1. Paz-Ares LG, J Clin Oncol 2013 Aug 8;31(23):2895–902

2. PARAMOUNT

4. PARAMOUNT: Study Overview
• Most patients have Stage IIIB/IV NSCLC when diagnosed1
• Platinum-based combinations are recommended for
first-line treatment2
• Pemetrexed has demonstrated efficacy in advanced ns NSCLC
– In combination with cisplatin as first-line doublet3
– As maintenance agent following non-pemetrexed platinum doublet4
• PARAMOUNT evaluated pemetrexed maintenance after induction with
pemetrexed/cisplatin doublet:
– Primary endpoint was met: pemetrexed significantly reduced risk of
disease progression over placebo (HR = 0.62; 95% CI: 0.49-0.79;
p<.0001)5
..
1. http://seer.cancer.gov/statfacts/html/lungb.html
2. Azzoli et al. J Clin Oncol 2011;29(28):3825-31.
3. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51.
4. Ciuleanu et al. Lancet 2009;374(9699):1432-40.
5. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55.
6. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902

5. Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs.
Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A
Randomized, Double-blind, Phase 3 Study (JMEN)
• Phase III, multicenter, randomized, double-blind, placebo-controlled
study conducted at 83 centers in 20 countries in patients with stage
IIIB or IV NSCLC who had not progressed on 4 cycles of platinum-based
chemotherapy
• Patients (N = 663) randomized 2:1 to receive i.v. (Day 1), either
pemetrexed (500 mg/m2) + BSC (N = 441) or placebo (0.9% NaCl) + BSC
(N = 222) in 21-day cycles until disease progression
• All patients received vitamin B12, folic acid, and dexamethasone
• Primary endpoint: Progression-free survival1
• Secondary endpoints: Overall survival, objective tumor response
rate, safety,1 and patient-reported outcomes(QoL)2
1. Ciuleanu et al. Lancet 2009;374(9699):1432-40.
2. Belani et al. Lancet Oncol 2012;13(3):292-9.

6. • Primary endpoint = progression-free survival (study fully powered for
secondary objective of overall survival)
• Histology subgroups (adenocarcinoma, large-cell carcinoma, squamous-
cell carcinoma, other NSCLC NOS) were prespecified for statistical analysis
1. Ciuleanu et al. Lancet 2009;374(9699):1432-40.
Induction regimen
4 cycles
Taxane/platinum
or gemcitabine/platinum
No
PD
R
a
n
d
o
m
i
z
e
Pemetrexed 500 mg/m2 +
BSC on Day 1 / q21d
Placebo +
BSC on Day 1 / q21d
2:1
PD
PD
Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs.
Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A
Randomized, Double-blind, Phase 3 Study (JMEN)

7. Baseline Characteristics
Characteristics, n (%) Placebo (N = 222) Pemetrexed (N = 441)
Histologic type
Nonsquamous
Adenocarcinoma
Large cell carcinoma
Other
Squamous cell carcinoma
156 (70)
106 (48)
10 (5)
40 (18)
66 (30)
325 (74)
222 (50)
10 (2)
93 (21)
116 (26)
Smoking status
Smoker
Never smoker
158 (71)
63 (28)
324 (73)
113 (26)
Best response to first-line
therapy
CR + PR
Stable disease
115 (52)
107 (48)
207 (47)
230 (52)c
PS
0
1
85 (38%)
137 (62%)
176 (40%)
263 (60%)
Ciuleanu et al. Lancet 2009;374(9699):1432-40.
• c3 patients had progressive disease (protocol violation) and
1 unknown after first-line therapy
• CR: complete response, PR: partial response

8. Pemetrexed maintenance therapy is well tolerated and offers significantly
improved PFS and OS compared with placebo, making it a new treatment
option for patients with advanced ns NSCLC who do not progress after initial
induction therapy.
Ciuleanu et al. Lancet 2009;374(9699):1432-40.
Median PFS (Months) Median OS (Months)
Pbo Pem
HR
(95% CI)
p-value Pbo Pem
HR
(95% CI)
p-value
All patients
(N = 663)
2.6 4.3
0.50
(0.42-0.61)
<.0001 10.6 13.4
0.79
(0.65-0.95)
.012
Nonsquamous
(N = 481)
2.6 4.5
0.44
(0.36-0.55)
<.0001 10.3 15.5
0.70
(0.56-0.88)
.002
Squamous
(N = 182)
2.6 2.8
0.69
(0.49-0.98)
.039 10.8 9.9
1.07
(0.77-1.50)
.678
Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs.
Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A
Randomized, Double-blind, Phase 3 Study (JMEN)

9. Ciuleanu et al. Lancet 2009;374(9699):1432-40.
Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs.
Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A
Randomized, Double-blind, Phase 3 Study (JMEN)
Población general
Población no escamosa
15.5 vs 10.3 m4.5 vs 2.6 m
4.3 vs 2.6 m 13.4 vs 10.6 m

