1. Study JMDB - A Randomised Phase III Trial of Cisplatin + Pemetrexed vs
Study JMDB - A Randomised Phase III Trial of Cisplatin + Pemetrexed vs. Cisplatin + Gemcitabine in Locally Advanced or Metastatic Non-small Cell Lung Cancer
(Scagliotti et al, 2007)
Prescribing information can be found on the last slide
IEALM00180 November 2012

2. Current indications for ALIMTA (EU)1
Regimen
First-line Non-squamous NSCLC
Alimta in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology
The recommended dose of ALIMTA is 500mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75mg/m2 BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle.
Second-line Non-squamous NSCLC
ALIMTA is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non‑small cell lung cancer other than predominantly squamous cell histology
In patients treated for non‑small cell lung cancer after prior chemotherapy, the recommended dose of ALIMTA is 500mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
Malignant pleural mesothelioma (MPM)
ALIMTA in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.
Maintenance Therapy in Non-squamous NSCLC
ALIMTA is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. First-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel
1. Refer to Summary of Product Characteristics for full Prescribing Information

3. ALIMTA® (Pemetrexed) Mechanism of Action*1
ALIMTA is a folate analog metabolic inhibitor that exerts its action by disrupting folate‑dependent metabolic processes essential for cell replication by inhibiting folate‑dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. In-vitro studies have shown that pemetrexed inhibits:
Glycinamide ribonucleotide formyltransferase (GARFT)
Dihydrofolate reductase (DHFR)
Thymidylate synthase (TS)
ALIMTA is taken into cells by membrane carriers such as the reduced folate carrier, membrane folate binding protein transport systems. Once in the cell, Pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase.
The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.
Polyglutamation is a time‑ and concentration‑dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues.
Polyglutamated metabolites are thought to have an increased intracellular half‑life resulting in prolonged drug action in malignant cells.
*As determined through in-vitro studies
1. ALIMTA Summary of Product Characteristics. Eli Lilly and Co; February 2010.

4. ALIMTA® (Pemetrexed): Mechanism of Action1
1. Robinson DM, et al.American Journal of Cancer (6):

5. JMDB Background (Scagliotti et al, 2007)
Cisplatin/Gemcitabine is an effective, widely-used reference regimen for the first-line treatment of advanced NSCLC1
Pemetrexed is one of the standards of care for second-line treatment of NSCLC2
Cisplatin/Pemetrexed is the standard of care for the management of malignant pleural mesothelioma
Phase II studies of Pemetrexed plus platinum compounds have shown activity in advanced NSCLC3,4
1. Le Chevalier T, et al. Lung Cancer (1): Hanna N, et al. J Clin Oncol (9): Scagliotti GV et al. Clin Cancer Res (2 Pt 1): Zinner RG, et al. Cancer (11):

6. JMDB Background (Scagliotti et al, 2007)
Pemetrexed is a multitargeted antifolate which inhibits TS, DHFR and GARFT1
TS expression is lower in non-squamous tumours2
Lower intratumoural TS levels increase chemosensitivity to pemetrexed3,4
1.ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. January Ceppi P et al, Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107: Eismann U et al, Pemetrexed: mRNA expression of the target genes TS, GARFT and DHFR correlates with the in-vitro chemosensitivity of human solid tumours. Int J Clin Pharmacol Ther 43: , Hanauske AR et al, In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression. Invest New Drugs 25(5): , 2007

7. JMDB (Scagliotti et al, 2007) – Study Design1
Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1
Randomization Factors
Stage
Performance status
Gender
Histologic vs cytologic diagnosis
History of brain metastases R
Each cycle repeated q3 weeks up to 6 cycles
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
Vitamin B12, folate, and dexamethasone given in both arms
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

8. JMDB (Scagliotti et al, 2007) – Main Inclusion Criteria1
Histologic or cytologic diagnosis of NSCLC stage IIIB/IV
At least 1 measurable lesion per RECIST
ECOG PS 0-1
At least 18 years of age
Adequate organ function
Prior radiation allowed to <25% of bone marrow if completed at least 4 weeks before enrollment
Estimated life expectancy of 12 weeks
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

9. JMDB (Scagliotti et al, 2007) – Main Exclusion Criteria1
Symptomatic brain metastases
Peripheral neuropathy grade 1
Weight loss 10% over previous 6 weeks
Uncontrolled pleural effusions
Prior systemic chemotherapy
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

10. JMDB (Scagliotti et al, 2007) – Endpoints1
Primary Endpoint
Overall survival
Secondary Endpoints
Response rate
Duration of response
Progression-free survival
Time to progressive disease
Time to treatment failure
Toxicity
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

