1. Can we select patients most likely to benefit from pemetrexed continuation maintenance?
SEONC00109

2. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
Pemetrexed Arm %Pts Median age (yrs)
Sex/ethnic group Age <65 Male Caucasian
Smoker Ever smoker Never smoker
ECOG PS
Stage IV
Histology Adenocarcinoma Large cell
Induction response CR/PR SD PD/Unknown
Baseline 91
86 7
6 mos 92
89 6
6 mos 92
89 6
12 mos 92
89 7
12 mos 92
89 7
18 mos 92
88 7
18 mos 92
88 7
24mos 90
89 6
24mos 90
89 6

3. Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
Pemetrexed Arm %Pts Median age (yrs)
Sex/ethnic group Age <65 Male Caucasian
Smoker Ever smoker Never smoker
ECOG PS
Stage IV
Histology Adenocarcinoma Large cell
Induction response CR/PR SD PD/Unknown
Baseline 91
86 7
6 mos 92
89 6
12 mos 92
89 7
18 mos 92
88 7
24mos 90
89 6
ECOG PS
Induction response CR/PR SD PD/Unknown

4. OS benefit seen across all subgroups
Baseline characteristics for patients surviving at least 6, 12, 18 and 24 months1
Pemetrexed Arm %Pts Median age (yrs)
Sex/ethnic group Age <65 Male Caucasian
Smoker Ever smoker Never smoker
ECOG PS
Stage IV
Histology Adenocarcinoma Large cell
Induction response CR/PR SD PD/Unknown
OS benefit seen across all subgroups
Baseline 91
86 7
6 mos 92
89 6
12 mos 92
89 7
18 mos 92
88 7
24mos 90
89 6
PARAMOUNT data shows

5. Maintenance Treatment Decision
Basis for maintenance treatment decision
Maintenance Treatment Decision
Overall treatment goals
Performance
status
Tolerance to induction therapy

6. Did PARAMOUNT assess patients’ Quality of Life?

7. 1 2 PARAMOUNT: study objectives2 Primary objective Secondary objective
Progression-free survival (PFS) 1
Primary objective 2
Overall survival (OS)
Objective tumor resposne rate (RR) (RESIST 1.0)
Patient-reported outcomes (EQ-5D)
Resource utilisation
Adverse events (AEs)
Secondary objective

8. EQ-5D: EuroQol 5-dimensional questionnaire3
By placing a tick in one box in each group below, please indicate which statements best describe your own health state today.
Mobility I have no problems in walking about ☐ I have some problems in walking about ☐ I am confined to bed ☐
Self-Care I have no problems with self-care ☐ I have some problems washing or dressing myself ☐ I am unable to wash or dress myself ☐
Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities ☐ I have some problems with performing my usual activities ☐ I am unable to perform my usual activities ☐
Pain/Discomfort I have no pain or discomfort ☐ I have moderate pain or discomfort ☐ I have extreme pain or discomfort ☐
Anxiety/Depression I am not anxious or depressed ☐ I am moderately anxious or depressed ☐ I am extremely anxious or depressed ☐ ✔
Best imaginable health state
Worst imaginable health state
VAS (Visual Analog Scale)

9. High EQ-5D compliance3 84.3% 80.9% 79.4% Pemetrexed arm Placeboarm
Induction
84.3%
80.9%
79.4%

10. PARAMOUNT: EQ-5D results and safety data
>10 MTC Cycles
Grade 1
Grade 2
Grade 3/4
Event (%)
PEM
PBO
Fatigue 15 13 8 6
Renal* 4 1
Rash
Edema
Anemia 12 7
Neutropenia 11

11. What are the QoL and safety results in PARAMOUNT?

12. QoL and safety in PARAMOUNT
Good Overall QoL during maintenance
Induction therapy Maintenance therapy

13. QoL and safety in PARAMOUNT
Good Overall QoL during maintenance
Induction therapy Maintenance therapy

14. Low rate of discontinuations due to adverse events3
QoL and safety in PARAMOUNT
Rate of AEs possibly related to maintenance pemetrexed vs placebo2,†
Low rate of discontinuations due to adverse events3
9.2% for maintenance pemetrexed % for placebo
Anaemia
Neutropenia
Leucopenia
Thrombo-cytopenia
Fatigue
Infection
Pain
Neuropathy
Pemetrexed
(n=359)
placebo
(n=180)
4%* n=16
<1%* n=1
4%* n=13
0%* n=1
2% n=6
1% n=4
0% n=1
4%* n=15
<1%* n=1
1% n=4
1% n=2
1% n=3
0% n=1
1% n=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 adverse events were reported for less than 1% of patients.
Adapted from: 1,2

