Gemzar ® in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian Cancer March 13, 2006 Richard Gaynor, MD Vice President, Global

Gemzar® in Combination with Carboplatin as Treatment for Women

with Recurrent Ovarian Cancer

March 13, 2006

Richard Gaynor, MDVice President, Global Oncology

Lilly Research Laboratories

Oncologic Drugs Advisory Committee Presentation

8001.01

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AgendaIntroduction and Objectives

Management of Ovarian Cancer

Clinical Efficacy of Gemzar/Carboplatin

Safety Results and Patient Benefit

Robustness of Efficacy Results

Risk/Benefit Overview

8002.01

Richard Gaynor, MD Vice President, Oncology Lilly Research Laboratories

Robert Ozols, MD, PhDSr. Vice President Medical Science, Fox Chase Cancer Center

Allen Melemed, MD Associate Medical Director, Oncology – Eli Lilly and Co.

Richard Gralla, MDMultinational Association of Supportive Care in Cancer

Daniel Sargent, PhDDirector, Cancer Center Statistics, Mayo Clinic

Tate Thigpen, MD Professor of Medicine, University of Mississippi School of Medicine

3

Expert ParticipantsEli Lilly and Company

Medical

Richard Gaynor, MD

Marek Kania, MD, MBA

Martin Marciniak, PhD

Allen Melemed, MD

Regulatory Affairs

Cheryl Beal Anderson, PharmD

Colleen Mockbee, RPh

Statistics

James Symanowski, PhD

Annamaria Zimmermann, MS

External Consultants

Richard Gralla, MDMultinational Association of Supportive Care in Cancer

Robert Ozols, MD, PhDSr. Vice President Medical Science, Fox Chase Cancer Center

Jacobus Pfisterer, MD, PhD Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany, AGO co-Chair, GCIG Chair

Dan Sargent, PhDDirector, Cancer Center Statistics, Mayo Clinic, Rochester

Tate Thigpen, MDProfessor of Medicine, University of Mississippi School of Medicine

8003.01

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Ovarian Cancer Supplemental NDA

•sNDA for ovarian cancer indication was submitted 16 June 2005 – Submission based on a 356 patient randomized Phase 3 study

conducted by AGO-OVAR that met its primary endpoint of statistically significant improvement in progression free survival (PFS)

•Indication– Gemzar in combination with carboplatin for the treatment of women

with recurrent ovarian cancer that have relapsed at least 6 mo following platinum‑based therapy.

•Dosage– Gemzar 1000 mg/m2 days 1 and 8– Carboplatin AUC 4 day 1

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Gemzar sNDA Ovarian Cancer

8005.01

•Oncolytic agents are often used off-label

– Gemzar alone and in combination with carboplatin listed in NCCN 2006 practice guidelines for treatment of women with recurrent ovarian cancer and is currently used in the treatment of this disease

•“FDA Guidance on New Treatment Indications” goals:

– Submission of data for supplemental indications

– Label all indications where data exists to establish safety and efficacy

– Recognize alternative data sources from cancer clinical trial organizations with track record of high quality research

•Current study performed by a well-known European cooperative group is consistent with FDA guidance and demonstrates the efficacy of GCb in recurrent ovarian cancer

6

Regulatory Background

8006.01

•Historically, overall response rate has been primarily used for approval in recurrent ovarian cancer

•Lilly requested meeting with FDA to discuss potential for submission (December 2004)

– FDA agreed data package met criteria for submission

– PFS endpoint, used in this trial, is acknowledged as a measure of clinical benefit in lung and colorectal cancers

•Lilly will discuss that the totality of data including PFS, ORR, PRO and time off chemotherapy supports full approval of Gemzar /carboplatin for treatment of women with recurrent ovarian cancer

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Background on Gemzar

8007.01

•Pyrimidine anti-metabolite with broad activity across numerous tumor types

•Over 1.3 million patients treated globally with Gemzar

•FDA regular approvals for:

– Pancreas (single agent – 1996)