11. JMDB (Scagliotti et al, 2007) – Study Statistics1
Non-inferiority study design - Fixed Margin Method
80% power to reject H0. H0 is that Cisplatin plus Gemcitabine would provide a 15% reduction in the risk of death over Cisplatin plus Pemetrexed
H0 = HR (upper 95% CI) 1.176 vs HA < 1.176
Assuming HR = 1.0, 1190 deaths needed
Randomize 850 patients per arm, 30% censored
Pre-specified subset analyses: randomization factors plus age, ethnicity, smoking & histology
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

12. JMDB (Scagliotti et al, 2007) – Main Patient Characteristics1
Pemetrexed/Cisplatin (N=862)
Gemcitabine/Cisplatin (N=863)
Median age (range)
61.1 (29–83)
61.0 (26–79)
Age < 65 years
541 (62.8%)
577 (66.9%)
Males
605 (70.2%)
605 (70.1%)
ECOG PS 1
556 (64.5%)
554 (64.2%)
Never-smokers
128 (14.8%)
122 (14.1%)
Caucasians
669(77.6%)
680(78.8%)
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

13. JMDB (Scagliotti et al, 2007) – Main Disease Characteristics1
Cis/Pem
N=862
Cis/Gem
N=863
Adenocarcinoma
Squamous cell
Large cell
NSCLC, NOS
436 (50.6%)
244 (28.3%)
76 (8.8%)
106 (12.3%)
411 (47.6%)
229 (26.5%)
77 (8.9%)
146 (16.9%)
Stage IV
Stage IIIB (all)
Stage IIIB (wet only)
657 (76.2%)
205 (23.8%)
67 (7.8%)
653 (75.7%)
210 (24.3%)
51 (6.0%)
Brain metastases
17 (2.0%)
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

14. JMDB (Scagliotti et al, 2007) – CTC Grade 3 & 4 Drug-related Toxicities*1
Cis/Pem N=839
Cis/Gem N=830
P-value
Neutropenia
127 (15.1%)
222 (26.7%)
< 0.001
Anaemia
47(5.6%)
82 (9.9%)
0.001
Thrombocytopenia
34 (4.1%)
105 (12.7%)
Leukocytes
40 (4.8%)
63 (7.6%)
0.019
Febrile neutropenia
11 (1.3%)
31 (3.7%)
0.002
Alopecia (any grade)
100 (11.9%)
178 (21.4%)
Nausea
60 (7.2%)
32 (3.9%)
0.004
Vomiting
51 (6.1%)
1.000
Fatigue
56 (6.7%)
41 (4.9%)
0.143
Dehydration (any grade)
30 (3.6%)
17 (2.0%)
0.075
*Includes toxicities reported in at least 3% of patients in at least one arm.
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

15. JMDB (Scagliotti et al, 2007) – Transfusions and Supportive Care1
% of Patients
Treatment
Cis/Pem N=839
Cis/Gem N=830
P-value
Any transfusion
Platelet
Red Blood Cell
138 (16.4%)
15 (1.8%)
135 (16.1%)
240 (28.9%)
37 (4.5%)
227 (27.3%)
< 0.001
0.002
Erythropoiesis Stimulating Agents*
90 (10.4%)
156 (18.1%)
G-CSF/GM-CSF*
27 (3.1%)
53 (6.1%)
0.004
*Based on intent–to-treat population
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
Version:
Modified by: ; Date:

16. JMDB (Scagliotti et al, 2007) – Drug Delivery1
Cis/Pem N=839
Cis/Gem N=830
Median no. cycles
5.0
Cycles delayed*
315 (8.6%)
408 (11.3 %)
Doses reduced*
Cis 64 (1.8%)
Pem 54 (1.5%)
Cis 154 (4.2%)
Gem 362 (10.0%)
Gem day-8 omission*
Not Applicable
339 (9.3%)
Relative dose intensity
Cis 95.0%
Pem 94.8%
Cis 93.5%
Gem 85.8%
* % of total cycles
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

17. JMDB (Scagliotti et al, 2007) – Response Rates1
Cis/Pem N=762
Cis/Gem N=755
P-value CR
2 (0.3%)
3 (0.4%)
0.647 PR
231 (30.3%)
210 (27.8%)
0.284 SD
314 (41.2%)
346 (45.8%)
0.070 PD
174 (22.8%)
155 (20.5%)
0.276
ORR (95% CI)
233 (30.6%) (27.3, 33.9%)
213 (28.2%) (25.0, 31.4%)
0.312
Duration of response
4.5 months
(4.27, 5.32)
5.1 months
(4.57, 5.52)
0.198
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

