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
21. Refer to Summary of Product Characteristics for full Prescribing Information
Current indications for ALIMTA (EU)1
Indication Regimen
First-line Non-squamous NSCLCAlimta 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 NSCLCALIMTA 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.
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.
Maintenance Therapy in Non-squamous NSCLCALIMTA 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
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.
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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)
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.
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.
*As determined through in-vitro studies
1. ALIMTA Summary of Product Characteristics. Eli Lilly and Co; February 2010.
41. Robinson DM, et al.American Journal of Cancer. 2004 2 (6):387-399.
ALIMTA® (Pemetrexed): Mechanism of Action1
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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. 2005 47(1):69-80. 2. Hanna N, et al. J Clin Oncol. 2004 22(9):1589-97. 3. Scagliotti GV et al. Clin Cancer Res. 2005 11(2 Pt 1):690-6. 4. Zinner RG, et al. Cancer. 2005 104(11):2449-56.
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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 2009 2.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 107:1589-1596. 2006 3.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 43:567-569, 2005 4.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):417-423, 2007
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Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
Randomization Factors • Stage • Performance status • Gender • Histologic vs
cytologic diagnosis• History of brain
metastases
R
Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1
Vitamin B12, folate, and dexamethasone given in both arms
Each cycle repeated q3 weeks up to 6 cycles
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
JMDB (Scagliotti et al, 2007) – Study Design1
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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.
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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.
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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.
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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.
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Patient Characteristic 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%)
JMDB (Scagliotti et al, 2007) – Main Patient Characteristics1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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JMDB (Scagliotti et al, 2007) – Main Disease Characteristics1
Cis/Pem N=862
Cis/Gem N=863
AdenocarcinomaSquamous cellLarge cellNSCLC, 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%) 17 (2.0%)
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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Toxicities Cis/PemN=839
Cis/GemN=830
P-value
Neutropenia 127 (15.1%) 222 (26.7%) < 0.001Anaemia 47(5.6%) 82 (9.9%) 0.001Thrombocytopenia 34 (4.1%) 105 (12.7%) < 0.001Leukocytes 40 (4.8%) 63 (7.6%) 0.019Febrile neutropenia 11 (1.3%) 31 (3.7%) 0.002
Alopecia (any grade) 100 (11.9%) 178 (21.4%) < 0.001
Nausea 60 (7.2%) 32 (3.9%) 0.004
Vomiting 51 (6.1%) 51 (6.1%) 1.000Fatigue 56 (6.7%) 41 (4.9%) 0.143Dehydration (any grade) 30 (3.6%) 17 (2.0%) 0.075
*Includes toxicities reported in at least 3% of patients in at least one arm.
JMDB (Scagliotti et al, 2007) – CTC Grade 3 & 4 Drug-related Toxicities*1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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*Based on intent–to-treat population
% of Patients
Treatment Cis/PemN=839
Cis/GemN=830
P-value
Any transfusionPlateletRed Blood Cell
138 (16.4%)15 (1.8%)
135 (16.1%)
240 (28.9%)37 (4.5%)
227 (27.3%)
< 0.001 0.002< 0.001
Erythropoiesis Stimulating Agents* 90 (10.4%) 156 (18.1%) < 0.001
G-CSF/GM-CSF* 27 (3.1%) 53 (6.1%) 0.004
JMDB (Scagliotti et al, 2007) – Transfusions and Supportive Care1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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Cis/PemN=839
Cis/GemN=830
Median no. cycles 5.0 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 intensityCis 95.0% Pem 94.8%
Cis 93.5% Gem 85.8%
* % of total cycles
JMDB (Scagliotti et al, 2007) – Drug Delivery1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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Cis/PemN=762
Cis/GemN=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
JMDB (Scagliotti et al, 2007) – Response Rates1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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ALIMTA + Cisplatin(N=862)
GEMZAR + Cisplatin(N=863)
Median OS(95% CI)
10.3 mos (9.8, 11.2)
10.3 mos(9.6, 10.9)
Adjusted HR (95% CI) 0.94 (0.84, 1.05)
p<0.001*
JMDB (Scagliotti et al, 2007) – Overall Survival (Total population)1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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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*
JMDB (Scagliotti et al, 2007) – Progression-free Survival (PFS) in Overall Population1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
20
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.