– NSCLC (combination with cisplatin – 1998)

– Metastatic Breast Cancer (combination with paclitaxel – 2004)

•Gemzar plus carboplatin (GCb) combinations are used extensively in lung, breast, and bladder cancers

•Gemzar as a single agent, and in combination with carboplatin, has been extensively studied in ovarian cancer

•Safety profile well-characterized with relatively low toxicity

8

Objectives of Presentation

8008.01

Gemzar plus carboplatin is an effective, less neurotoxic treatment option for women with recurrent ovarian cancer

• Gemzar is active in ovarian cancer

• Gemzar plus carboplatin provides a clinical benefit for women with recurrent ovarian cancer

– Superior PFS, overall and complete response rates

– Robust and internally consistent efficacy

– Improved patient reported outcomes and time off chemotherapy

• Safe and well-tolerated regimen

– No new safety issues

– Low incidence of neurotoxicity

9

Management of Ovarian Cancer

Robert Ozols, MD, PhD

Sr. Vice President Medical Science Fox Chase Cancer Center

8009.01

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Ovarian Cancer – Current Clinical Practice• 20,180 new cases and 15,310 deaths estimated in 2006

• Current standard therapy for initial treatment:

– Debulking surgery followed by Cb + paclitaxel

• After 1st-line treatment with Cb + paclitaxel therapy for advanced stage disease:

– 75% of patients will achieve a complete clinical remission

– Of those, 75% will ultimately relapse

– Median disease-free interval of < 2 years

– Median survival after relapse is 18-24 mo

– Neuropathy is a significant issue following initial therapy

– 75% - 80% have grade 1-4 neurotoxicity

– 30% of patients with > grade 2 neurosensory toxicity

– 7% of patients with > grade 2 neuromotor toxicity

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• Selection of chemotherapy dependent on:

– Platinum-free interval at time of relapse

– Platinum resistant

– Platinum sensitive

– Residual toxicity, performance status, co-morbid conditions

• Platinum resistant: <6 mo interval between treatment and PD

• Current treatment options

– Liposomal doxorubicin*

– Topotecan*

– Paclitaxel*

– Gemzar

• Response rates for platinum-resistant patients ~10%

• Time to progression for platinum-resistant patients ~3 mo

Chemotherapy for Platinum-Resistant Disease

8011.01

* FDA-approved agent

12

Efficacy Results of Select Single-Agent Chemotherapies in Ovarian Cancer

Liposomal doxorubicin

Topotecan Paclitaxel

Patient Population

Recurrent / Platinum-resistant

Recurrent /Platinum – resistant

Recurrent

N (Number and phase of studies)

384(3 Ph 2, 1 Ph 3)

223(1 Ph 2, 1 Ph 3)

499(2 Ph 2, 1 Ph 3)

ORR, % 0 – 22* 14 – 21 13 – 22

Median TtPD, mo

3.7** 2.6 – 4.4 2.8 – 4.4

* Does not include an outlier study in which no responders were reported** Combined data from all three studies

8499.01

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Gemzar Monotherapy: Recurrent Ovarian Cancer

8013.01

Lund Friedlander Von Minckwitz

Patient Population

Platinum-resistant

Recurrent Recurrent

N 42 36 36

ORR, % 19 14 22

CR, % 0 6 5

Median TtPD, mo

2.8 3.0 3.6

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Chemotherapy for Platinum-Sensitive Disease and Combination Therapy

* FDA-approved agent

8498.01

• Platinum sensitive: 6 mo interval between treatment and PD

• Current treatment options based on Cb therapy

– Single Agent*

– Combination with Gemzar, paclitaxel

• ICON 4

– Important proof-of-concept for use of combination

– Improved OS and PFS

– Toxicities limit utility

– High percent of neurotoxicity (>Gr. 2 = 20%)

– Only 45% patients received prior taxane in ICON 4

– Neurotoxicity may be higher in US due to standard of care in 1st line (Carbo plus paclitaxel)