15. % Change from Baseline in ECOG Performance Status
QoL and safety in PARAMOUNT
Change in ECOG PS from randomisation to last maintenance treatment3
100 90 80 70 60 50 40 30 20 10
% Change from Baseline in ECOG Performance Status
Pemetrexed
Placebo
Worse
No Change
Better
14.7%
12.6%
77.8%
77.3%
7.5%
10.2%
* 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 adverse events were reported for less than 1% of patients.
Adapted from: 1,2

16. QoL and safety in PARAMOUNT
EQ-5D index scores: Quality of life was maintained throughout treatment3
0.8
0.7
0.6
Improvement
Mean score
Induction cycles
* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3

17. QoL and safety in PARAMOUNT
EQ-5D index scores: Quality of life was maintained throughout treatment3
0.8
0.7
0.6
Improvement
Mean score
Induction cycles
Maintenance cycles
Pemetrexed
Placebo
* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3

18. QoL and safety in PARAMOUNT
VAS: No overall treatment differences in quality of life were observed during induction3
0.8
0.7
0.6
Improvement
Mean score
Induction cycles
Maintenance cycles
Pemetrexed
Placebo
† p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3

19. QoL and safety in PARAMOUNT
VAS: No overall treatment differences in quality of life were observed during induction3
0.8
0.7
0.6
Improvement
Mean score
Induction cycles
Maintenance cycles
Pemetrexed
Placebo
† p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adapted from: 3

20. QoL and safety in PARAMOUNT
Survival significantly improved with pemetrexed continuation maintenance therapy vs placebo5
HR=0.78 (95% CI: )5
No statistical differences observed in patient-reported QoL between maintenance treatment arms3

21. Does long-term pemetrexed maintenance have an impact on QoL?

22. Induction = 4 cycles of pemetrexed/cisplatin
Pemetrexed/cisplatin followed by pemetrexed demonstrated a statistically significant OS benefit in advanced non-squamous NSCLC6
Time from randomisation (months) 6 12 18 24 30
1.0
0.8
0.9
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Overall survival from randomisation
Induction = 4 cycles of pemetrexed/cisplatin
NOT reflected in the data endpoints
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
HR=0.78 (95% CI 0.64–0.96); p=0.0195 36
Survival probabality (%)
24-months
survival rate
32%
32%
21%

23. Summary of maintenance therapy4
Pemetrexed
(n=359)
Placebo
(n=180)
Median number of cycles (range)
4 (1–44)
4 (1–38)
Mean number of cycles 8 5
% of pts receiving MTC
≤10 cycles 76 90
>10 cycles 24 9
% discontinuations due to possibly drug-related AE 12 4
Median number of cycles (range)
4 (1–44)
4 (1–38)
Mean number of cycles 8 5
>10 cycles 24 9
Adapted from: 4

24. Possible drug-related CTCAEs occurring
in all cycles of maintenance therapy4
>10 MTC Cycles
Grade 1
Grade 2
Grade 3/4
Event (%)
PEM
PBO
Fatigue 15 13 8 6
Renal* 4 1
Rash
Edema
Anemia 12 7
Neutropenia 11
* creatinine, GFR, ranal failure, and genitourinary-other.

