1. Non-small Cell Lung Cancer
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

2. 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 2Azzoli CG et al. J Clin Oncol 2009; 27:6251–6266 3Scagliotti GV et al. J Clin Oncol 2008;26: ; 4Ciuleanu T et al. Lancet 2009;374:

3. PARAMOUNT: Study Design
Study Treatment Period
Progression
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 (PFS)
Secondary Objectives: OS, RR, QOL, Resource utilization & adverse events

4. PARAMOUNT: Investigator Assessed PFS (from Maintenance)
Pem + BSC
Placebo + BSC
Pemetrexed: median =4.1 mos ( )
Placebo: median =2.8 mos ( )
Log-rank P=
Unadjusted HR: 0.62 ( )
Patients at Risk
Pem + BSC
N=359
132 57 21 4
Placebo + BSC
N=180 52 15 5

5. PARAMOUNT: Independently Reviewed PFS (from Maintenance)
88% of patients were independently reviewed (472/539)
Pem + BSC
Placebo + BSC
Pemetrexed: median =3.9 mos ( )
Placebo: median =2.6 mos ( )
Log-rank P=0.0002
Unadjusted HR: 0.64 ( )
Patients at Risk
Pem + BSC
N=316
128 56 16 4
Placebo + BSC
N=156 44 13 7

6. PARAMOUNT: Investigator Assessed PFS (from Induction)
Pem + BSC
Placebo + BSC
Pem: median = 6.90 ( )
Placebo: median = 5.59 ( )
Log Rank p<
Unadjusted HR : 0.59 ( )
Patients at Risk
Pem + BSC
N=359
320
141 59 24 4
Placebo + BSC
N=180
157 51 14 5

7. PARAMOUNT: Post-discontinuation therapy (PDT-eligible patients)
Pemetrexed
(N=200)
n (%)
Placebo
(N=122)
P Value
Patients with PDT
116 (58)
78 (64)
0.348
Drug Name:
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)
0.580
Vinorelbine
8 (4)
2 (2)
Bevacizumab
3 (2)
1 (0.8)
1.00
Cisplatin
Other
13 (7)
6 (5) --
2 (1.0)
Postdiscontinuation therapy (PDT) was administered at the discretion of the investigator. A similar percentage of patients on both arms received PDT (pemetrexed: 58%; placebo: 64%; P=0.348). There were 217 patients who did not receive PDT at the time of this analysis; 179 (82%) of the 217 patients were still receiving maintenance treatment at this time. The PDT selections were well balanced between the treatment arms.
Note: In the table in this slide, percentages are based on the population of patients who received postdiscontinuation therapy, plus any other patients who were alive 30 days after study treatment discontinuation (defined as “PDT eligible patients”).
Note also: Systemic therapies administered to ≤1% of patients on both arms are summarized under “Other”. These therapies included: carboplatin, pemetrexed, BIBF 1120, paclitaxel, placebo, acetylsalicylic acid (aspirin), aflibercept, cyclophosphamide, gefitinib, ifosfamide, vinflunine, and other antineoplastic agents.

8. PARAMOUNT: CTCAEs Grade 3/4 Drug-related Toxicities (Randomized Patients)
Grade 3/4 Event
Pemetrexed
N=359
(%)
Placebo
N=180
Fatigue*
4.2
0.6
Anemia*
4.5
Neutropenia*
3.6
Leukopenia
1.7
Anorexia
0.3
Nausea
Neuropathy-sensory
Mucositis/stomatitis
ALT (SGPT)
*Statistically significant between arms (Fisher’s exact test P≤0.05)

9. 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: