1 Presentation to the Oncologic Drugs Advisory Committee Paolo Paoletti, MD Vice President Clinical...

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Presentation to the Oncologic Drugs Advisory Committee

Paolo Paoletti, MDVice President Clinical Research Oncology

27 July 2004Eli Lilly and Company

Alimta® (Pemetrexed) as a Second-Line Treatment for Patients with

Non-Small Cell Lung Cancer

2

Agenda Introduction Paolo Paoletti, MD

– Objectives of Presentation Vice President, Clinical Research Oncology, Eli Lilly and Company

Background Frances A. Shepherd, MD – 2nd-Line Treatment of NSCLC Professor of Medicine, University of Toronto

Scott Taylor Chair in Lung Cancer Research, President IASLC

Alimta Development Roy Herbst, MD, PhDChief, Thoracic Oncology, University of Texas M.D. Anderson Cancer Center

Clinical Efficacy Paul A. Bunn, Jr., MD– Pivotal Study JMEI Director, University of Colorado Cancer Center

Safety Profile Richard J. Gralla, MD– Pivotal Study JMEI President, Multinational Association of

Supportive Care in Cancer, Director IASLC

Conclusions Paul A. Bunn, Jr., MD

3

List of External ExpertsRobert Allen, MD

University of Colorado, United States

Donald Berry, PhD

University of Texas, MD Anderson, United States

Hilary Calvert, MD

University of Newcastle, United Kingdom

Scott Emerson, MD, PhD

University of Washington, United States

Nasser Hanna, MD

Indiana University, United States

Axel Hanauske, MD, PhD

Allgemeines Krankenhaus St Georg, Hamburg, Germany

Christian Manegold, MD

Thorax Klinik, Heidelberg, Germany

Giorgio Scagliotti, MD

University of Turin, Torino, Italy

4

Lilly Team

Medical

William John, MD

Louis Kayitalire, MD

Astra Liepa, PharmD

Binh Nguyen, MD, PhD

Paolo Paoletti, MD

Regulatory Affairs

Jeffrey Ferguson

Anne Kehely, MD

Debasish Roychowdhury, MD

John Worzalla

Statistics

Clet Niyikiza, PhD

Sofia Paul, PhD

Patrick Peterson, PhD

Jim Symanowski, PhD

Non-Clinical Studies

Ajai Chaudhary, PhD

Victor Chen, PhD

Vijay Reddy, PhD, DVM

Rebecca Wrishko, PhD

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Provide evidence that Alimta is effective and safe.

Lilly intends to show that given its superior safety, Alimta has a better risk-benefit profile than docetaxel (Taxotere®) and provides clinical benefit to patients with non-small cell lung cancer (NSCLC).

Alimta is a novel, effective agent in the treatment of NSCLC– Demonstrates similar efficacy to docetaxel– Shows consistent results across all assessed endpoints and

subgroups – Estimated to retain 102% of docetaxel's benefit over BSC – Is superior to historical BSC

Alimta has an excellent safety profile – Has a superior safety profile to docetaxel

Alimta offers an effective and safer option in the treatment of second-line NSCLC

Objective of Presentation

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Proposed Indication and Dosage Schedule

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

Dose: 500 mg/m2 iv, 10 minutes, Day 1 of each 21-day cycle

Folic Acid: 350-1000 µg orally daily; Vitamin B12 1000 µg im, q 3 cycles

Dexamethasone: 4 mg bid on d-1, d0, d+1

7

Development of Alimta in Second-Line Treatment of NSCLC

Consistent evidence of activity in seven Phase II studies

– Single agent (3 studies)

– In combination with platinum agents (4 studies)

– Both in 1st and 2nd-line

Supplementation with Folic Acid/B12 improved safety profile of Alimta

– Degree of toxicity reduction was not fully characterized

Decision to proceed with a Phase III study (JMEI) in 2nd-line treatment of NSCLC

8

Design of Global, Pivotal Study JMEI

Decision to run “Head to Head” trial of Alimta vs docetaxel

– Global study to support global registration

– BSC in 2nd-line NSCLC considered not feasible in US

– Combination chemotherapy not appropriate in 2nd-line setting

– Docetaxel only approved agent for treatment of 2nd-line NSCLC

Survival as a primary endpoint

– Limited historical data on the effect of docetaxel

– “Pure equivalency” study would require >4000 pts

9

Design of Global, Pivotal Study JMEI

Sample size of 520 patients allows for testing both superiority and non inferiority

Compare treatment arms by HR for survival

Protocol Specified:– Superiority

– 10% fixed margin NI (EU regulatory)

Statistical Analysis Plan Specified (prior to unblinding):– Percent Retention of the effect of docetaxel over BSC

– 50% retention – basis of approval for capecitabine (colorectal) and docetaxel (breast cancer)

– Percent Retention methodology published January 2003

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JMEI first patient enrolled 20 March 2001

JMEI last patient enrolled 06 February 2002

Final Statistical Analysis Plan for 24 January 2003 JMEI approved

Unblinding of JMEI analysis data sets 30 January 2003

US fast track designation for 2nd- 23 July 2003line treatment of NSCLC

US NSCLC submission 04 November 2003

NSCLC 2nd Line and Mesothelioma 22 June 2004EU-CHMP positive opinion

Alimta Second-Line Treatment of NSCLC Global Development Timeline

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Alimta in Combination with Cisplatin is Approved in the US for Mesothelioma – 04 February 2004

MST = 12.1 mo

HR: 0.77Log rank p-value = 0.020

MST = 9.3 mo

0 5 10 15 20 25 30

100

Months

75

50

25

0

Method: Kaplan-Meier

% A

live

Alimta+Cis (n=226)

Cis (n=222)

12

Seven Alimta Phase II studies show consistent evidence of activity

From this large Phase III randomized study in 2nd-line NSCLC, consistently similar efficacy results compared to docetaxel:

– All primary and secondary efficacy endpoints

– All subgroup analyses

Significantly better efficacy than historical BSC Alimta has a significantly better safety profile when

compared with docetaxel for clinically relevant events

Alimta is safe and effective and offers a superiorbenefit-to-risk profile compared to docetaxel

Why Alimta Merits FDA Approval as Second-Line Treatment for NSCLC

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Points for Consideration

Docetaxel is effective in the 2nd-line treatment of NSCLC, but its use is limited by toxicity

– Results in the 288 patients receiving docetaxel in the JMEI trial confirms docetaxel’s survival effect and safety profile

The small size of the docetaxel vs BSC pivotal trial made non-inferiority designs and analyses very challenging.

Inevitable post study treatment may confound a survival endpoint; analysis of JMEI data suggest such a confounding effect is unlikely

Interpretation of the results we present must consider the whole body of evidence

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Non-Small Cell Lung Cancer

Second-Line Treatment

Frances A. Shepherd, MD, FRCPC Scott Taylor Chair in Lung Cancer Research,

Princess Margaret Hospital

Professor of Medicine, University of Toronto

President, International Association for the Study of Lung Cancer

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1997 ASCO Guidelines for NSCLC

“…there is no current evidence that either confirms or refutes that 2nd-line chemotherapy improves survival in … patients with advanced NSCLC.”*

* Treatment Guidelines For Unresectable NSCLC. JCO 15: 2996-3019, 1997.

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6-11 mo.8-21%272Docetaxel

4-10 mo.0-23%112Paclitaxel

4-8 mo.0-21%201

3 mo.0-20%63Vinorelbine

Median Survival

Overall RRNAgent

Monotherapy for Previously Treated Patients With Advanced NSCLC

Gemcitabine

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Study Design - TAX 317

NSCLCStratified by:

• ECOG PS (0,1 vs 2)

• Best response to prior platinum

(PD vs. non-PD)

• 10 Objective: survival

• No prior paclitaxel

RANDOMIZE

317A

Docetaxel 100 mg/m2, one-hour iv infusion on Day 1 q 21d Premedication:

Dexamethasone 8 mg x 10 doses, beginning 12 hours before docetaxel

By Protocol Amendment:

Docetaxel 75 mg/m2, one-hour IV infusion on Day 1 q 21d

Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before docetaxel

317B

Best Supportive Carewithout chemotherapy

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Summary of Efficacy Results – TAX 317

Doc100 (n=49)

Doc75 (n=55)

BSC (n=49)

Partial Response 6% 6% —

TTPD — 2.8 mo 1.6 mo

Median Survival 5.9 mo 7.5 mo 4.6 mo

Log-rank p-value 0.780 0.010* —

One-Year Survival 19% 37% 12%

* 44% reduction in risk of death compared to BSC

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Median 7.5 mo vs. 4.6 moLog-rank p = 0.010