18. JMDB (Scagliotti et al, 2007) – Overall Survival (Total population)1
ALIMTA + Cisplatin
(N=862)
GEMZAR + Cisplatin
(N=863)
Median OS (95% CI)
10.3 mos
(9.8, 11.2)
(9.6, 10.9)
Adjusted HR (95% CI)
0.94 (0.84, 1.05)
p<0.001*
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

19. JMDB (Scagliotti et al, 2007) – Progression-free Survival (PFS) in Overall Population1
ALIMTA + Cisplatin
(N=862)
GEMZAR + Cisplatin
(N=863)
Median PFS (95% CI)
4.8 mos
(4.6, 5.3)
5.1 mos
(4.6, 5.5)
Adjusted HR (95% CI)
1.04 (0.94, 1.15)
p=0.008*
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

20. JMDB (Scagliotti et al, 2007) – Overall Survival: Adenocarcinoma or Large Cell1
ALIMTA + Cisplatin
(N=512)
GEMZAR + Cisplatin
(N=488)
Median (95% CI)
11.8 mos
(10.4, 13.2)
10.4 mos
(9.6, 11.2)
Adjusted HR (95% CI)
0.81 (0.70, 0.94)
p=0.005*
*Superiority p-value.
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

21. JMDB (Scagliotti et al, 2007) – Progression Free Survival (PFS): Adenocarcinoma or Large Cell1
ALIMTA + Cisplatin
(N=512)
GEMZAR + Cisplatin
(N=488)
Median PFS
(95% CI)
5.3 mos
(4.8, 5.7)
4.7 mos
(4.4, 5.4)
Adjusted HR (95% CI)
0.90 (0.79,1.02)
p=0.096*
*Superiority p-value; Data on file. Eli Lilly and Company.
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

22. JMDB (Manegold et al, 2007) – Efficacy by Histology1
MST*, mos
Adjusted
P-value
HR (95% CI)
PFS#, mos
RR**, %
C/P
C/G
Adeno
(n=847)
12.6
10.9
P= (0.71, 0.99)
5.5
5.0
P= (0.78, 1.03)
31.9
24.5
0.024
Large Cell
(n=153)
10.4
6.7
P= (0.48, 0.96)
4.5
4.2
P= (0.65, 1.24)
31.3
30.9
0.954
Squamous
(n=473)
9.4
10.8
P= (1.00, 1.51)
4.4
P= (1.12, 1.65)
26.9
36.7
0.033
NSCLC, NOS
(n=252)
8.6
9.2
P= (0.81, 1.45)
5.6
P= (0.99, 1.67)
33.0
24.2
0.156
*MST=Median Survival Time #PFS=Progression Free Survival **RR=Response Rate
Manegold C et al, Presented at 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.

23. JMDB (Scagliotti et al, 2007) – Systemic Post-study Therapy1
Drug name
Cis/Pem N=862
Cis/Gem N=863
P-value
Any post-study treatment
453 (52.6%)
484 (56.1%)
0.147
Gemcitabine
144 (16.7%)
74 (8.6%)
< 0.001
Pemetrexed
30 (3.5%)
116 (13.4%)
Cisplatin
53 (6.1%)
34 (3.9%)
0.037
Carboplatin
73 (8.5%)
84 (9.7%)
0.403
Docetaxel
219 (25.4%)
238 (27.6%)
0.326
Paclitaxel
42 (4.9%)
37 (4.3%)
0.567
Vinorelbine
63 (7.3%)
64 (7.4%)
1.000
Bevacizumab
9 (1.0%)
6 (0.7%)
0.452
Cetuximab
1 (0.1%)
2 (0.2%)
TKI (Erlotinib or Gefitinib)
215 (24.9%)
194 (22.5%)
0.235
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

24. JMDB (Scagliotti et al, 2007) – Subgroup Analyses Forest Plot1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

25. JMDB (Scagliotti et al, 2007) – Prognostic Variables*1
Subgroups
HR (95% CI)
Superiority P-value
Females vs males
0.76 (0.67, 0.86)
< 0.001
Ever/Former- vs never-smoker
1.74 (1.44, 2.09)
Age (continuous)
1.00 (0.99, 1.00)
0.656
Caucasian vs others
1.36 (1.18, 1.57)
E/SE Asian vs others
0.65 (0.54, 0.78)
ECOG PS 0 vs 1
0.65 (0.58, 0.73)
Stage IIIB vs IV
0.82 (0.71, 0.93)
0.003
Histo vs Cyto Dx
1.02 (0.91, 1.15)
0.693
Adeno vs others
0.75 (0.67, 0.84)
Squamous cell vs others
1.12 (0.98, 1.27)
0.088
Large cell vs others
1.29 (1.07, 1.54)
0.007
*From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