15

AGO-OVAR Development of Gemzar • Effective, less neurotoxic regimen needed in recurrent

disease

– Gemzar and Cb both active agents

• AGO-OVAR

– Well-established European cooperative group specializing in gynecological malignancies

– Member of Gynecological Cancer Intergroup

– Organization of 15 international cooperative groups

– Participated in ICON 4 (OVAR 2.2), withdrew due to toxicity

• Evaluated safety and efficacy of GCb in Ph 1/2 (SO026)

– Observed low incidence of neurotoxicity

• Designed JHQJ / OVAR 2.5

– GCb is effective regimen in treatment of recurrent disease

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PFS for Evaluation of Ovarian Cancer Agents

8018.01

• Recognized as an important endpoint for 1st and 2nd line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference

• Not confounded by post discontinuation therapies

– Survival may be confounded with multiple lines of therapy

– Represents efficacy of only study therapy

• Earlier identification of active treatments

• PFS in conjunction with other efficacy parameters (ORR, CR, QoL) can be a measure of clinical benefit in ovarian cancer

• AGO JHQJ / OVAR 2.5 met the primary endpoint of a statistically significant improvement in PFS

17

Clinical Efficacy

Pivotal Study JHQJ / OVAR 2.5

Allen Melemed, MD

Associate Medical Director,Eli Lilly and Co.

8021.01

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GCb Submission for Recurrent Ovarian Cancer

8022.01

Study ID Phase ORR (%)Median PFS

(mo)Median Survival

(mo)JHQJ / OVAR 2.5 Phase 3 47.2 8.6 18.0

OVAR 2.4 / O026 Phase 1-2 62.5 10.0 22.5

JHRW Phase 2 62.5 9.6 26.9

• Additional Supportive Studies in ovarian cancer:

– Three Phase 2 studies using Gemzar + carboplatin

– Ten Phase 2 studies using Gemzar monotherapy

19

RANDOMIZATION

Gemzar 1000 mg/m² D1+8 Carboplatin AUC 4 D1 q 3w for 6 cycles

Carboplatin AUC 5 D1 q 3w for

6 cycles

Stratified at central AGO office by:

Platinum-free interval(PFI) (6-12 or > 12 mo)

Type of 1st-lineplatinum therapy(platinum-paclitaxel or other platinum therapy)

Bidimensionallymeasurable disease (yes or no)

Study Design for JHQJ / OVAR 2.5

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Key Trial Features: Study Endpoints

8025.01

•Randomized Phase 3 study

– AGO, NCIC-CTG, EORTC

– 12 countries, 105 investigators

•Primary Endpoint: PFS

– Time from randomization to progressive disease (PD) or death

– Patients who were alive without PD were censored at last visit

– 85% power to detect 41% improvement in PFS (HR=0.71) at =0.05 (requiring ~300 events)

•Secondary Endpoints:

– Overall survival

– Response rate

– PRO (measured by EORTC QLQ-C30, OV28 instruments)

– Toxicity

21

Methodology for Disease Assessment for Study JHQJ / OVAR 2.5

8027.01

•Disease assessments every 6 weeks on-study

– Radiologic imaging studies (same method as baseline)

– Physical examination for tumor size

•Thirty days after study discontinuation (V101) disease assessments occurred every 3 mo

– Using the same method as baseline

•Determination of events for PFS:

– Death

– Objective tumor progression

– Clinical progression (performance status decline of 2 levels; progressive peritoneal carcinomatosis with increasing bowel dysfunction; increased ascites requiring palliative drainage)

22

Patient Characteristics for JHQJ / OVAR 2.5

8030.01

GCb (N=178) Cb (N=178)

Mean age, years (range) 58.1 (36.0-78.0) 56.5 (21.0-81.0)

ECOG PS, n (%)

0-1 162 (91.0) 165 (92.7)

2 11 (6.3) 9 (5.2)

FIGO stage at initial diagnosis, n (%)

Ia-IIIa 38 (21.3) 26 (14.6)