10. Grade 3/4 Toxicities
Toxicity, n (%) Placebo (N = 222) Pemetrexed (N = 434)
Hematological
Neutropenia 0 13 (3)*
Anemia 1 (<1) 12 (3)
Leukopenia 1 (<1) 7 (2)
Nonhematological
Fatigue 1 (0<1) 22 (5)*
Anorexia 0 8 (2)
Infection 0 7 (2)
Nausea 1 (<1) 4 (<1)
Ciuleanu et al. Lancet 2009;374(9699):1432-40.
• *p<.05
Ciuleanu et al: Maintenance Pemetrexed Plus Best Supportive Care vs.
Placebo Plus Best Supportive Care for Non-small Cell Lung Cancer: A
Randomized, Double-blind, Phase 3 Study (JMEN)

12. “En España pendiente de autorización de precio y condiciones de reembolso”
PARAMOUNT: Elegibility criteria
• Inclusion criteria: Induction phase
– Histological or cytological diagnosis of advanced (Stage IIIB/IV)
nonsquamous NSCLC
– ≥1 measurable lesion per RECIST 1.0
– No prior systemic chemotherapy for lung cancer
– ECOG PS of 0 or 1
• Inclusion criteria: Maintenance phasea
– Completion of 4 cycles pemetrexed-cisplatin induction therapy, with
radiographic evidence of CR, PR, or SD
– ECOG PS of 0 or 1
aAll patients randomized to maintenance phase were eligible for efficacy and safety analyses
1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55.
2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

14. PARAMOUNT: Study Design
• Primary objective: Investigator-as PFS
• Secondary objectives:
– OS
– Objective tumor response rate (RR)
– Patient-reported outcomes (EQ-5D)
– Resource utilization
– Adverse events (AEs) 1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55.
2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
Randomized, placebo-controlled, double-blind, Phase III study
Pemetrexed 500 mg/m2; cisplatin 75 mg/m2
Induction Therapy
4 cycles, q21d
Continuation Maintenance Therapy
q21d until PD
Pemetrexed
+ BSC
Placebo
+ BSC
Pemetrexed
+ Cisplatin
CR/PR/SD
per
RECIST
R
2:1
• Previously
untreated
• PS 0 or 1
• Stage IIIB/IV
NS-NSCLC
Stratified for:
• PS (0 vs. 1)
• Disease Stage (IIIB vs. IV) prior to induction
• Response to induction (CR/PR vs. SD)

15. PARAMOUNT: Statistical Analyses
• OS was analyzed using the unadjusted Cox proportional hazards
regression models (HR, 95% CI)
• Powered for secondary endpoint, OS
• Final OS: 93% power, assuming a minimum 390 events
(30% censoring) and HR = 0.70, 2-sided α = 0.0498
• Planned subgroup analyses of OS performed using stratification and
predefined prognostic variables
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

17. PARAMOUNT: Drug Administration
1. Paz-Ares et al. Presented at: ASCO Annual Meeting, June 1-5, 2012; Chicago, Illinois. Abstract LBA7507.
2. Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
Maintenance Phase
Placebo + BSC
(N = 180)
Pemetrexed + BSC
(N = 359)
Patients treateda 178 357
Number of cycles/patient
Median 4 4
Range 1-38 1-44
Mean (SD) 5.0 (5.2) 7.9 (8.3)
Patients completing >6 cycles, % 18.3 37.0
Patients completing ≥10 cycles, % 11.7 27.6
Dose intensity of planned mean dose, % NA 93.7
Median follow-up, months (95% CI)
For all patients 12.5 (11.1-13.7)
For alive patients 24.3 (23.2-25.1)

18. PARAMOUNT: Patient and Disease Characteristics of
All Randomized Patientsa
aData derived from reporting database at time of OS datalock, bProtocol violations
Patient and Disease Characteristics
Placebo + BSC
(N = 180)
Pemetrexed + BSC
(N = 359)
Gender, male, n (%) 112 (62) 201 (56)
Median age at randomization, years 62 61
Age, <65 years, n (%) 112 (62) 238 (66)
Origin, Caucasian, n (%) 171 (95) 339 (94)
Smoking status, n (%)
Smoker
Nonsmoker
144 (80)
34 (19)
274 (76)
83 (23)
ECOG PS at randomization, n (%)
0
1
2-3b
60 (33)
118 (66)
2 (1)
113 (31)
245 (68)
1 (0.3)
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

19. PARAMOUNT: Patient and Disease Characteristics of All
Randomized Patients (Cont.)a
aData derived from reporting database at time of OS datalock
Patient and Disease Characteristics
Placebo + BSC
(N = 180)
Pemetrexed + BSC
(N = 359)
Disease Stage IV before maintenance
therapy, n (%)
162 (90) 328 (91)
Best tumor response to induction therapy,
n (%)
CR/PR
SD
PD/unknown
75 (42)
95 (53)
10 (5)
159 (44)
190 (53)
10 (3.3)
Histological classifications, n (%)
Adenocarcinoma
Large cell carcinoma
Other nonsquamous
160 (89)
12 (7)
8 (4)
310 (86)
24 (7)
25 (7)
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