26. JMDB (Scagliotti et al, 2008) Dosing and administration: 1st-line treatment of NSCLC1
Physician
Cycle 1
Cycle 2
Vitamin B μg IM (once during pre-treatment, then once after every 3rd cycle)
ALIMTA 500 mg/m2 IV over 10 minutes (every 21 days)
Cisplatin 75 mg/m2 over 2 hours (every 21 days)
Day -7 -6 -5 -4 -3 -2 -1 DD +1 +2 +3 +4 +5 +6 +7 +8 +9
+10
+11
+12
+13
+14
+15
+16
+17
+18
+19
+20
Patient
Cycle 1
Cycle 2
Folic Acid μg PO daily from Day-7 until 20 days after last ALIMTA infusion
Dexamethasone (or equivalent) 4 mg PO BID for 3 days
Day -7 -6 -5 -4 -3 -2 -1 DD +1 +2 +3 +4 +5 +6 +7 +8 +9
+10
+11
+12
+13
+14
+15
+16
+17
+18
+19
+20
ALIMTA Summary of Product Characteristics (Eli Lilly, 2010).

27. Dosing modifications for ALIMTA® (Pemetrexed) injection as a single agent or in combination with cisplatin1
1. ALIMTA Summary of Product Characteristics. Eli Lilly and Company Limited. July 2009
UKALM00065 October 2009

28. Summary
In this large randomized phase III trial concluded in first-line advanced NSCLC, Pemetrexed/cisplatin demonstrated similar overall survival compared to Gemcitabine/cisplatin (HR=0.94) in the ITT population and met its primary endpoint.
Pemetrexed/cisplatin demonstrates improved efficacy in non squamous population compared to Gemcitabine/cisplatin.
Pemetrexed/cisplatin provided tolerability advantages over Gemcitabine/cisplatin by demonstrating fewer Grades 3/4 events for select hematologic toxicities (anaemia, neutropenia, thrombocytopenia, febrile neutropenia).
Patients receiving Pemetrexed/cisplatin required fewer transfusions (RBC and platelet) and were less dependent on haematopoietic growth factors compared with Gemcitabine/cisplatin.
This is the first phase III NSCLC trial to report survival differences for a platinum doublet based on histology.
A prespecified analysis of the impact of NSCLC histology on overall survival was examined.
Clinically relevant differences in survival according to histology were observed.
This difference in treatment effect for Pemetrexed based on histology was also observed in a post-hoc analysis of the single-agent, second-line study.

29. Backup
UKALM00065 October 2009

30. ALIMTA/Cisplatin (N=839) GEMZAR/Cisplatin (N=830)
Dose Intensity: ALIMTA (Pemetrexed for injection)/cisplatin vs GEMZAR (Gemcitabine HCl for injection)/cisplatin1
ALIMTA/Cisplatin (N=839)
GEMZAR/Cisplatin (N=830)
Median cycles/patient (range)
5.0 (1–7a)
5.0 (1–8b)
Total cycles administered
3648c
3626c
% of total cycles delayed
8.6%
11.3%
Dose adjustments
Doses reduced on day 1 (%)
ALIMTA: 1.5% Cisplatin: 1.8%
GEMZAR: 10% Cisplatin: 4.2%
Doses omitted on day 8 (%)
Not applicable
GEMZAR: 9.3%
Relative dose intensity
ALIMTA: 94.8%
Cisplatin: 95.0%
GEMZAR: 85.8%
Cisplatin: 93.5%
aOne patient on ALIMTA/cisplatin arm received more than 6 cycles.
bFour patients on GEMZAR/cisplatin arm received more than 6 cycles.
cClinical Trials Registry available at (accessed April 27, 2008).
1. Scagliotti GV, et al. J Clin Oncol

31. 1st line NSCLC: Recent plateau of efficacy
1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311: Cardenal F et al: Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 12:12-18, Sandler AB et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18: , Scagliotti et al: Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 20: , Schiller JH et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, Sandler A et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355: , Scagliotti GV et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26: , 2008

32. JMDB (Scagliotti et al, 2008) – Patients Enrolled by Geographic Region1
1. Manegold C et al, Presented at 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.