IIIb-IIIc 113 (63.5) 129 (72.5)

IV 27 (15.2) 22 (12.4)

First-line therapy, n (%)

Platinum 178 (100) 178 (100)

Platinum and paclitaxel 122 (68.5) 120 (67.4)

Platinum-free interval, n (%)

6-12 months 71 (39.9) 71 (39.9)

>12 months 105 (59.0) 106 (59.6)

23

JHQJ / OVAR 2.5 Primary Endpoint: Progression-Free Survival

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.0

0.2

0.4

0.6

0.8

1.0

Progression-Free Survival Time (mo)

Pro

gre

ss

ion

-Fre

e P

rob

ab

ilit

y

GCb: median = 8.6 mo Censoring: 12.4%

Cb: median = 5.8 moCensoring: 12.9%

8031.01

Cb Arm (N=178)

GCb Arm (N=178)

Log-rank p-value = 0.0038

Unadjusted HR = 0.72 (0.57 to 0.90)

Adjusted HR* = 0.71 (0.57 to 0.89)

* Adjusted for PFI, Tumor size

24

JHQJ / OVAR 2.5 Efficacy Results: Overall Survival

0.0

0.8

0.2

0.3

0.4

0.5

0.6

0.7

0.9

1.0

0.1

0 6 12 18 60544842363024

Pro

po

rtio

n S

urv

ivin

g

Months

Median = 18.0 mo Censoring: 18.5%

Median = 17.3 mo Censoring: 22.5%

8032.01

Cb Arm (N=178)

GCb Arm (N=178)

* Adjusted for PFI, Tumor size and performance status

Log-rank p-value = 0.8977

Unadjusted HR = 0.98 (0.78 to 1.24)

Adjusted* HR = 0.92 (0.72 to 1.16)

25

JHQJ / OVAR 2.5 Post-Discontinuation Therapy

Percent of Patients

Post-discontinuation therapyGCb

(N=178)Cb

(N=178)Any post-discontinuation therapy 83.7 78.7

Chemotherapy 75.8 72.5

1 regimen 16.3 13.5

2 regimens 12.4 15.7

3 or more regimens 9.6 10.7

Unspecified number of regimens 37.6 32.6

Hormonal, immuno or biological therapy 19.7 18.0

Radiation 5.1 9.6

Other therapy – not specified 15.7 15.2

8033.01

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JHQJ / OVAR 2.5: Overall Response Rate

GCb Arm (N=178)

Cb Arm(N=178)

Chi-square p-value

ORR (95% CI)

47.2% (39.9 - 54.5)

30.9% (24.1- 37.7)

0.0016

CR Rate (95% CI)

14.6% (9.4 to 19.8)

6.2% (2.6 to 9.7)

0.0092

8354.01

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Efficacy Conclusions

• Well designed, Phase 3, co-operative group study

– Patient characteristics well-balanced

– Study population representative of a high-risk recurrent ovarian cancer patients

– High percent of prior taxane therapy

• Primary endpoint (PFS) is highly significant in favor of the combination arm

– 28% reduction in risk

• Overall and complete response rates are significantly improved in the GCb arm vs the Cb arm

8054.01

Gemzar plus carboplatin demonstrated clinically meaningful benefit for women with recurrent ovarian cancer

28

Safety Results and Patient Benefit

Pivotal Study JHQJ / OVAR 2.5

Richard Gralla, MD Multinational Association of Supportive Care in Cancer

8021.01

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Objectives

•Patient safety – Toxicities and adverse events

– Significant consequences

•Translating PFS improvement to patient benefit

– Patient reported outcomes

– Time off chemotherapy

8410.01

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JHQJ / OVAR 2.5: Selected Grade 3/4 Toxicities Regardless of Causality

8038.01

Percent of Patients

GCb Arm (N=175) Cb Arm (N=174)