JMDB (Scagliotti et al, 2007) – Overall Survival: Adenocarcinoma or Large Cell1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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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)
*Superiority p-value; Data on file. Eli Lilly and Company.
p=0.096*
JMDB (Scagliotti et al, 2007) – Progression Free Survival (PFS): Adenocarcinoma or Large Cell1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
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MST*, mos Adjusted P-value
HR (95% CI)
PFS#, mos Adjusted P-value
HR (95% CI)
RR**, % P-value
C/P C/G C/P C/G C/P C/G
Adeno
(n=847)12.6 10.9
P=0.033
0.84 (0.71, 0.99)5.5 5.0
P=0.125
0.90 (0.78, 1.03)31.9 24.5 0.024
Large Cell (n=153)
10.4 6.7 P=0.0270.67 (0.48, 0.96) 4.5 4.2 P=0.499
0.89 (0.65, 1.24) 31.3 30.9 0.954
Squamous (n=473)
9.4 10.8 P=0.0501.23 (1.00, 1.51) 4.4 5.5 P=0.002
1.36 (1.12, 1.65) 26.9 36.7 0.033
NSCLC, NOS (n=252)
8.6 9.2 P=0.5861.08 (0.81, 1.45) 4.5 5.6 P=0.064
1.28 (0.99, 1.67) 33.0 24.2 0.156
Manegold C et al, Presented at 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.
*MST=Median Survival Time #PFS=Progression Free Survival **RR=Response Rate
JMDB (Manegold et al, 2007) – Efficacy by Histology1
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Drug name Cis/PemN=862
Cis/GemN=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%) < 0.001
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%) 1.000
TKI (Erlotinib or Gefitinib) 215 (24.9%) 194 (22.5%) 0.235
JMDB (Scagliotti et al, 2007) – Systemic Post-study Therapy1
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
*From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis
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) < 0.001
Age (continuous) 1.00 (0.99, 1.00) 0.656
Caucasian vs others 1.36 (1.18, 1.57) < 0.001
E/SE Asian vs others 0.65 (0.54, 0.78) < 0.001
ECOG PS 0 vs 1 0.65 (0.58, 0.73) < 0.001
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) < 0.001
Squamous cell vs others 1.12 (0.98, 1.27) 0.088
Large cell vs others 1.29 (1.07, 1.54) 0.007
JMDB (Scagliotti et al, 2007) – Prognostic Variables*1
1. Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
26
Physician Cycle 1 Cycle 2
Vitamin B12 1000 μg IM (once during pre-treatment, then once after every 3rd cycle)
ALIMTA500 mg/m2 IV over 10 minutes (every 21 days)
Cisplatin75 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 DD +1 +2
JMDB (Scagliotti et al, 2008) Dosing and administration: 1st-line treatment of NSCLC1
1. ALIMTA Summary of Product Characteristics (Eli Lilly, 2010).
Patient Cycle 1 Cycle 2
Folic Acid350-1000 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 DD +1 +2
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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.
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Backup
UKALM00065 October 2009
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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 intensityALIMTA: 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 www.clinicalstudyresults.org (accessed April 27, 2008).
1. Scagliotti GV, et al. J Clin Oncol. 2008.
Dose Intensity: ALIMTA (Pemetrexed for injection)/cisplatin vs GEMZAR (Gemcitabine HCl for injection)/cisplatin1
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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 311:899-909 2. 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, 1999 3. 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 18:122-130, 2000 4. Scagliotti et al: Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 20:4285-4291, 2002 5. Schiller JH et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 6.Sandler A et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 7. 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 26:3543-3551, 2008
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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.
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