20. PARAMOUNT: Summary of OS from Randomization
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
Summary of OS from Randomization
Placebo + BSC
(N = 180)
Pemetrexed + BSC
(N = 359)
Patient deaths, n (%) 141 (78) 256 (71)
Patients censored, n (%) 39 (22) 103 (29)
OS
Median, months 11.0 13.9
95% CI 10.0-12.5 12.8-16.0
Log -rank p -value .0195
Hazard ratio 0.78
95% CI 0.64-0.96
Wald p-value .0199
Survival rate, %
1-year 45 58
95% CI 38-53 53-63
p-value .0062
2-year 21 32
95% CI 15-28 27-37
p-value .0103

21. PARAMOUNT: Final OS from Randomization
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
SurvivalProbability(%)
Time from Randomization (Months)
Placebo + BSC
Median OS = 11.0 mos (95% CI: 10.0-12.5)
Pemetrexed + BSC
Median OS = 13.9 mos (95% CI: 12.8-16.0)
Log-rank p = .0195
Unadjusted HR: 0.78 (95% CI: 0.64-0.96)
Patients at Risk
Placebo + BSC
Pem + BSC
180
359
169
333
131
272
103
235
78
200
65
166
49
138
35
105
23
79
12
43
8
15
3
2
0
0
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

22. PARAMOUNT: Final OS from Induction
Placebo + BSC
Median OS = 14.0 mos (95% CI: 12.9-15.5)
Pemetrexed + BSC
Median OS = 16.9 mos (95% CI: 15.8-19.0)
Log-rank p = .0191
Unadjusted HR: 0.78 (95% CI: 0.64-0.96)
SurvivalProbability(%)
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
Patients at Risk
Placebo + BSC
Pem + BSC
180
359
168
335
132
276
103
234
78
200
63
164
49
138
35
106
23
77
12
42
8
15
3
2
0
0
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

23. PARAMOUNT: PFS Reassessed at Time of Final OS
(from random)
Patients at Risk
Placebo + BSC
Pem + BSC
Progression-freeSurvival(%)
Time (Months)
Placebo + BSC
Median PFS = 2.8 mos (95% CI: 2.6-3.0)
Pemetrexed + BSC
Median PFS = 4.4 mos (95% CI: 4.1-5.7)
Log-rank p<.00001
Unadjusted HR: 0.60 (95% CI: 0.50-0.73)
1.0
0.9
0.8
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
180
359
75
215
33
139
16
97
9
67
7
47
6
32
4
22
2
16
0
5
0
0
0
0
0
10
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

24. PARAMOUNT: OS from Induction Response Subgroups
There was not a significant interaction term of response by treatment (CR/PR vs. SD, p = .731) using
the Cox model of response, treatment, and response by treatment interaction
OS by CR/PR Induction Response
Placebo + BSC
Median OS = 11.2 mos (95% CI: 8.4-15.8)
Pemetrexed + BSC
Median OS = 15.5 mos (95% CI: 12.5-18.8)
Log-rank p = .194
Unadjusted HR: 0.81 (95% CI: 0.59-1.11)
SurvivalProbability(%)
Time from Randomization (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
Placebo + BSC
Median OS = 11.1 mos (95% CI: 9.8-13.8)
Pemetrexed + BSC
Median OS = 13.7 mos (95% CI: 12.5-15.8)
Log-rank p = .0575
Unadjusted HR: 0.76 (95% CI: 0.57-1.01)
OS by SD Induction Response
SurvivalProbability(%) Time from Randomization (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
Patients at Risk
Placebo + BSC
Pem + BSC
75
159
68
146
53
120
41
108
33
89
31
79
24
66
18
50
12
37
6
18
5
8
2
0
0
0
95
190
91
180
72
149
57
124
42
108
32
84
23
69
16
52
10
40
6
25
3
7
1
2
0
0
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

25. PARAMOUNT: Postdiscontinuation Therapy
aData expressed as % of randomized patients; systemic therapies used in ≥1% of patients in either arm are
shown. bApproved second-line therapies. cAll patients received pemetrexed as induction therapy
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
Summary of Postdiscontinuation Therapy
Placebo + BSC
(N = 180)
n, (%) a
Pemetrexed + BSC
(N = 359)
n, (%) a p-value
Patients receiving postdiscontinuation therapy 129 (72) 231 (64) .099
Erlotinibb 78 (43) 142 (40) .405
Docetaxelb 78 (43) 116 (32) .013
Gemcitabine 15 (8) 36 (10) .640
Vinorelbine 11 (6) 28 (8) .597
Investigational drug 8 (4) 20 (6) .683
Carboplatin 8 (4) 18 (5) .835
Paclitaxel 6 (3) 9 (3) .587
Pemetrexedb,c 7 (4) 7 (2) .249
Cisplatin 4 (2) 5 (1) .490
Bevacizumab 1 (0.6) 6 (2) .433
Gefitinib 2 (1) 3 (0.8) 1.000
Afatinib 2 (1) 2 (0.6) .604
Placebo 0 (0) 4 (1) .307

