Presented by Martin H. Cohen, M.D.

at the27 July 2004

meeting of the Oncologic Drugs Advisory

Committee

NDA 21-677

Alimta®

Pemetrexed

LY231514

Proposed Indication

Alimta as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy

Study Design

One randomized trial comparing treatment with Alimta to treatment with docetaxel 75 mg/2

Stratification factors:

P.S.; Disease stage; Number of prior regimens;

Response to last prior chemo; prior platinum; prior paclitaxel; baseline homocysteine; treatment site

Docetaxel 2nd line

Survival

Pts RR Med (mo)

p

OS

1 yr

(%)

p

1 yr

DOC 75 vs BSC

55

49

5.5%

--

7.5

4.6

0.01 37

12

<0.05

Doc 75

Vs

IC (V/I)

125

123

5.7

0.8

5.7

5.6

0.13 30

20

0.025

Alimta Administration

Alimta 500 mg/m2 IV infusion over 10 minutes on Day 1 of each 21-day cycle.

Folic acid 350-1000 mcg daily

Vitamin B12 1000 mcg every 3rd cycle

Dexamethasone 4mg po bid days -1, 0, +1 (rash prophylaxis)

Docetaxel Administration

Docetaxel 75 mg/m2 as an intravenous infusion over 60 minutes on Day 1 of each 21-day cycle.

Dexamethasone 8 mg po bid days -1, 0, +1 (fluid retention & hypersensitivity)

Study Conduct

• 135 Investigational sites in 23 countries

• Approximately 21% of the study population came from United States Institutions

Selected Patient Characteristics

Alimta

N=283

Docetaxel

N=288

PS 0-1 89% 88%

1 Prior chemo regimen 94% 95%

Prior platinum 91% 93%

Prior paclitaxel 27% 26%

Homocysteine > 12 30% 29%

Efficacy Endpoints

•Primary – Overall Survival

•Secondary

– Response Rate and Duration

– Time to Progression

– Progression Free Survival

– Symptom Burden (LCSS)

Response Rate & Duration

Alimta

N=264

Docetaxel

N=274

CR (%) 1 (0.4) 0

PR (%) 23 (8.7) 24 (8.8)

Total RR 9.1% 8.8%

95% CI 5.9, 13.2 5.7,12.8

Resp Dur (median) 4.6 mo 5.3 mo

Time to Progression

ITT RT

Alimta

N=283

Doc

N=288

Alimta n=265

Doc

N=276

Median (mo) 3.4 3.1 3.1 3.5

% censored 25 28 20 25

Post-study chemotherapy

Alimta

N=265

Docetaxel

N=276

Any drug 126 (48%) 107 (39%)

Docetaxel 85 (32%) 11 (4%)

Gemcitabine 17 (6%) 32 (12%)

Vinorelbine 6 (2%) 25 (9%)

Gefitinib 5 (2%) 21 (8%)

Post-study chemotherapy & Survival

Alimta

N=265

Docetaxel

N=276

N MS N MS

No P-S chemotherapy 139 6.2 mo 169 5.0 mo

Post-study docetaxel 85 9.6 mo 11 10.1 mo

Other chemotherapy 41 10.6 mo 96 11.2 mo

No post-study chemo. Last PS

Last PS

Alimta

N=139

Docetaxel

N=169

0 or 1 108 (78%) 123 (73%)

2 28 (20%) 37 (22%)

3 or 4 1 (1%) 7 (4%)

Unknown 2 (1%) 2 (1%)

Post-study chemotherapy & Survival

Alimta

N=265

Docetaxel

N=276

N MS N MS

No P-S chemotherapy 139 6.2 mo 169 5.0 mo

Post-study docetaxel 85 9.6 mo 11 10.1 mo

Other chemotherapy 41 10.6 mo 96 11.2 mo

Patient Exposure

Alimta

N=265

Docetaxel

N=276

Median No. of cycles 4 4

% of planned dose intensity

96.6 94.4

All Toxicities Regardless of Causality Percent of Patients

Toxicity AlimtaN=265

DocetaxelN=276

p-value

Grade 1 97.4 94.6 0.128

Grade 2 96.6 96.7 1.0

Grade 3 66.4 76.8 0.008

Grade 4 18.1 49.2 0.000

Grade 3 or 4 69.0 84.1 0.000

CTC Grade 3 or 4 Neutropenia*

Alimta

N=265

Docetaxel

N=276

Febrile neutropenia* 5 (2) 35 (13)

Infection with neutropenia 0 (0) 16 (5.8)

* Uncorrected p value <0.001

All Toxicities Regardless of Causality Excluding WBC Events*

Toxicity AlimtaN=265

DocetaxelN=276

p-value

Grade 1 95.5 92.0 0.112

Grade 2 95.1 95.3 >0.999

Grade 3 63.8 65.2 0.788

Grade 4 16.6 21.7 0.156

Grade 3 or 4 67.9 69.2 0.781

* febrile neutropenia, leukocytes, lymphopenia, neutrophils/ granulocytes, infection with grade 3 or 4 neutropenia, infection/febrile neutropenia, other

CTC Grade 3 or 4 AE’s

Alimta (%) Docetaxel (%) p-value

Alopecia 0.4 3.0 0.04

Diarrhea 0.4 4.0 0.01

Fatigue 15.8 16.7 0.817

Nausea 3.8 2.5 0.466

Vomiting 1.5 1.4 1.0

Stomatitis 1.1 1.1 1.0

Pulmonary 6.8 9.8 0.217

Neurosensory* 7.5 9.8 0.365* Grade 2-4

Selected TEAEs – All grades*

Alimta Docetaxel

Nausea 98 (37%) 59 (21%)

Weight loss 76 (29) 44 (16)

ALT increased 23 (9) 6 (2)

AST increase 20 (8) 3 (1)

Ccr decreased 12 (5) 1 (0.4)

Alopecia 19 (7) 108 (39)* Selection based on an uncorrected p value < 0.001

Selected TEAEs –All Grades*

Alimta Docetaxel

Myalgias 23 (9) 42 (15)

Arthralgias 19(7) 36 (13)

Neurotoxicity 2 (1) 10 (4)

Diarrhea 60 (23) 91 (33)

Constipation 58 (22) 34 (12)

Fatigue 133 (50) 115 (42)

Rash 37 (14) 19 (7)

* Selection based on an uncorrected p value <0.05

Hospitalizations

Alimta

N=265

Docetaxel

N=276

Admissions 337 364

Days 1722 1410

Efficacy Conclusions• Post-study chemotherapy confounds survival

results- 85 (32%) of Alimta pts received post-study docetaxel

- Patients who did not receive post-study chemotherapy had shorter survival - 30 more docetaxel treated patients received no post-study chemotherapy compared to Alimta treated patients.

- Majority of untreated P-S patients had PS 0-1• Response rates were 9.1% (A) and 8.8% (D)

Safety Conclusions

• Toxicity spectrum of Docetaxel and Alimta differ.

- Docetaxel produces more neutropenia and neutropenic complications (febrile neutropenia, infections, G-CSF use)

neurotoxicity, myalgias, alopecia and diarrhea

- Alimta produces more thrombocytopenia, skin rash, fatigue, nausea and vomiting, ALT and AST increase, decreased CCr, and weight loss.

• Folic acid and Vitamin B12 supplements are known to decrease Alimta toxicity. Whether they would also decrease docetaxel toxicity is unknown.