1-year 37% vs. 12%Chi-square p = 0.003

Doc75 (n=55)

BSC75 (n=49)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

3 6 9 12 15 18 21

Survival Time (months)

Cu

mu

lati

ve P

rob

abili

ty

Survival – TAX 317BDocetaxel 75mg/m2 vs BSC

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TAX 317B Updated Survival (Number of Prior Regimens)

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Study Design – TAX 320

RANDOMIZE

NSCLC Stratified by:

Best response to last platinum

(PD vs. non-PD)

ECOG PS (0,1 vs. 2)

10 Objective:

survival

Prior Paclitaxel allowed

Docetaxel 100 mg/m² iv q 3wksPremedication: Dexamethasone 8 mg x 5

doses, beginning 12 hours before docetaxel

Docetaxel 75 mg/m² iv q 3wksPremedication: Dexamethasone 8 mg x 5

doses, beginning 12 hours before docetaxel

Vinorelbine 30 mg/m² iv Days 1, 8, 15 q 3wks

- or - Ifosfamide 2 gm/m² iv (+ Mesna)

Days 1, 2, 3 q 3wks

Response assessment every 2 cycles

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Summary of Efficacy Results – TAX 320

Doc100 (n=124)

Doc75 (n=124)

V/I (n=122)

Partial Response 11% 7% 1%

TTPD 1.9 mo 2.0 mo 1.8 mo

Median Survival 5.5 mo 5.7 mo* 5.6 mo

One-Year Survival 21% 32%** 19%

* Log-rank p=0.13

** Chi square p=0.05

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Cu

mu

lati

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rob

abili

ty

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Survival Time (Mo)0 3 6 9 12 15 18 21

Doc100Doc75V/I

Doc75 vs. V / ILog-rank Test p= 0.121-Year 32% vs 19%

(p = 0.05, Chi-square)

Doc100 vs. V / ILog-rank Test p= 0.131-Year 21% vs 19%

Overall Survival – TAX 320

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Docetaxel Toxicities (75 mg/m2) Regardless of Causality (per Label)*

Toxicity Any Grade 3/4

Neutropenia 84.1 65.3

Febrile Neutropenia n/a 6.3**

Infection 33.5 10.2

Diarrhea 22.7 2.8

Neurosensory 23.3 1.7

Alopecia 56.3 n/a

* Data combined from TAX 317 and TAX 320

** Grade 4 neutropenia with fever >38°C with iv antibiotics or hospitalizationn/a = Not Applicable

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Opioid Analgesic Use – TAX 317BChange from Baseline

p=ns p<0.001 p<0.001

20%

13%

5%

49%

35%

18%

0%

10%

20%

30%

40%

50%

60%

Ongoing atBaseline

Additional Opioid Analgesic

Newly-started Opioid Analgesic

Per

cen

tag

e o

f P

atie

nts

Doc75BSC75

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Weight Loss During TreatmentPercent of Patients with Weight Loss > 10%

5 %

8 %

0%

5%

10%

15%

20%

25%

T75 V/I

TAX 317B TAX 320

2 %

25 %

0%

5%

10%

15%

20%

25%

T75 BSC75

p<0.001 p=ns

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Performance Status Evaluation

Performance Status (ECOG)

Cycle 1

Cycle 2

Cycle 3

Mean Across Cycles 1-3Last Assessment

TAX 317B TAX 320

Better forBSC75

Better forDoc75

Better forV/I

Better forDoc75

-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6

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Showed that 2nd-line chemotherapy could prolong survival in NSCLC

Showed that 2nd-line chemotherapy could improve performance status and symptom control in NSCLC

Showed that 2nd-line chemotherapy did not have a negative impact on QoL in NSCLC

Led to the approval of docetaxel 75 mg/m2 for the 2nd-line treatment of NSCLC in 1999

These Landmark Trials …

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Current ASCO Guidelines for NSCLC

“Docetaxel is recommended as 2nd-line therapy for patients with advanced or metastatic NSCLC with adequate performance status who have progressed on 1st-line platinum-based therapy.”*

* ASCO Treatment of Unresectable NSCLC Guideline. JCO 22-: 330-353, 2004

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Current Second-Line Treatment of NSCLC