27. PARAMOUNT: Possible Drug-related Laboratory CTCAEs During
Maintenance Therapy
Data were derived from the February 2011 safety update. Toxicities of any grade occurring
in ≥2% of patients in either arm are listed, along with some select toxicities. Toxicities were
reported using CTCAE version 3.0 (NCI 2006)
*p≤.05
Placebo + BSC
(N = 180)
Pemetrexed + BSC
(N = 359)
Laboratory Toxicities
Grade 1/2
%
Grade 3/4
%
Grade 1/2
%
Grade 3/4
%
Anemia 4.4* 0.6* 11.7* 6.4*
Neutropenia 0.6* 0.0* 5.0* 5.8*
Leukopenia 0.0* 0.0 2.8* 2.2
Thrombocytopenia 0.0 0.0 2.2 1.9
Creatinine 1.1 0.0 2.8 0.0
ALT 0.6 0.0 2.5 0.3
AST 0.0* 0.0 2.5* 0.0
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.

28. PARAMOUNT: Possible Drug-related
Nonlaboratory CTCAEs During Maintenance Therapy
Data were derived from the February 2011 safety update. Toxicities of any grade occurring in ≥2% of patients in either arm are
listed, along with some select toxicities. Toxicities were reported using CTCAE version 3.0 (NCI 2006)
*p≤.05
Paz-Ares LG et al. J Clin Oncol 2013;31:2895-2902.
Placebo + BSC (N = 180) Pemetrexed + BSC (N = 359)
Nonlaboratory Toxicities
Grade 1/2
%
Grade 3/4
%
Grade 1/2
%
Grade 3/4
%
Fatigue 10.6* 1.1* 17.5* 4.7*
Nausea 2.2* 0.0 13.4* 0.6
Vomiting 1.1* 0.0 7.5* 0.3
Edema, limb 3.3 0.0 6.7 0.0
Neuropathy, sensory 6.1 0.6 5.3 0.3
Mucositis/stomatitis, oral cavity 1.1* 0.0 4.5* 0.6
Anorexia 1.1* 0.0 4.5* 0.3
Diarrhea 2.2 0.0 4.2 0.3
Glomerular filtration rate 1.7 0.0 4.2 0.0
Watery eye (epiphora, tearing) 0.6* 0.0 4.2* 0.0
Pain, any event 2.2 0.0 4.2 1.1
Fever, without neutropenia 0.0* 0.0 2.8* 0.0
Constipation 2.8 0.0 2.5 0.0
Dry eye syndrome 0.0 0.0 2.2 0.0
Rash, desquamation 0.0 0.0 1.4 0.0
Febrile neutropenia 0.0 0.0 0.0 1.9

30. PARAMOUNT: Conclusions
• PARAMOUNT met its primary endpoint by showing significantly improved PFS
in patients treated with ALIMTA continuation maintenance therapy as
compared with placebo.1
• PARAMOUNT demonstrated that ALIMTA continuation maintenance
significantly improves overall survival for patients with advanced
nonsquamous* NSCLC, compared with placebo (HR 0.78).2
• The overall survival results were internally consistent across all
subgroups, including response to induction (complete/partial response vs
stable disease).2
• ALIMTA continuation maintenance had a safety profile similar to that observed
in the previous trials with single-agent ALIMTA.2-4
• The EQ-5D† suggests that patients can tolerate long-term ALIMTA maintenance
without worsening of quality of life.4
1. Paz-Ares L, et al. Lancet Oncol. 2012;13:247-255.
2. Paz-Ares LG, et al. J Clin Oncol. 2013. doi:10.1200/JCO.2012.47.1102.
3. Ciuleanu T, et al. Lancet. 2009;374:1432-1440.
4. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
5. Gridelli C, et al. J Thorac Oncol. 2012;7:1713-1721.
* Includes adenocarcinoma, large cell, and other histologies except
those with squamous cell type.
† Health-related quality of life assessment.