Grade 3 Grade 4 Grade 3 Grade 4

Hemoglobin 22.3* 5.7 8.6 2.3

Neutrophils 41.7* 28.6* 10.9 1.1

Platelets 30.3* 4.6 10.3 1.1

Nausea 6.3 0 2.9 0

Vomiting 5.7 0 2.3 0.6

Diarrhea 3.4 0 0.6 0

Constipation 6.3 1.1 2.9 0

* p-value <0.01

31

JHQJ / OVAR 2.5: Maximum CTC Neurotoxicity in Patients with Pre-Existing Neuropathy at Baseline

Max. Neuropathy On Study (%)Patients with neuropathy at baseline Gr 1 Gr 2 Gr 3 Gr 4

GCb Arm (N=38) Motor Neuropathy 0 0 2.6 0

Sensory Neuropathy 0 10.5 2.6 0

Cb Arm (N=29) Motor Neuropathy 0 0 0 0

Sensory Neuropathy 0 6.9 6.9 0

8040.01

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JHQJ / OVAR 2.5: Overview of Adverse Events

8037.01

N (Percent of Patients)

GCb Arm (N=175)

Cb Arm (N=174) p-value

Serious adverse events

All 49 (28.0) 37 (21.3) 0.1718

Possibly related to study drug 29 (16.6) 17 (9.8) 0.0810

Discontinuations due to AEs All 19 (10.9) 17 (9.8) 0.8606


33

JHQJ / OVAR 2.5: Selected Grade 3/4 Non-Laboratory Toxicities Regardless of Causality

Percent of Patients

GCb (N=175) Cb (N=174)

Grade 3 Grade 4 Grade 3 Grade 4

Hemorrhage 1.8 0.6 0 1.1

Febrile neutropenia 1.1 0 0 0

Neuropathy – sensory 1.1 0 2.3 0

Neuropathy – motor 1.1 0 0.6 0

8039.01

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JHQJ / OVAR 2.5: Overview of Hospitalizations and Deaths

8429.01

N, (Percent of Patients

GCb Arm (N=175)

Cb Arm (N=174) p-value

Patients hospitalized due to AE*

All 44 (24.7) 32 (18.0) 0.1545


Deaths

On study (during treatment period) 4 (2.3) 3 (1.7) 1.0000

Within 30-day poststudy follow up 1 (0.6) 2 (1.1) 0.6228

* Based on all randomized patients, N=178 per arm

35

JHQJ / OVAR 2.5 Safety Conclusions

• GCb is a safe and well-tolerated regimen

– No new safety issues emerge in JHQJ / OVAR 2.5

– Certain hematologic Gr 3/4 toxicities increased in GCb arm

– Clinically significant sequelae occurred at low and comparable rates

– Low incidence of neurotoxicity

8041.01

Gemzar plus carboplatin is a safe regimen for treatment of women with recurrent ovarian cancer.

36

Patient Benefit

•Patient reported outcomes

– EORTC QLQ-C30 cancer specific instrument (validated – Aaronson, 1993 and Groenvold, 1997)

– EORTC QLQ-OV28 ovarian specific instrument (validated – Cull, 2001 and Greimel, 2003)

– AUC

– Analysis to 10-Point Change

•Time off chemotherapy

– Duration of time patients were off chemotherapy

8430.01

37

JHQJ / OVAR 2.5: Patient Reported Outcome Assessment Methodology

8434.01

•Total of 22 symptom scales included in the EORTC QLQ-OV28 and EORTC QLQ-C30

•Symptoms most relevant to ovarian patients

– Nausea/vomiting

– Constipation

– Diarrhea

– Abdominal / GI (i.e. bloating)

– Fatigue

– Pain

– Anorexia

•Study designed to treat patients for 6 cycles or to progression

•Compliance rate completing PRO instrument ~90%

38

JHQJ / OVAR 2.5: Percent of Patients with Symptoms* at Baseline

* Nausea/vomiting, constipation, diarrhea, abdominal GI symptoms, fatigue, pain, or anorexia