Patients benefit from treatment with docetaxel

Safer or more effective alternatives to docetaxel are needed

Unmet medical need

– Performance status and toxicity of 1st-line therapy may preclude docetaxel use

– Increased use of 1st-line docetaxel

No other approved options

There is a need for additional options in second-line treatment of NSCLC

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Roy Herbst, MD, PhDChief and Associate Professor, Thoracic Oncology, University of Texas

M. D. Anderson Cancer Center

Alimta Development

32

NHO

HO2CCO2H

NHN

NH

O

NH2

Alimta (Pemetrexed)Chemical Structure

N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-

pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-

glutamic acid

Alimta (Pemetrexed)

Folic Acid

N

NNH

N

NHO

NH2

NH

O CO2H

CO2H

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GARFT RNA & DNA Synthesis

AMP

GMP

DHFRTS

DNA Synthesis

IMPPRPP + Gln

10-CHO-FH4

5, 10-CH2-FH4

FH4dUMP

FH2

dTMP

Cel

lM

emb

ran

e

Alimta-Glun

Alimta

FPGS

Folate Carriers (mainly

RFC)

Alimta

Alimta Mechanism of Action

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Alimta Preclinical Results in Non Small Cell Lung Cancer

Tumor Graft DoseIn vivo %

Tumor Inhibition

LX-1 Lung 300100

7562

Tumor Cell Lines In vitroIC50 (nM)

NSCLC LX-1 4NSCLC H460 60NSCLC H23 50NSCLC A549 156

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First-Line NSCLC Monotherapy – Alimta and Docetaxel Efficacy

N Evaluable RegimenDose

(mg/m2)Response Rate (%)

Median Survival

Fossella 41 Docetaxel 100 33 10.8 mo

Gandara 80 Docetaxel 100 16 7.0 mo

Alexopoulos 60 Docetaxel 100 25 7.4 mo

Miller 20 Docetaxel 75 25 NR

Roszkowski* 137 Docetaxel 100 13 6.0 mo

Clarke1 57 Alimta 600 16 7.2 mo

Rusthoven1** 30 Alimta 500 23 9.2 mo

* Phase III study ** Dosage amended from 600 mg/m2 due to toxicity1 No Vitamin Supplementation

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First-Line NSCLC Combination – Alimta Phase II Studies

Manegold et al. (2000)*

Shepherd et al. (2001)*

Scagliottiet al. (2003)

Koshy et al. (2003)

N 36 29 39 50

Alimta (mg/m2)

Combination (d1 q21d)

500

Cisplatin75 mg/m2

500

Cisplatin 75 mg/m2

500

CarboplatinAUC 6

500

CarboplatinAUC 6

Response Rate

Median Survival

1-Year Survival

Median TTPD

39%

10.9 mo

50%

6.3 mo

45%

8.9 mo

49%

NR

31.6%

10.5 mo

NR

5.7 mo

29%

13.5 mo

55.8%

4.8 mo

* Before vitamin supplementation

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Second-Line NSCLC Monotherapy –Alimta Phase II Study (N=79)

Smit et al. (2003)*

100%

66%

Relapsed < 3 mo

Relapsed < 1 mo

Response Rate

Median Survival

1-Year Survival

Median TTPD

8.9%

5.7 mo

23%

2.0 mo

* Before vitamin supplementation

38

Alimta Safety Profile

As with most antifolates, the primary toxicity is hematologic

Early data showed that high serum homocysteine levels – a surrogate for functional folate and/or B12

deficiency – correlated with higher levels of toxicity

A decision was made to supplement all patients with folic acid and vitamin B12

This resulted in decreased toxicity with no detrimental effect on efficacy

39

0

20

40% Without FA/B12 (N=246)

With FA/B12 (N=220)

Or

G3/

4 Non

hem

Tox

Toxicity in Patients With and Without FA/ Vitamin B12 Supplementation

P=<0.0001

P =<0.0001

P =0.0053 P =0.026

* No toxic death reported

*

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Summary of the Development of Alimta

Alimta has shown activity in NSCLC

– Single agent 1st and 2nd-line

– Combination with platinum agents in 1st-line

Safety of Alimta has been well characterized

– Toxicity significantly reduced after Folic Acid / B12

– Very low incidence of neutropenia, febrile neutropenia, and other non-hematologic toxicities

A pivotal Phase III study in the treatment of 2nd-line NSCLC was indicated

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Pivotal Study JMEI

Randomized Phase III Study of Alimta vs Docetaxel in Patients with Locally

Advanced or Metastatic NSCLC Previously Treated with Chemotherapy

Paul A. Bunn, Jr., MD Grohne/Stapp Professor & Director, University of Colorado Cancer Center Executive Director, International Association for the Study of Lung Cancer