31. Safety, Resource Use, and Quality of Life in
PARAMOUNT: A Phase III Study of Maintenance
Pemetrexed Versus Placebo After Induction Pemetrexed
Plus Cisplatin for Advanced Nonsquamous Non-small
Cell Lung Cancer
Cesare Gridelli1, Filippo de Marinis2, Jean-Louis Pujol3, Martin Reck4, Rodryg
Ramlau5, Barbara Parente6, Thierry Pieters7, Gary Middleton8, Jesus
Corral9, Katherine Winfree10, Symantha Melemed10, Anna Zimmermann10, William
John10, Julie Beyrer10, Nadia Chouaki11, Carla Visseren-Grul12, Luis Paz-Ares9
Gridelli et al. J Thorac Oncol 2012;7(11):1713-21

32. Introduction (Cont.)
• The PARAMOUNT study was conducted to assess
maintenance treatment with pemetrexed after induction with
pemetrexed plus cisplatin in patients with advanced
nonsquamous NSCLC1
• As a secondary objective of PARAMOUNT, QoL was measured
using the EQ-5D questionnaire2
• This manuscript focused on the prespecified secondary
endpoints of safety, resource use, and QoL data from the EQ-
5D questionnaire in PARAMOUNT
1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-55.
2. Health Policy 1990;16(3):199-208.

33. Measures
• Safety
– AEs, standard laboratory tests, physical
examination (weight, blood pressure, pulse)
• Resource use
– Concomitant medications, transfusions,
treatment-related hospitalizations, basic
supportive care measures
• QoL
– EQ-5D

34. Statistical Analyses
Safety and resource use
• Analyses include all patients treated with ≥1 dose of pemetrexed or cisplatin
during the study period
• Fisher’s exact test used to compare treatment arms in the maintenance
period
QoL (EQ-5D)
• Analyses included all patients who provided a baseline and ≥1 postbaseline
assessment
• Paired t-test was used to compare patients’ induction baseline values with
postbaseline values during induction

35. Statistical Analyses (Cont.)
• QoL (EQ-5D) (Cont.)
– Paired t-test was used to compare treatment
differences in mean change from baseline
(maintenance) at each maintenance cycle
– Mixed-effects analysis of variance model was also
used to compare treatment differences over time
during maintenance
• ECOG PS
– Student’s t-test was used to compare changes in
ECOG PS from baseline (maintenance)

36. Resource Use: Concomitant
Medications and Nutritional Support
aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05.
bReported for ≥2% of patients in either treatment period or maintenance arm.
Induction Maintenance
Pemetrexed + Cisplatin
(N = 939)
%
Pemetrexed
(N = 359)
%
Placebo
(N = 180)
% p-valuea
Concomitant medications
Analgesics 56.7 48.7 51.7 .524
Anti-emetics 66.7 34.0 36.1 .633
Anti-infectives 26.9 25.3 16.7 .028
ESAs 6.5 10.9 6.1 .084
Transfusions 10.3 13.4 5.0 .003
G-CSF or GM-CSF 6.5 5.3 0.0 <.001
Nutritional supportb
Oral 3.2 1.4 0.0 .175

37. Resource Use: Supportive Care
Procedures
aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05
bReported for ≥2% of patients in either treatment period or maintenance arm
Induction Maintenance
Procedures: Supportive Careb
Pemetrexed + Cisplatin
(N = 939)
%
Pemetrexed
(N = 359)
%
Placebo
(N = 180)
% p-valuea
Computed tomography, spiral 2.9 0.0 0.0 –
Electrocardiogram 3.0 0.8 0.0 .554
Examination, laboratory 2.7 0.0 0.0 –
Examination, physical 2.6 0.0 0.0 –
Examination, vital sign 2.6 0.0 0.0 –
Extrathoracic palliative radiotherapy 4.6 0.6 3.3 .019
Injection 2.6 0.8 0.0 .554
Insertion, portacath 2.3 0.0 0.0 –
Intravenous fluid administration 2.9 0.8 0.0 .554
Thoracentesis 2.3 1.1 0.6 .669
X-ray, chest 2.0 0.0 0.0 –

38. Summary of All Hospitalizations
aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05.
Induction Maintenance
Pemetrexed +
Cisplatin
(N = 939)
Pemetrexed
(N = 359)
Placebo
(N = 180) p-valuea
Patients with ≥1 hospitalizations, n
(%)
229 (24.4) 69 (19.2) 32 (17.8) .727
All hospitalizations 295 91 37
Mean (SD) length of stay,
nights
7.87 (7.18) 8.57 (7.01) 8.95 (9.66) .807
Median (range) length of
stay, nights
5.00 (0.00, 45.00) 6.00 (1.00, 34.00) 6.00 (1.00, 53.00)
Patients hospitalized because of
drug-related AEs, n (%)
126 (13.4) 30 (8.4) 6 (3.3) .028
Hospitalizations involving
drug-related AEs
148 35 7
Mean (SD) length of stay,
nights
8.08 (7.06) 8.14 (7.00) 10.57 (8.26) .421
Length of stay, nights, median
(range)
6.00 (0.00-45.00) 6.00 (1.00-31.00) 9.00 (2.00-27.00)