25. No significant differences in drug-related
grade 3/5 toxicities – except grade 3/4 neutropenia3
maintenance cycles ≤6
>6
Neutropenia Grade 3/4
2.2%
8.3%
p=0.015
Infections Grade 3/5
2.9%
1.2%
p=0.691

26. Possible drug-related grade 1/2 adverse events3
maintenance cycles ≤6
>6
Nausea
Neutropenia
Sensory neuropathy
Ocular/visual events
Headache
8.7%
16.7%
p=0.044
2.5%
11.9%
p=0.001
1.5%
6.0%
p=0.036
2.5%
13.1%
p=0.001
0.4%
3.6%
p=0.041

27. Majority of patients maintain QoL
Long-term pemetrexed maintenance impact on QoL
EQ-5D results
Pemetrexed well-tolerated safety profile
PS changes
Majority of patients maintain QoL

28. Are PARAMOUNT QoL and safety results consistent with JMEN?

29. PARAMOUNT JMEN Maintenance pemetrexed in PARAMOUNT2 and JMEN7,8
Paz-Ares et al. 2012
Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial
• Well-tolerated safety profile, consistently reported
• QoL is well maintained and similar to placebo
JMEN
Ciuleanu et al. 2009
Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study

30. JMEN: Drug-related toxic effects8
Grades 3 or 4
Pemetrexed
Placebo
Hematologic toxicities
Neutropenia* 13
(3%)
Anemia 12 1
(<1%)
Leukoperia 7
(2%)
Non-hematologic toxicities
ALT
AST
Fatigue† 22
(5%)
Anorexia 8
Infection
Diarrhoea 2
Nausea 4
Vomiting
Sensory neuropathy 3
Mukositis stomatitis
Rash
Neutropenia* 13
(3%)
Fatigue† 22
(5%) 1
(<1%)
ALT=alanine aminotransferase. AST=aspartate aminotransferase. *p<0.05 for grade 3 or 4 rates of neutropenia and fatigue between study groups.
†Updated safety analysis done 6 months after initial analysis of progression-free survival. For the purpose of this table, a cut-off of 5% was used for inclusion of all events for which the investigator considered a possible link with pemetrexed.
Adapted from: 4

31. PARAMOUNT: CTCAEs possibly related to study drug during maintenance3
Grades 3 or 4
Pemetrexed
Placebo
Toxicity*
Laboratory
Anemia 16 1
(0.6%)
Neutropenia 13
Non-laboratory
Fatigue (asthenia, lethargy, malaise) 15
(4%)
Anorexia
(0.3%)
Constipation
Diarrhea
Mucositis stomatitis
Nausea
Vomoting
Edema
Sensory neuropathy
Watery eye (epiphora, tearing)
Pain 3
(0.8%)
Anemia 16 1
(0.6%)
Neutropenia 13
Fatigue (asthenia, lethargy, malaise) 15
(4%) 1
(0.6%)
Toxicities were reported using CTCAE version 3.0 (National Cancer Institute 2006). Toxicities occurring in ≥ 3% of patients on either or both arms are listed. Two grade 5 events (deaths) considered possibly related to study drug occurred during the maintenance period: pemetrexed – pneumonia; placebo-sudden death. Difference between treatment arms is statistically significant (Fisher‘s exact test p ≤0.05). CTCAE, Common Terminology Criteria for Adverse Events.
Adapted from: 4

32. QoL in PARAMOUNT and JMEN
QoL Measurement
PARAMOUNT3
EQ-5D
JMEN7
LCSS

33. Overall quality of life
QoL in PARAMOUNT and JMEN
Mean maximum improvement in LCSS items7 12 10 8 6 4 2
Mean maximum improvement (mm)
Pemetrexed
Placebo
Inter-ference with activity
Symptom distress
Pain
Haemo-lysis
Dyspnoea
Coogh
Loss of appetite
p=0.592
p=0.533
p=0.039
p=0.831
p=0.204
p=0.192
p=0.136
Overall quality of life
p=0.897
Fatigue
p=0.959
Overall quality of life
p=0.959
Fatigue
p=0.897
Adapted from: 1,2

34. Induction = 4 cycles of pemetrexed/cisplatin
QoL in PARAMOUNT and JMEN
Patients are able to maintain their overall good quality of life3
Quality of lifeBest
imaginable health state
Worst imaginable health state
Time from randomisation (months) 6 12 18 24 30
1.0
0.8
0.9
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Overall survival from randomisation
Induction = 4 cycles of pemetrexed/cisplatin
NOT reflected in the data endpoints
pemetrexed + BSC (n=359)
placebo + BSC (n=180)
HR=0.78 (95% CI 0.64–0.96); p=0.0195
32%
21% 36
24-months
survival rate
Survival probabality (%)