42

Study Design

Patient Characteristics

Survival

Survival Analysis

– Alimta vs docetaxel

– Alimta vs historical BSC

Other Secondary Endpoints

Toxicity

Conclusion

Outline of Presentation

43

Alimta (N=283) 500 mg/m2 iv q3wks

(folic acid 350-1000 µg daily + vitamin B12 1000 µg q 9wks;

dexamethasone 4 mg bid on d-1, d0, d+1)

Balanced for:

ECOG PS 0/1 vs 2

Stage III vs IV

No. of prior regimens (1 or 2)

Best response to prior chemo

Time since last chemo

(< or > 3 mo)

Prior platinum Prior taxane

Homocysteine level (< or > 12 µm)

Center

Phase III Study of Alimta vs Docetaxel in 2nd-Line NSCLC

RANDOMIZE

Docetaxel (N=288)75 mg/m2 iv q3wks

(dexamethasone 8 mg bid on d-1, d0, d+1)

44

Primary Endpoint:

– Overall Survival HR

Major Secondary Endpoints:

– Progression-Free Survival

– Time to Progressive Disease

– Tumor Response Rate

– Toxicity

– Lung Cancer Symptom Scale

JMEI: Endpoints

45

Definition of Populations

Intent to treat (ITT): All randomized patients,

regardless of therapy. Primarily used for

efficacy analyses.

Randomized and Treated (RT): All randomized

patients who received at least one dose of

chemotherapy. Primarily used for safety

analyses.

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Inclusion Criteria– Histologic/cytologic Stage III or IV NSCLC

– Only 1 regimen for metastatic disease

– ECOG PS 0-2

– Adequate end organ function

Exclusion Criteria– Symptomatic brain metastasis

– Grade 3 or 4 peripheral neuropathy

– Weight loss > 10% over previous 6 weeks

– Uncontrolled pleural effusions

– Prior docetaxel therapy

JMEI: Inclusion/Exclusion Criteria

47

JMEI: Baseline Characteristics (ITT)

Percent of PatientsAlimta

(N=283)Docetaxel(N=288)

ECOG PS 2 11.4% 12.4%

Stage IV 74.9% 74.7%

Median Age, years (range)

Male

59 (22-81)

68.6%

57 (28-87)

75.3%

HistologyAdenocarcinomaSquamous

54.4%27.6%

49.3%32.3%

Homocysteine levels <12 μm 71.4% 68.9%

48

JMEI: Baseline Characteristics (ITT)

Percent of PatientsAlimta

(N=283)Docetaxel(N=288)

Best Response to Prior ChemoCR/PR 35.6% 36.5%

< 3 mo since Last Chemo 50.4% 48.1%

Prior Taxane 25.8% 27.8%

Prior Platinum 92.6% 89.9%

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JMEI: Treatment Delivered (RT)

Alimta(N=265)

Docetaxel(N=276)

No Treatment Delivered (ITT-RT) 18 12

Patients Received > 4 Cycles 136 139

No. Cycles, Median (range) 4 (1-20) 4 (1-14)

Planned Dose Intensity 96.6% 94.4%

Dose Delays 19.8% 17.8%

Dose Reductions* 1.2% 5.6%

* p<0.001

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MST 8.3 mo1-yr OS: 29.7%

MST 7.9 mo1-yr OS: 29.7%

MST = median survival time * Test of superiority and 10% non-inferiority not statistically significant

JMEI: Survival (ITT)

0 181512963 21

1.00

0.75

0.50

0.25

0.00

Su

rviv

al D

istr

ibu

tio

n

Months

HR 0.99

95% CI of HR (0.82, 1.20*)

Alimta (N=283)

Docetaxel (N=288)

51

Interpreting the Efficacy of Alimta Relative to BSC

Retention method was used to estimate the percent of

docetaxel benefit over BSC retained by Alimta

– 95% CI for %-retention pre-specified in the Analysis Plan

– Based on TAX 317B (75 mg/m2 docetaxel randomized vs BSC)

– Accounts for variability (sample size) in TAX 317B and JMEI

– Allows for a survival comparison of Alimta to historical BSC

– Assumes a reasonable comparability of TAX 317B and JMEI

52

Patient Demographics for TAX 317 and JMEI

TAX 317 Data (N=204)