39. Summary of All Hospitalizations (Cont.)
aFisher’s exact test p-value comparing maintenance treatments. Significant if p≤.05.
Induction Maintenance
Pemetrexed +
Cisplatin
(N = 939)
%
Pemetrexed
(N = 359)
%
Placebo
(N = 180)
% p-valuea
Patients hospitalized because
of nondrug-related AEs, n (%)
139 (14.8) 48 (13.4) 26 (14.4) .791
Hospitalizations not involving drug-related
events
167 63 30
Mean (SD) length of stay, nights 8.13 (7.34) 9.17 (7.03) 9.77 (10.40) .747
Median (range) length of stay, nights
5.00
(0.00, 37.00)
8.00
(1.00, 34.00)
6.00
(1.00, 53.00)

40. EQ-5D Compliance
• During induction period: 79.4%
• During maintenance period
– Placebo arm: 80.9%
– Pemetrexed arm: 84.3%
– At postdiscontinuation visit
• Placebo arm: 44.3%
• Pemetrexed arm: 43.9%
Compliance was defined as the number of completed EQ-5D assessments divided by the number of expected
EQ-5D assessments (ie, patients still on study at that time)

41. EQ-5D UK Population-based Index Score During
Induction: All Enrolled Patients
*p≤.05, within-group change from baseline
0.60
0.70
0.80
0.00
0.01
0.03
0.03
Top of bar = mean value at that cycle for pemetrexed + cisplatin
Induction Cycles
N = 445 N = 682 N = 583 N = 522
MeanScore(Scale-0.59to+1.0)
Improvement
*
*
Mean value at baseline (Cycle 0)
Mean change from baseline
1 2 3 4
*
*

42. EQ-5D VAS Rating During Induction:
All Enrolled Patients
No p≤.05, within-group change from baseline
67
68
69
70
71
-0.47
-0.22
0.60
1.13
MeanRating(scale0to100)
Improvement
1 2 3 4Induction Cycles
N = 440 N = 681 N = 573 N = 517
Top of bar = mean value at that cycle for pemetrexed + cisplatin
Mean change from baseline
Mean value at baseline (Cycle 0)

43. EQ-5D UK Population-based Index Score During
Maintenance: All Randomized Patients
*p≤.05, comparing the difference in mean changes from baseline between treatment arms
0.65
0.70
0.75
0.80
0.85
0.90
-0.01
0.01
0.01
0.01
-0.02
0.04
0.02
0.01
0.00
0.03
-0.01
-0.00
*
Maintenance Cycles 1 2 3 4 5 6
N = 265 132 241 129 160 83 149 66 108 48 98 36
MeanScore(scale-0.59to+1.0)
Improvement
Top of bar = mean value at that cycle for pemetrexed
Top of bar = mean value at that cycle for placebo
Mean value at baseline (Cycle 0)
Mean change from baseline

44. EQ-5D VAS Rating During Maintenance:
All Randomized Patients
*p≤.05, comparing the difference in mean changes from baseline between treatment arms
65
70
75
80
1.42
1.65
5.76
6.15
3.15
1.82
4.90
0.69
1.24
1.55
5.99
3.01* *
Maintenance Cycles 1 2 3 4 5 6
N = 266 126 239 127 162 81 147 65 107 48 98 36
Improvement
MeanRating(scale0to100)
Top of bar = mean value at that cycle for pemetrexed
Top of bar = mean value at that cycle for placebo
Mean value at baseline (Cycle 0)
Mean change from baseline
* *

45. Change in ECOG PS from Baseline
Placebo
N = 180
Pemetrexed
N = 359
Worse, % 12.6 14.7
No Change, % 77.3 77.8
Better, % 10.2 7.5
There were no significant differences in ECOG PS between placebo and pemetrexed arms (p = .3673)

46. Discussion: Safety
• Safety of pemetrexed-cisplatin induction therapy was similar to
a previous study of pemetrexed-cisplatin as a first-line
treatment1
• Single-agent maintenance pemetrexed safety was similar to
previous maintenance study of pemetrexed2
– Few (<5%) Grade 3/4 events: anemia, fatigue, neutropenia
– Few (≤10%) Grade 1/2 events: nausea, anemia, vomiting, neutropenia
1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51.
2. Ciuleanu et al. Lancet 2009;374(9699):1432-40.

47. Discussion: Safety (Cont.)
• Skin and renal toxicity described in the literature
were rare, mainly low-grade events, and similarly
distributed between treatment arms1,2
• Exposure to >6 maintenance cycles vs. ≤6
maintenance cycles of pemetrexed showed higher
incidence of Grade 3/4 neutropenia (8.3% vs. 2.2%,
p = .015) but did not result in increased infections
(1.2% vs. 2.9%, p = .691)
1. Equia et al. J Thorac Oncol
2011;6(12):2083-9.
2. Glezerman et al. Am J Kidney Dis
2011;58(5):817-20.

