares et al, ASCO 2011, abstract CRA7510
Survival Probability
PARAMOUNT: Investigator Assessed PFS
(from Maintenance)
1.0
Pem + BSC
0.9
Placebo + BSC
0.8
Pemetrexed: median =4.1 mos (3.2-4.6)
Placebo: median =2.8 mos (2.6-3.1)
Log-rank P=0.00006
Unadjusted HR: 0.62 (0.49-0.79)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
Time (Months)
12
15
PARAMOUNT: Subgroup PFS Hazard Ratios
All Randomized Patients (N=539)
─0.62
Stage IV (n=489)
─0.62
Stage IIIB (n=50)
─0.55
Induction Response CR/PR (n=242)
─0.48
Induction Response SD (n=280)
─0.74
Pre-randomization PS 1 (n=366)
─0.67
Pre-randomization PS 0 (n=170)
─0.53
Non-smoker (n=116)
─0.41
Smoker (n=419)
─0.70
Male (n=313)
─0.74
Female (n=226)
─0.49
Age <70 (n=447)
─0.69
Age ≥70 (n=92)
─0.34
Age <65 (n=350)
─0.70
Age > 65 (n=189)
─0.64
Other Histologic Diagnosis (n=32)
Large Cell Carcinoma (n=36)
─0.39
Adenocarcinoma (n=471)
─0.62
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Treatment Hazard Ratio (95% CI)
Favors Pemetrexed
Favors Placebo
PFS results were internally consistent; benefit was seen across all subgroups
PARAMOUNT: Final OS from Induction
1.0
Pemetrexed
Median OS =16.9 mos (95% CI: 15.8–19.0)
Survival Probability
0.9
0.8
Placebo
Median OS =14.0 mos (95% CI: 12.9–15.5)
Log-rank P=0.0191
HR=0.78 (95% CI: 0.64–0.96)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Time from Induction (Months)
Patients at Risk
Pem + BSC
359
42
15
2
Placebo + BSC 180
12
8
335
0
168
3
276
234
200
164
138
106
77
132
0
103
78
63
49
35
23
PARAMOUNT: Subgroup OS Hazard Ratios
Hazard Ratio
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)
0.78
0.79
0.82
0.81
0.76
0.82
0.70
0.75
0.83
0.82
0.73
0.75
0.89
0.82
0.71
0.81
0.44
0.80
0.0
0.5
1.0
1.5
2.0
Treatment Hazard Ratio (95% CI)
Favors Pemetrexed
♦
Favors Placebo
The survival results were internally consistent; benefit was seen across all subgroups
2.5
PARAMOUNT: Induction Response Subgroups
OS Hazard Ratios
Hazard Ratio
0.70
0.75
0.83
0.82
0.73
0.75
0.89
0.82
0.71
0.81
0.44
0.80
0.0
0.5
1.0
1.5
Treatment Hazard Ratio (95%% CI)
Favors Pemetrexed
♦
2.0
Survival probability
0
9
18
27
36
SD
HR = 0.76
Survival probability
0.78
0.79
0.82
0.81
0.76
0.82
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)
CR/PR
HR = 0.81
0
9
18
27
Time from Randomization (Months)
Favors Placebo
The survival results were consistent across both induction response subgroups
36
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
6.6 months
13.0 months
BSC
5.0 months
(p<.001)
11.0 months
Maintenance Gem:
ANC14.9%, Plts 1.7%;
blood transfusion 20%
gemcitabine vs. 6.3% BSC
Gemcitabine 1000 mg/m2 d 1,8
7.4 months
8.0 months
BSC
7.7 months
(p=.575)
9.3 months
(p=.838)
Gemcitabine 1000 mg/m2 d 1,8
3.3 months
NR
BSC
1.9 months
(p<.001)
NR
Pemetrexed 500 mg/m2 d 1
4.1 months
13.9 months
BSC
2.8 months
(p=.0006)
11.1 months
(p=0.034)
Belani
Perol
Paz Ares
2010
2010
2011
Gemcitabine 1000 mg/m2 d 1,8 +
carboplatin AUC 5 d1 x 4
Gemcitabine 1250 mg/m2 d 1, 8 +
cisplatin 80 mg/m2 d 1 x 4
Pemetrexed 500 mg/m2 d 1 +
cisplatin 75 mg/m2 d 1 x 4
ANC 15% chemo, 2% BSC;
Plts 9% chemo, 4% BSC;
fatigue: 5% chemo, 2%
BSC
At least 1 grade 3/4 AE:
chemotherapy 27.9%,
observation 2.6%
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
Gemcitabine 1250 mg/m2 d 1,8
6.6 months
13.0 months
BSC
5.0 months
(p<.001)
11.0 months
Maintenance Gem:
ANC14.9%, Plts 1.7%;
blood transfusion 20%
gemcitabine vs. 6.3% BSC
Gemcitabine 1000 mg/m2 d 1,8
7.4 months
8.0 months
BSC
7.7 months
(p=.575)
9.3 months
(p=.838)
Gemcitabine 1000 mg/m2 d 1,8
3.3 months
NR
BSC
1.9 months
(p<.001)
NR
Pemetrexed 500 mg/m2 d 1
4.1 months
13.9 months
BSC
2.8 months
(p=.0006)
11.1 months
(p=0.034)
Belani
Perol
Paz Ares
2010
2010
2011
Gemcitabine 1000 mg/m2 d 1,8 +
carboplatin AUC 5 d1 x 4
Gemcitabine 1250 mg/m2 d 1, 8 +
cisplatin 80 mg/m2 d 1 x 4
Pemetrexed 500 mg/m2 d 1 +
cisplatin 75 mg/m2 d 1 x 4
ANC 15% chemo, 2% BSC;
Plts 9% chemo, 4% BSC;
fatigue: 5% chemo, 2%
BSC
At least 1 grade 3/4 AE:
chemotherapy 27.9%,
observation 2.6%
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?