Cb Arm

GCb Arm

8436.01

0

1

2

3

>4

Nu

mb

er o

f S

ymp

tom

s

60504030200 10Percent of Patients

Most Frequent Symptoms:Fatigue 86%Abdominal symptoms 84% Pain 71%

39

JHQJ / OVAR 2.5: AUC Results for QoL Scales/Items Relevant to Ovarian Cancer

8137.01

Cb Arm

GCb Arm

GlobalQoL

N/V Constipation Diarrhea Abd/ GI Fatigue Pain Anorexia0

10

20

30

40

50

60

70

80

Symptom

Per

cen

t o

f M

axim

um

AU

C

Overall improvements in the GCb arm in 21 of 22 scalesSign test <0.0001

40

JHQJ / OVAR 2.5 - Global Quality of Life: 10-Point Changes (% Improved and Time to Worsening)

8438.01

GlobalQoL

0

10

20

30

40

50

60

70

Per

cen

t o

f P

atie

nts

Cb Arm

GCb Arm

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0.00 6 123 9

Time to > 10 Point Worsening in Global QoL (mo)

HR (95% CI): 0.75 (0.54 – 1.04)Log-rank p-value: 0.084

GCb median=6.2 months; 61.2% censoringCb median=4.3 months; 57.9% censoring

Percent of PatientsImproved by at Least 10 Points (p = 0.106)

41

Patient Benefit

Patient reported outcomes

• EORTC QLQ-C30 cancer specific instrument (validated – Aaronson, 1993 and Groenvold, 1997)

• EORTC QLQ-OV28 ovarian specific instrument (validated – Cull, 2001 and Greimel, 2003)

• AUC

• Analysis to 10-Point Change

Time Off Chemotherapy

• Duration of time patients were off chemotherapy

8430.01

42

JHQJ / OVAR 2.5: Time Off Chemotherapy


Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0.0

0.1

0.3

0.5

0.7

0.9

0.00 6 12 18 24 30 36 42

Months

GCb median=5.6 months; e=169; 5.1% censoringCb median=2.6 months; e=165; 7.3% censoring

8433.01

43

JHQJ / OVAR 2.5: Patient Benefit Conclusions

8041.01

Gemzar plus carboplatin shows improved patient benefit with low toxicity and longer time off chemotherapy.

• The GCb regimen is safe with an acceptable toxicity profile

• Quality of life and patient reported outcome differences between the arms consistently favor the GCb regimen

• Women on the GCb regimen experienced a significantly greater time off chemotherapy following study therapy

44

Robustness of JHQJ / OVAR 2.5 Efficacy Results

Daniel J Sargent, PhD

Director, Cancer Center StatisticsMayo Clinic, Rochester

8042.01

45

Objectives

• Confirm robustness of the primary endpoint PFS

– Sensitivity analyses

– Consistency of results in key subgroups

• Assess possible impact of investigator bias

– PFS

– Response rate

– Investigator vs independent assessments

8043.01

46

Robustness of PFS Results in Study JHQJ / OVAR 2.5

8366.01

• Sensitivity analysis including only objective progressions (SA1)

– Clinical progressions ignored

• Sensitivity analysis including only documented objective progressions (SA3)

– Clinical progressions ignored

– Objective progressions without lesion measurements ignored

– Objective progressions following missed / incomplete assessments back-dated

– Interval trimmed at 7 mo or at study discontinuation (V101)

47

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

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ree

Pro

bab

ility

0 6 12 18 24 30 36

Progression Free Survival Time (Months)

8363.01

GCb: Median: 9.7 mo ; events=148; Cens: 16.9%

Cb: Median: 6.7 mo ; events=149; Cens: 16.3%


Cb Arm

GCb Arm

JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Objective Progressions (SA1)

48

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n F

ree

Pro

bab

ility

0 2 4 6 8 10

Progression Free Survival Time (mo)

8365.01

GCb Median : 6.7 mo Events=47Cens: 73.6%

Cb Median: 5.2 mo Events=84Cens: 52.8%

HR (95% CI): 0.45 (0.32 – 0.64)Log-rank p-value: <0.0001

Cb Arm

GCb Arm

JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Documented Objective Progressions (SA3)