48. Discussion: Resource Use
• Resource use during induction was common for traditionally
cisplatin-related toxicities (antiemetics 66.7%, hospitalizations
for drug-related AEs 13.4%)
• Resource use during maintenance was low and comparable to
previous single-agent pemetrexed studies1-3
– Significantly higher use of transfusions, CSFs, anti-infectives, and
hospitalizations due to study drug with pemetrexed vs. placebo but
differences in comparison with placebo were small (5%-8%
differences)
1. Cileneau et al. Lancet
2009;374(9699):1432-40.
2. Hanna et al. J Clin Oncol 2004;22(9):1589-
97.
3. Belani et al. Lancet Oncol 2012;13(3):292-
9.

49. Discussion: EQ-5D
• Good compliance on completing the EQ-5D questionnaire
(~80%-85% during induction and maintenance)
• No overall treatment differences were observed in the EQ-5D
index scores and VAS ratings
• Statistically significant differences between pemetrexed and
placebo in a few cycles, but no changes during maintenance
treatment exceeded the MID thresholds reported by Pickard
and colleagues (2007)

50. Discussion: EQ-5D (Cont.)
• The majority of patients were able to maintain PS and a
similar number of patients between treatment arms
showed improvement or worsening in PS
• Maintenance pemetrexed did not have a detrimental effect
on QoL
– Most patients maintained their relatively good overall QoL as
measured by EQ-5D or changes from baseline in ECOG PS (most
remained PS 0 or 1)

51. Scagliotti et al. J Thorac Oncol 2011;6(6
Suppl 2):S1160.

52. Background
JMDB Trial: Key Findingsa
In patients with advanced NSCLC
• Overall survival for pemetrexed/cisplatin was noninferior to
gemcitabine/cisplatin1
• Other efficacy outcomes were also comparable between the 2
regimens1
• Pemetrexed/cisplatin had a better safety profile compared with
gemcitabine/cisplatin1
Compared with gemcitabine/cisplatin, pemetrexed/cisplatin
regimen showed a statistically superior overall survival in
patients with nonsquamous histology (p = .011)1,2
aThese findings are the independent opinion of the publication’s authors
1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51.
2. Scagliotti et al. Oncologist 2009;14(3):253-63.

53. Background (Cont.)
PARAMOUNT Trial: Key Findingsa
In patients with advanced nonsquamous NSCLC,
pemetrexed/cisplatin induction therapy followed by
pemetrexed maintenance significantly improved progression-
free survival (p<.0001) compared with placebo1
Compared with placebo, pemetrexed maintenance arm had a
significantly higher incidence of drug-related Grade > 3
laboratory toxicity (9% vs. <1%; p≤.05)1
aThese findings are the independent opinion of the publication’s authors
1. Paz-Ares et al. Lancet Oncol 2012;13(3):247-255.

54. Objective
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
To compare indirectly the efficacy and safety results
from two Phase 3 trials, JMDB and PARAMOUNT
(induction phase prior to randomization), involving first-
line pemetrexed/cisplatin treatment of chemonaïve
patients with advanced nonsquamous NSCLC

55. Patient Population
1. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51.
2. Scagliotti et al. Oncologist 2009;14(3):253-63.
3. Paz-Ares et al. Lancet Oncol 2012;13(3):247-255.
JMDB trial: Nonsquamous subpopulation (N = 618) from
the pemetrexed/cisplatin treatment group1,2
PARAMOUNT trial: All patients (N = 939) who received
pemetrexed/cisplatin induction therapy (prior to
randomization to pemetrexed continuation maintenance
or placebo)3

56. Study design:
JMDB and PARAMOUNT
aIncludes all patients who received pemetrexed/cisplatin as induction treatment
All patients received vitamin B12, folic acid, and dexamethasone in both trials
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
• Pemetrexed (500 mg/m2)
• Cisplatin (75 mg/m2)
Day 1 every 21 days
Efficacy and safety assessment
of JMDB and PARAMOUNTb
treated population
PARAMOUNT
Inclusion criteria
• Nonsquamous NSCLC
• Stage IIIB/IV
• No prior systemic therapy
• ECOG PS 0/1
up to 4 cycles
• Pemetrexed (500 mg/m2)
• Cisplatin (75 mg/m2)
Day 1 every 21 days
JMDB
Inclusion criteria
• All histologies NSCLC
• Stage IIIB/IV
• No prior systemic therapy
• ECOG PS 0/1
Randomizationa
up to 6 cycles
Nonsquamous
population
Induction Phase
Or
Gemcitabine + cisplatin

57. Baseline Demographics and Disease
Characteristics
JMDB Trial
N = 618
PARAMOUNT Trial
N = 939
Age, median, years 60.7 61.3
Gender, %
Female 36 39
Male 64 61
ECOG PS, %
0 35 32
1 65 68
NSCLC stage, %
IIIB 21 11a
IV 79 90a
Histology, %
Adenocarcinoma 71 87
Large cell carcinoma 12 7
Other or unknown 17 6
aSum is not equal to 100% due to rounding
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