35. How robust are the findings of PARAMOUNT to support a change in the treatment paradigm?

36. The robust PARAMOUNT results are based on a number of valid points
The robust findings of PARAMOUNT and their
likely impact on the current treatment paradigm2,5,10
The robust PARAMOUNT results are based on a number of valid points

37. OS: 16.9 vs 14.0 months from induction
The robust findings of PARAMOUNT and their
likely impact on the current treatment paradigm2,5,10
PFS: 4.1 vs 2.8 months
HR 0.62 (95% CI ; p<0.0001)
OS: 16.9 vs 14.0 months from induction
HR 0.78 (95% CI ; p=0.0195)
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance

38. Survival probability (%)
The robust findings of PARAMOUNT and their
likely impact on the current treatment paradigm2,5,10
PFS: Primary endpoint
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Survival probability (%)
pemetrexed + BSC (n=358)
placebo + BSC (n=180)
HR 0.62 (0.49–0.79)
Time (months)
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
Investigator-determined PFS results confirmed by independent review

39. CR/PR patients: OS HR=0.81 SD patients: OS HR=0.76
The robust findings of PARAMOUNT and their
likely impact on the current treatment paradigm2,5,10
Favours pemetrexed Favours placebo
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
Investigator-determined PFS results confirmed by independent review
Subgroup OS Hazard Ratio N
HR (95% CI)
All
539
0.78
Stage IV
490
0.79
IIIB 49
0.82
Induction response
CR/PR
234
0.81 SD
285
0.76
Pre-randomisation ECOG PS 1
363
173
0.70
Smoking status
Never-smoker
117
0.75
Smoker
418
0.83
Sex
Male
313
Female
226
0.73
Age (years)
<70
447
≥70 92
0.89
<65
350
≥65
189
0.71
Histology
Adenocarcinoma
471
0.80
Large cell carcinoma 36
0.44
Other 32
CR/PR patients: OS HR=0.81
SD patients: OS HR=0.76
Relative treatment effect of pemetrexed consistent across subgroups

40. The robust findings of PARAMOUNT and their
likely impact on the current treatment paradigm2,5,10
placebo
(n=180) %* 72 43 8 6 4 3 2
pemetrexed
(n=359) %* 64 40 32 10 5 1
Patients with PDT
Drug name
Erlotinib
Docetaxel†
Gemcitabine
Vinorelbine
Investigational drug
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
* Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown.
† Only docetaxel usage differed significantly between arms (p=0.013).
Direction of magnitude of PFS and OS results are consistent and favour pemetrexed continuation maintenance
Investigator-determined PFS results confirmed by independent review
Relative treatment effect of pemetrexed consistent across subgroups
Post-discontinuation treatment options were well balanced between the two arms

41. What are the key takeaways for clinical practice?

42. Key PARAMOUNT takeaways2 4 1 3
Results confirm the importance of choosing the best treatment up-front, based on histology and other patient characteristics2,10
OS Benefit consistent across all sub-groups, with acceptable toxicity2,10
Significant OS benefit in favor of Pemetrexed Continuation Maintenance10
PARAMOUNT: first study to show that Continuation Maintenance has an impact on disease course10

43. References
Reck M et al. PARAMOUNT: Descriptive subgroup analyses of final overall survival (OS) for the phase III study of maintenance pemetrexed (PEM) versus placebo (PLB) following induction treatment with PEM plus cisplatin (CIS) for advanced nonsquamous (NS) non-small cell lung cancer. ESMO Congress, Vienna, Austria, Abstract 1235PD.
Paz-Ares L et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012;13:
Gridelli C et al. 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. J Thorac Oncol. 2012;7(11):
Pujol JL et al. Updated safety and quality of life results of PARAMOUNT study: maintenance pemetrexed + best supportive care (BSC) vs placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. ESMO Congress, Vienna, Austria, Abstract 3376.
Paz-Ares L et al. PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (PLB) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. November 2012.
Belani CP et al. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 2012;13:
Ciuleanu T et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:
Hanna N et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.