1. PARAMOUNT: phase III study of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC.

2. All Chapters at a glance: please click on box to review
Maintenance strategies in non-squamous NSCLC 1
PARAMOUNT:
study design
and objectives 2
PARAMOUNT:
patient & disease characteristics,
drug administration 3
PARAMOUNT:
PFS results 4
PARAMOUNT:
post-discontinuation therapy 5
PARAMOUNT:
safety & tolerability 6
PARAMOUNT: conclusions 7

3. Increase the duration of disease control
Objectives of maintenance therapy1
Maintaining
tolerability
Improve overall survival

4. Tolerance to maintenance drug is known from induction treatment
Maximise
the potential
of the drug used in 1st-line
Potential advantages of continuation maintenance approach2–4
Saves
a drug for subsequent treatment
lines

5. PARAMOUNT: pemetrexed/cisplatin followed by pemetrexed for advanced non-squamous* NSCLC1
2:1 randomisation
pemetrexed†
500 mg/m2 IV + BSC
day 1, q 21 days; n=359
pemetrexed 500 mg/m2 IV +
cisplatin 75 mg/m2
day 1, q 21 days; n=939
Non-squamous* NSCLC patients only
CR, PR, or SD after 4 cycles of pemetrexed/cisplatin
n=539
progressive disease
placebo† + BSC
day 1, q 21 days; n=180
*Adenocarcinoma, large cell carcinoma and other histologies
† Vitamin B12, folic acid and dexamethasone given during induction therapy and in both maintenance arms.
BSC=Best Supportive Care
Patients enrolled if:
• non-squamous* 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)

6. PARAMOUNT: study objectives1
• Progression-free survival (PFS)
Primary objective
Secondary objectives
• Overall survival (OS)
• Objective tumour response rate (RR) (RECIST 1.0)
• Patient-reported outcomes (EQ-5D)
• Resource utilisation
• Adverse events (AEs)

7. PARAMOUNT: patient characteristics (randomised patients)1
placebo
n=180
Median age, yrs
Age <65 yrs
Male
Caucasian
Smoker
Ever smoker
Never smoker
ECOG PS 1
2/3*
*Protocol violations
238
(66%)
201
(56%)
339
(94%)
275
(77%) 82
(23%)
115
(32%)
243
(68%)
(<1%)
112
(62%)
171
(95%)
144
(80%) 34
(19%) 55
(31%)
123 2
(1%)
pemetrexed
n=359 61 62
Caucasian 339 (94%) 171 (95%)

8. PARAMOUNT: disease characteristics (randomised patients)1
placebo
n=180
Disease stage IV*
Histology
Adenocarcinoma/bronchoalveolar
Large cell
Other non-squamous
Best tumour response to induction
CR/PR SD
PD/Unknown†
* Lung Cancer Staging System Version V
† Protocol violations
pemetrexed
n=359
328
310 24 25
166
186 7
(91%)
(86%)
(7%)
(46%)
(52%)
(2%)
161
160 12 8 76 94 10
(89%)
(4%)
(42%)
(6%)
Disease stage IV* (91%) (89%)
Adenocarcinoma/bronchoalveolar (86%) (89%)

9. PARAMOUNT: drug administration (randomised patients)1
Data related to the primary endpoint (PFS) data analysis. Figures are likely to change at the time of the final OS analysis.
pemetrexed
n=359
placebo
n=180
mean # of cycles
patients > 6 cycles
dose intensity
4.9
4.2
23%
14%
95%
n.a.

10. Induction = 4 cycles of pemetrexed/cisplatin
Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1
Progression-free survival (%)
Time (months) 3 6 9 12 15
1.0
0.8
0.9
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Investigator-assessed PFS
Induction = 4 cycles of pemetrexed/cisplatin
NOT reflected in the data endpoints
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
HR=0.62 (95% CI 0.49–0.79); p<0.0001
BSC=Best Supportive Care
Median PFS (95% CI)
Pemetrexed 4.1 ( )
Placebo 2.8 ( )
4.1
2.8
HR 0.62
reduction in the
risk of progression
38%

11. Induction = 4 cycles of pemetrexed/cisplatin
Pemetrexed continuation maintenance demonstrated significant PFS benefit for patients1
Progression-free survival (%)
Time (months) 3 6 9 12 15
1.0
0.8
0.9
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Independently reviewed PFS†
Induction = 4 cycles of pemetrexed/cisplatin
NOT reflected in the data endpoints
pemetrexed + BSC (n=316)
placebo + BSC (n=156)
HR=0.64 (95% CI 0.51–0.81); p<0.0002
† 88% of patients were independently reviewed (472/539); BSC=Best Supportive Care
Median PFS (95% CI)
Pemetrexed 3.9 (3.0–4.2)
Placebo 2.6 (2.2–2.9)
3.9
2.6
HR 0.64