58. JMDB Trial
N = 618
PARAMOUNT Trial
N = 939
Patients received study treatment, n 604 939
Treatment cycles administered
Median (range) 5.0 (1-7) 4.0 (1-4)
Mean (SD) 4.4 (1.8) 3.3 (1.1)
Treatment cycles completeda
≥4 cycles, n (%) 432 (70) 637 (68)
≥6 cycles, n (%) 284 (46) NA
Dose intensity, %b
Pemetrexed 95.1 95.2
Cisplatin 95.1 94.7

59. Response
JMDB Trial
N = 618
n (%)
PARAMOUNT Trial
N = 939
n (%)
Complete response 1 (0.2) 1 (0.1)
Partial response 176 (29) 282 (30)
Response ratea 177 (29)b 283 (30)
Stable disease 217 (35) 417 (44)
Disease control ratec 394 (64) 700 (75)
Progressive disease 158 (26) 114 (12)
Unknown/not done 66 (11) 125 (13)
aResponse rate = complete response + partial response
bResponse was achieved for 90.5% of patients within the first 4 cycles
cDisease control rate = complete response + partial response + stable disease
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

60. Drug-related Toxicity
JMDB Trial
N = 604a
n (%)
PARAMOUNT Trial
N = 939a
n (%)
Drug-related deathsb 6 (1) 11 (1)
Drug-related SAEs 99 (16) 133 (14)
Discontinuations due to AE 66 (11) 51 (5)
≥1 Grade 3/4 drug-relatedc
Laboratory toxicities 129 (21) 129 (14)
Nonlaboratory toxicities 132 (22) 139 (15)
aStudy-drug treated population
bDuring study treatment due to previously described drug-related hematologic, gastrointestinal, and renal toxicity
cGraded according to common terminology criteria for adverse events
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

61. Grade 3/4 Drug-related Hematologic
Toxicitiesa
JMDB Trialb
N = 604
n (%)
PARAMOUNT Trial
N = 939
n (%)
Neutropenia 90 (15) 79 (8)
Anemia 30 (5) 34 (4)
Thrombocytopenia 22 (4) 18 (2)
Leukopenia 25 (4) 10 (1)
aIncludes events occurring on therapy or within 30 days of final study drug dose and
graded according to common terminology criteria for adverse events
bStudy-drug treated population
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

62. Grade 3/4 Drug-related
Nonlaboratory Toxicitiesa
JMDB Trial
N = 604b
n (%)
PARAMOUNT Trial
N = 939
n (%)
Nausea 48 (8) 29 (3)
Fatigue 40 (7) 27 (3)
Vomiting 38 (6) 34 (4)
Anorexia 11 (2) 9 (1)
Febrile neutropenia 8 (1) 11 (1)
Diarrhea 7 (1) 12 (1)
Dehydration 7 (1) 9 (1)
aIncludes events occurring at >1% incidence on therapy or within 30 days of final study drug dose and
graded according to common terminology criteria for adverse events
bStudy-drug treated population
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

63. Supportive Care
JMDB Trial
N = 604a
n (%)
PARAMOUNT Trial
N = 939
n (%)
Antiemetics 89 67
Antibiotics 29 22
Transfusions 15 14
Erythropoiesis-stimulating agents 11 7
G-CSF/GM-CSF 3 7
aStudy-drug treated population
Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.

64. Conclusionsa
Results of the pemetrexed/cisplatin induction therapy of the
PARAMOUNT were consistent with the findings of the
pemetrexed/cisplatin-treated nonsquamous subpopulation of the
JMDB trial1
Response rates and disease control rates with first-line
pemetrexed/cisplatin treatment of advanced nonsquamous NSCLC
were consistent in both trials1
Types of AEs reported in the two trials were similar; however, the
frequency of some of the AEs and the usage of antiemetics was
higher on the JMDB trial, possibly due to the greater number of
cycles of cisplatin administered1
Toxicity profiles in both trials were consistent with the known safety
profiles of pemetrexed/cisplatin2,3
aThese conclusions are the independent opinion of the publication’s authors
1. Scagliotti et al. J Thorac Oncol 2011;6(6 Suppl 2):S1160.
2. Scagliotti et al. J Clin Oncol 2008;26(21):3543-51.
3. Vogelzang et al. J Clin Oncol 2003;21(14):2636-44.

65. Conclusiones
• PARAMOUNT: demuestra eficacia de pemetrexed de
mantenimiento vs placebo:
– Mejoría en la SLP
– Mejoría SG
• Perfil de toxicidad favorable, similar a estudios en
monoterapia previos
• No empeoramiento en calidad de vida ni en PS
• Consumo bajo de recursos

66. Annals of Oncology, 25 de marzo de 2014