49

JHQJ / OVAR 2.5: Summary of New Sensitivity Analyses for PFS

8362.01

Median GCb(censoring)

Median Cb(censoring)

LR p-valueHR

Primary PFS 8.6 mo(12.4%)

5.8 mo(12.9%)

0.00380.72

Sensitivity Analysis Including Only Objective Progressions (SA1)

9.7 mo(16.9%)

6.7 mo(16.3%)

0.0157 0.76

Sensitivity Analysis Including Only Documented Objective Progressions (SA3)

6.7 mo(73.6%)

5.2 mo(52.8%)

<0.00010.45

50

JHQJ / OVAR 2.5: Internal Consistency of PFS in Subgroups

Subgroup HR (95% CI)Interaction

p-value

Age <60 y 0.74 (0.54-1.01)0.8552>60 y 0.70 (0.51-0.97)

Performance status 0 0.69 (0.50-0.95)0.73921 or 2 0.73 (0.53-1.01)

Platinum-free 6-12 mo 0.69 (0.49-0.98)0.7500

interval >12 mo 0.72 (0.54-0.97)

1st Line paclitaxel Yes 0.61 (0.47-0.80)0.0704No 0.91 (0.61-1.36)

Median tumor area <18.7 0.84 (0.60-1.17)0.1636(cm2) >18.7 0.60 (0.43-0.83)

8049.01

51

JHQJ / OVAR 2.5: Independent Assessment of Response Rate

8035.01

• Process for independent review:

– All imaging films submitted by the investigator were given to the review board

– Patients needed to have a baseline and one subsequent radiologic image

– Ultrasound and physical exam data were not included in the review

• Members of the review board (3 outside radiologists) were blinded to the treatment arm, investigator assessment and target lesions

• Independent assessment was performed on the subset of 222 patients with radiologic imaging available

– Reduced power

52

Independent Review

Investigator Assessment Responders Non-Responders

Responders 66 25 (11%)

Non-Responders 26 (12%) 105

JHQJ / OVAR 2.5: Response in Independently Reviewed Cohort (Investigator vs Independent)

8053.01

53

Independently Reviewed

Investigator Assessed

GCb, (N=121)

Response Rate 46.3% 46.3%

CR/PR 11/45 15/41

Cb, (N=101)

Response Rate 35.6% 34.7%

CR/PR 4/32 4/31

p-value 0.1091 0.0794

JHQJ / OVAR 2.5: Response Rate in Independently Reviewed Cohort

8052.01

54

Conclusions

• Primary endpoint (PFS) is statistically convincing and internally consistent

– Multiple sensitivity analyses confirm robustness of primary analysis

– Significant benefit reproduced in key patient subgroups

• No evidence of investigator bias

– Results from independent review of response consistent with investigator assessment

– Concordance analysis showed no bias

– Similar overall response rates among independent and investigator assessments

8054.01

55

Concluding Remarks

Benefit-Risk Summary:

OVAR 2.5 in Context

Tate Thigpen, MD

Professor of Medicine, University of Mississippi School of Medicine

8055.01

56

PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

8018.01


– AGO-OVAR was the host for the 2004 meeting




• PFS differences can alter treatment practices

• PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer

57

Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference- 2004

8514.01

58

PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

8018.01


– AGO-OVAR was the host for the 2004 meeting




• PFS differences can alter treatment practices

• PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer

598058.01

JHQJ / OVAR 2.5(N=356)

Efficacy Results

PFS (primary endpoint) 8.6 mo vs 5.8 moHR = 0.72 (p=0.0038)

