PARAMOUNT: Phase III Study of
Maintenance Pemetrexed (Pem) Plus Best
Supportive Care (BSC) Versus Placebo Plus
BSC Immediately Following Induction
Treatment with Pem Plus Cisplatin for
Advanced Nonsquamous
Non-small Cell Lung Cancer
L. G. Paz-Ares1, F. de Marinis2, M. Dediu3, M. Thomas4, J.L. Pujol5,
P. Bidoli6, O. Molinier7, T.P. Sahoo8, E. Laack9, M. Reck10, J. Corral1,
S. Melemed11, W. John11, N. Chouaki12, A. H. Zimmermann11,
C. Visseren-Grul13, C. Gridelli14
1University
Hospital - Virgen del Rocio, Seville, Spain; 2San Camillo - Forlanini Hospital, Rome, Italy; 3Institute of Oncology,
Bucharest, Romania; 4Clinic for Thoracic Diseases at University Hospital Heidelberg, Heidelberg, Germany; 5Montpellier
Academic Hospital, Montpellier, France; 6Medical Oncology Unit, S. Gerardo Hospital, Monza, Italy; 7Le Mans Regional
Hospital, Le Mans, France; 8Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal, India; 9University Hospital
Hamburg-Eppendorf, Germany; 10Hospital Grosshansdorf, Grosshansdorf, Germany; 11Eli Lilly and Company, Indianapolis,
IN, USA; 12Eli Lilly and Company, Suresnes, Hauts de Seine, France ;
13Eli Lilly and Company, Houten, The Netherlands; 14San Giuseppe Moscati Hospital, Avellino, Italy
PARAMOUNT: Background
 Most patients with NSCLC have stage IIIB/IV disease at the time
of diagnosis 1
 Platinum-based combinations are recommended as first-line
treatment 2
 Pemetrexed has demonstrated efficacy in treating advanced
nonsquamous NSCLC:
─ in combination with cisplatin as a first-line doublet 3
─ as a maintenance agent following a non-pemetrexed platinum
doublet 4
 Maintenance therapy is used to prolong tumor response or
stable disease, with a goal of improving PFS and OS
 Pemetrexed maintenance has not been studied following
pemetrexed-platinum induction in a phase III setting
1
http://seer.cancer.gov/statfacts/html/lungb.html; 2Azzoli CG et al. J Clin Oncol 2009; 27:6251–6266 3Scagliotti GV et al.
J Clin Oncol 2008;26:3543-51.; 4Ciuleanu T et al. Lancet 2009;374:1432-40.
PARAMOUNT: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
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
21 to 42 Days
Maintenance Therapy (Until PD)
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 (PFS)
 Secondary Objectives: OS, RR, QOL, Resource utilization & adverse
events
PARAMOUNT: Investigator Assessed PFS
(from Maintenance)
1.0
Pem + BSC
Survival Probability
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
12
9
6
Time (Months)
15
Patients at Risk
Pem + BSC
N=359
132
57
21
4
0
Placebo + BSC
N=180
52
15
5
0
0
PARAMOUNT: Independently Reviewed PFS
(from Maintenance)
88% of patients were independently reviewed (472/539)
1.0
Pem + BSC
0.9
Placebo + BSC
Survival Probability
0.8
Pemetrexed: median =3.9 mos (3.0-4.2)
Placebo: median =2.6 mos (2.2-2.9)
Log-rank P=0.0002
Unadjusted HR: 0.64 (0.51-0.81)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
Patients at Risk
6
9
Time (Months)
12
15
Pem + BSC
N=316
128
56
16
4
0
Placebo + BSC
N=156
44
13
7
0
0
PARAMOUNT: Investigator Assessed PFS
(from Induction)
1.0
Pem + BSC
0.9
Placebo + BSC
Survival Probability
0.8
Pem: median = 6.90 (6.2-7.5)
Placebo: median = 5.59 (5.5-6.0)
Log Rank p<0.00001
Unadjusted HR : 0.59 (0.47-0.74)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
Time (Months)
Patients at Risk
Pem + BSC
N=359
320
141
59
24
4
0
Placebo + BSC
N=180
157
51
14
5
0
0
PARAMOUNT: Post-discontinuation
therapy (PDT-eligible patients)
Pemetrexed
(N=200)
n (%)
Placebo
(N=122)
n (%)
P Value
116 (58)
78 (64)
0.348
Erlotinib
62 (31)
45 (37)
0.329
Docetaxel
58 (29)
43 (35)
0.266
Gemcitabine
15 (8)
4 (3)
0.147
Investigational drug
10 (5)
4 (3)
0.580
Vinorelbine
8 (4)
2 (2)
0.329
Bevacizumab
3 (2)
1 (0.8)
1.00
Cisplatin
3 (2)
1 (0.8)
1.00
Other
13 (7)
6 (5)
--
Pemetrexed
2 (1.0)
1 (0.8)
1.00
Patients with PDT
Drug Name:
PARAMOUNT: CTCAEs Grade 3/4 Drugrelated Toxicities (Randomized Patients)
Pemetrexed
N=359
(%)
Placebo
N=180
(%)
Fatigue*
4.2
0.6
Anemia*
4.5
0.6
Neutropenia*
3.6
0
Leukopenia
1.7
0
Anorexia
0.3
0
Nausea
0.3
0
Neuropathy-sensory
0.3
0.6
Mucositis/stomatitis
0.3
0
ALT (SGPT)
0.3
0
Grade 3/4 Event
*Statistically significant between arms (Fisher’s exact test P≤0.05)
PARAMOUNT: Conclusions
 PARAMOUNT met its primary endpoint by showing significantly
improved PFS in patients treated with pemetrexed continuation
maintenance therapy as compared to placebo
 The highly significant PFS results (HR = 0.62) demonstrate that
pemetrexed continuation maintenance therapy is an effective
treatment for patients with advanced nonsquamous NSCLC
following pemetrexed plus cisplatin induction therapy
 The independent review was comprehensive (88%) in the
percentage of scans and confirmed the robustness of the
primary endpoint of investigator-assessed PFS
 Pemetrexed had a well-tolerated safety profile, similar to the
previous pemetrexed maintenance trial in NSCLC1
 The study was fully powered for OS; this will be reported when data
are mature
1Ciuleanu
T, et al. Lancet 2009;374:1432-40.