12. Progression-free survival HRs in subgroups1
All
Stage
IIIB IV
Induction response
CR/PR SD
Pre-randomisation ECOG PS 1
Smoking status
Non-smoker
Smoker
Sex
Male
Female
Age (years)
<70
≥70
<65
≥65
Histology
Adenocarcinoma
Large Cell Carcinoma
Other
0.62 ( )
0.55 ( )
0.62 ( )
0.48 ( )
0.74 ( )
0.53 ( )
0.67 ( )
0.41 ( )
0.70 ( )
0.74 ( )
0.49 ( )
0.69 ( )
0.35 ( )
0.70 ( )
0.51 ( )
0.39 ( )
0.64 ( )
0.2
0.4
0.8
1.2
1.6
2.0
0.6
1.4
1.8
Favours pemetrexed
Favours placebo
539 50
489
242
280
170
366
116
419
313
226
447 92
350
189
471 36 32
HR (95% CI) N
Progression-free survival HRs in subgroups1
PFS results were internally consistent; benefit was seen across all subgroups

13. PARAMOUNT: median PFS according to response to induction treatment1
Survival time (months) 1 2 3 5
Response to induction treatment
Complete/Partial
response
n=242, HR=0.48,
( )
Stable disease
n=280, HR=0.74,
( ) 4
Numbers in brackets are the 95% CI values.
pemetrexed (n=166)
pemetrexed (n=186)
4.1 ( )
4.1 ( )
placebo (n=76)
placebo (n=94)
2.6 ( )
3.0 ( )

14. PARAMOUNT: post-discontinuation therapy (PDT-eligible patients)1
placebo
n=122 78
(64%) 45
(37%) 43
(35%) 4
(3%) 2
(2%) 1
(<1%) 6
(5%)
Patients with PDT
Drug name
Erlotinib
Docetaxel
Gemcitabine
Investigational drug
Vinorelbine
Bevacizumab
Cisplatin
Other†
p-value
0.35
0.33
0.27
0.15
0.58
1.00 –
pemetrexed
n=200
116
(58%) 62
(31%) 58
(29%) 15
(8%) 10 8
(4%) 3 13
(7%)
† Systemic therapies administered to 1% or fewer patients in both groups are summarised under “Other”. These therapies included carboplatin, pemetrexed, BIBF 1120, paclitaxel, placebo, aspirin, aflibercept, cyclophosphamide, gefitinib, ifosfamide, vinflunine, and other antineoplastic drugs.
(58%)
(64%)

15. Maintenance therapy with pemetrexed: generally well tolerated1
Overall, toxicity was low in both arms
pemetrexed
n=359
placebo
n=180
Patients with ≥ 1 grade 3/4/5
laboratory toxicity
9%*
n=33
<1%*
n=1
Patients with ≥ 1 grade 3/4/5
non-laboratory toxicity 9%
n=32 4%
n=8
* Difference between treatment groups was significant (Fisher’s exact test p ≤0.05).

16. PARAMOUNT: CTCAEs grade 3/4/5 drug-related toxicities (randomised patients)1†
* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).
† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006)
Alanine aminotransferase, Nausea, Vomiting, Mucositis or Stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4/5 adverse events were reported for less than 1% of patients.
placebo (n=180)
Anaemia
Neutropenia
Fatigue
Pain
Leucopenia
Thrombocytopenia
Infection
Neuropathy
pemetrexed (n=359) 10 20 30
4%* n=16
4%* n=13
2% n=6
1% n=4
4%* n=15
1% n=3
1% n=4
<1% n=1
<1%* n= 1
0%* n= 0
0% n=0
<1%* n= 1
1% n=2
0% n=0
<1% n=1

17. PARAMOUNT: health-related quality of life assessment (EQ-5D)1
Compliance at all time points during maintenance phase was >80%
No statistical differences in EQ-5D index score or visual analog scale were observed between treatment arms
EQ-5D results suggest that patients can tolerate long-term maintenance treatment with pemetrexed while maintaining their QoL

18. PARAMOUNT: conclusions1,10
PARAMOUNT demonstrates a positive risk/benefit ratio for the administration of pemetrexed continuation maintenance1,10
Pemetrexed continuation maintenance therapy offers significantly
improved PFS
Pemetrexed continuation maintenance therapy is well tolerated

19. Pemetrexed continuation maintenance therapy: approach to maximise outcomes for patients1,2
Proven efficacy ✔
Acceptable toxicity ✔
Conveniently administered ✔
Keeps other treatments available ✔

20. Acknowledgements We thank all of the patients and their caregivers
for participating in this trial.

21. References
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