study jmdb - a randomised phase iii trial of cisplatin + pemetrexed vs. cisplatin + gemcitabine in...

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


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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


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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


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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


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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


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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%)


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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


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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


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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


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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


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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


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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


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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


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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


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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


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JMDB (Scagliotti et al, 2007) – Subgroup Analyses Forest Plot1


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*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


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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

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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.

study jmdb - a randomised phase iii trial of cisplatin + pemetrexed vs. cisplatin + gemcitabine in...

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day cycle

recommended dose of

line nonsquamous nsclc

squamous cell histology

alimta eu

recommended dose of

pemetrexed infusion

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