ORR 47.2% vs 30.9%p-value = 0.0016

CR 14.6% vs 6.2%p-value = 0.0092

Patient Reported Outcomes Consistent trend for improvement

JHQJ / OVAR 2.5 Efficacy Results

60

Impact of Subsequent Chemotherapy on Survival for Recurrent Ovarian Cancer

8497.01

• Subsequent therapy for ovarian cancer may impact survival results

– Cisplatin vs paclitaxel vs paclitaxel/cisplatin

– Dox/Cyclo vs Cis/Dox/Cyclo

• Frequency of subsequent therapy in studies of platinum-sensitive recurrent ovarian cancer

– ICON 4 (3rd line therapy not reported)

– Standard practice in UK would be no 3rd-line therapy

– JHQJ / OVAR 2.5 (75% patients received 3rd-line therapy)

618065.01

Advancing the Treatment of Recurrent Ovarian Cancer

• Standard of care in front-line ovarian cancer is Cb plus paclitaxel

– Neurotoxicity is a frequent complication of this treatment

• Standard of care in recurrent platinum-sensitive ovarian cancer is platinum-based therapy

• Combination therapy has shown improvements in efficacy over single agent Cb in recurrent ovarian cancer

– Effective, less neurotoxic regimen is needed

628066.01

GCb is a Valuable Treatment Option for Patients with Recurrent Ovarian Cancer

• Gemzar plus carboplatin showed an advantage over carboplatin

– Clinically meaningful improvements in PFS that were robust, internally consistent, and statistically significant

– Significantly greater overall and complete response rates

– Manageable and well-characterized safety profile

– Infrequent neurotoxicity and alopecia

– Longer period without a decline in QoL

– Longer time without need for further chemotherapy

• JHQJ / OVAR 2.5 is a positive study with regard to its primary endpoint, PFS, and supporting endpoints

Gemzar plus carboplatin is an effective treatment option for women with recurrent ovarian cancer.

Back ups presented

64

JHQJ / OVAR 2.5: Pre- and Post-Discontinuation Assessment Intervals

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Weeks

On-Treatment* Off-Treatment**

Summary StatisticsGCb

(N=168)Cb

(N=159)GCb

(N=117)Cb

(N=80)

25th Percentile 5.4 5.0 4.6 4.4

Median 6.3 6.1 8.3 8.3

75th Percentile 7.7 7.6 10.0 10.5

* Intervals between disease assessment dates** Intervals between office visit dates

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JHQJ / OVAR 2.5: Clinical versus Objective Progressions

N (Percent of Patients)

On-Treatment Off-Treatment

Progressive DiseaseGCb

(N=35)Cb

(N=70)GCb

(N=117)*Cb

(N=80)**

Clinical Progression 1 (3) 7 (10) 28 (24) 16 (20)

Objective Progression 34 (97) 63 (90) 92 (79) 66 (82.5)

•Three patients were counted twice, all 3 patients had both larger/new lesions and deteriorating conditions as the basis of PD

** Two patients were counted twice, both patients had larger/new lesions and deteriorating conditions as the basis of PD

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66

JHQJ / OVAR 2.5: Measurement Methods at Baseline

Number of Patients (%)

Method GCb(N=178)

Cb(N=178)

CT-Scan 126 (71) 110 (62)

Ultra Sound 39 (22) 51 (29)

Physical Exam 14 (8) 21 (12)

MRI 5 (3) 6 (3)

Chest X-ray 1 (0.6) 1 (0.6)

Gynecological Exam 1 (0.6) 1 (0.6)

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JHQJ / OVAR 2.5: EORTC QLQ-C30 Within Arm Changes Over Time

QLQ-C30 GCb Arm (N=154) Cb Arm (N=152)

Global QoL Improved StablePhysical functioning Stable StableRole functioning Stable StableCognitive functioning Stable StableEmotional functioning Improved ImprovedSocial functioning Stable StableFatigue Stable StableNausea/vomiting Worsened WorsenedPain Improved ImprovedDyspnea Stable StableSleep disturbance Improved ImprovedAppetite loss Improved ImprovedConstipation Stable StableDiarrhea Stable StableFinancial impact Stable Stable

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Documents

Gemzar ® in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian Cancer March 13, 2006 Richard Gaynor, MD Vice President, Global