AVAPERL: Patient
disposition
CR/PR/SD by
RECIST
Patients
screened
(n=414)
First-line
induction with
Bev-cis-pem
Patients randomized
to maintenancea
(n=376)
(n=253)b
a RECIST-related
b Intent-to-treat
Bevacizumab
(n= 125)
5 patients not treated
Arm B:
PD
Not eligible for
randomization
(n=123)
Arm A:
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
end points measured from the preinduction phase.
population
bevacizumab +
pemetrexed
(n=128)
3 patients not treated
Median follow-up time for this
analysis: 11 months
91
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)
92
AVAPERL: PFS from inductiona
Progression -free survival (%)
100
Bev+pem
10.2 months (81 events)
Bev
6.6 months (104 events)
HR, 0.50 (0.37–0.69); P <.001
75
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)
50
25
0
0
3
Time (months)
Pts at risk
Bev+pem 128
Bev
125
a Randomized
126
122
6
103
73
pts, Intent-to-treat population
Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients.
9
12
15
18
66
38
25
12
4
2
0
0
93
AVAPERL: PFS from randomizationa
Progression -free survival
from date of randomization(%)
100
Bev+pem
7.4 months (81 events)
Bev
3.7 months (104 events)
HR, 0.48 (0.35–0.66); P <.001
75
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)
50
25
0
0
3
6
9
12
15
4
2
0
0
Time (months)
Pts at risk
a
Bev+pem 128
Bev
125
104
73
67
36
25
13
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.
94
AVAPERL: OS from inductiona
Overall survival (% of patients)
100
Bev+pem
Bev
HR:
NR (34 events)
15.7 months (42 events)
0.75 (0.47–1.20); P=0.23
75
50
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)
25
0
0
Pts at risk
Bev+pem 128
Bev
125
a Randomized
3
Time (months)
127
123
6
9
120
110
103
96
12
56
45
15
20
17
18
21
3
2
0
0
pts, Intent-to-treat population
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.
95
Phase II study of Carboplatin +
Pemetrexed + Bevacizumab
Patel et al, ASCO 2008, Abst 8044, JCO 2009
Carboplatin AUC 6 i.v. day 1
Chemotherapy-naïve
Pemetrexed 500 mg/m2 i.v. day 1
Stage IIIB/IV
Bevacizumab 15 mg/kg i.v. day 1
ECOG PS 0-1
Cycles q3 weeks X 6
Non-squamous histology
No CNS mets
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?
PointBreak: KM OS
from Randomization (ITT)
Pem+Cb+Bev
12.6
1.0
OS median (mo)
0.9
Survival Probability
0.8
0.7
0.6
0.5
Pac+Cb+Bev
13.4
HR (95% CI); P value
1.0 (0.86, 1.16); P=0.949
Censoring (%)
Survival rate (%)
1-year
2-year
27.8
27.2
52.7
24.4
54.1
21.2
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
Time from Induction (Months)
30
33
36
39
PointBreak: Kaplan-Meier (KM) PFS
from Randomization (ITT)
1.0
0.9
Pac+Cb+Bev
6.0
5.6
PFS median (mo)
0.8
Survival Probability
Pem+Cb+Bev
HR (95% CI); P value
0.7
G4 PFS median (mo)
0.6
HR (95% CI); P value
0.5
TTPD (mo)
0.83 (0.71, 0.96); P=0.012
4.3
0.74 (0.64, 0.86) P<.001
7.0
HR (95% CI); P value
0.4
3.0
6.0
0.79 (0.67, 0.94); P=0.006
ORR (%)
34.1
33.0
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Time from Induction (Months)
Censoring rate for Pem+Cb+Bev was 26.9; for Pac+Cb+Bev was 23.3
27
30
33
36
PointBreak: Prespecified Analysis of KM PFS from
Randomization for the Maint. Population
1.0
Pem+Cb+Bev Pac+Cb+Bev
(n=292)
(n=298)
8.6
6.9
0.9
PFS median (mo)
Survival Probability
0.8
Censoring (%)
0.7
24.7
14.1
0.6
0.5
0.4
Pem-Bev
0.3
0.2
Bev
0.1
0.0
0
3
6
9
12
15
18
21
24
Time from Induction (Months)
Prespecified exploratory non-comparative subgroup analyses
27
30
33
36
PointBreak: Prespecified Analysis of KM OS from
Randomization for the Maintenance Population
Pem+Cb+Bev Pac+Cb+Bev
(n=292)
(n=298)
1.0
0.9
Survival Probability
0.8
OS median (mo)
17.7
15.7
Censoring (%)
36.0
30.2
0.7
0.6
Pem-Bev
0.5
0.4
Bev
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
Time from Induction (Months)
Prespecified exploratory non-comparative subgroup analyses
30
33
36
39
ECOG 5508 Phase III Study Design
“Cont” Bev. vs “Switch” Pem. vs “Hybrid” Bev.+Pem.
Primary Endpoint = OS
Eligibility
 Stage IIIB/IV Bev eligible
NSCLC
 PS 0-1
 Tx Brain mets OK
 4 prior cycles of CarbTax
R
A
N
D
O
M
I
Z
E
Pemetrexed 500 mg/m2 (q21d)
Bevacizumab 15mg/kg (q21d)
+Bev (1236) , with CR,
PR, SD (864)
Pemetrexed 500 mg/m2 (q21d)
Randomization factors:
Bevacizumab 15mg/kg (q21d)
 Gender
 PS
 Stage
*B12, folate, and dexamethasone given in Pem. arms
 Best tumor response to
induction
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