JMEI (N=571)

Performance status (2) 15% 12%

Stage IV 79% 75%

Median Age, years 61 58

Male 67% 72%

Best response to prior chemo (other than CR/PR)

65% 64%

Prior taxane 0% 27%

Prior platinum 100% 91%

Number of prior chemo (2) 25% 6%

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JMEI Docetaxel (N=288) 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

3 6 9 12 15 18 21

Survival Time (months)

Cu

mu

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abili

ty

TAX 317 Docetaxel (N=55)

JMEI: Survival with TAX 317 (ITT)

HR (Alimta vs BSC) 0.55

95% CI: 0.33, 0.90

p-value= 0.019

JMEI Alimta (N=276)

TAX 317B BSC

(N=49)

54

JMEI: Overall Survival

* Percent retention based on TAX 317 (B) results

JMEI 95% CI

0%

0.70 1.400.82

157% 52%

Alimta superior to BSC*

1.33

1.20

102%Percent Retention*

Hazard Ratio

Alimta vs docetaxel

78%

1.11

Alimta within 10% margin of docetaxel

Alimta retains >50% of docetaxel benefit*

1.211.00

Alimta superior to docetaxel

0.99

55

JMEI: Overall Survival

ITT Population RT Population

Alimta(N=283)

Docetaxel (N=288)

Alimta (N=265)

Docetaxel (N=276)

Events 206 203 192 198

NI p-value for testing 50% retention

0.047 0.036

95% CI of estimated percent of efficacy retained by Alimta

(52%, 157%) (58%, 168%)

50% retention non-inferiority test based on point estimate of control effect (HR docetaxel/BSC = 0.555)

56

Stage of disease (III vs IV)

Performances status (0 or 1 vs 2)

Time since last chemotherapy ( 3 vs 3 mo)

Best response to prior chemotherapy (CR/PR vs SD vs PD/unknown)

Prior taxane use (Yes vs No)

Prior platinum use (Yes vs No)

Prior chemotherapies (1 vs 2)

JMEI: Stepwise Cox Multiple Regression Survival Model

57

Variable p-value HR

(95% CI for HR)

Performance Status (0 – 1 over 2)

< 0.001 0.25 (0.19, 0.34)

Time since last chemotherapy ( 3 mo over 3 mo)

0.004 0.74 (0.60, 0.90)

Stage of Disease (III over IV) 0.026 0.77 (0.60, 0.97)

Cox Multiple Regression Model

JMEI: Factors Predictive of Survival

58

JMEI: Adjusted Overall Survival (ITT)

0.70 1.400.76

JMEI 95% CI

Hazard Ratio 0.93

Alimta within 10% margin of docetaxel

3.6 days1.11

1.13

HR 0.93

95% CI of HR (0.76, 1.13)

p-value vs 1.11 = 0.051

59

JMEI: Survival Analyses for Key Subgroups

N Evaluable HRAdjusted

HR Prior Platinum 521 1.03 0.95 No Prior Platinum 50 0. 74 0.91

No Prior Taxane Prior Taxane

418153

1.030.97

0.970.84

Performance Status 0 or 1 474 1.00 0.99 Performance Status 2 64 0.75 0.73

Stage III 144 1.01 1.11 Stage IV 427 0.99 0.89

< 3 mo since last chemo 277 1.06 0.97 > 3 mo since last chemo 286 0.92 0.90

No treatment differences within subgroups

60

Primary Endpoint:

– Overall Survival HR


– Progression-Free Survival (PFS)

– Time to Progressive Disease (TTPD)


– Toxicity


JMEI: Endpoints

61MPFS = median progression-free survival

JMEI: Progression-Free Survival (ITT)

HR 0.97

95% CI of HR (0.82, 1.16)

MPFS = 2.9 mo

MPFS = 2.9 mo

0 181512963 21

1.00

0.75

0.50

0.25

0.00

Su

rviv

al D

istr

ibu

tio

n

Months

Alimta (N=283)

Docetaxel (N=288)

62

JMEI: Time to Disease Progression (ITT)

1.00

0.75

0.50

0.25

0.00

Su

rviv

al D

istr

ibu

tio

n F

acto

r

0 181512963 21

Alimta (N=283)

Docetaxel (N=288)

Months

MTTPD = 3.4 mo

MTTPD = 3.5 mo

HR 0.97

95% CI of HR (0.80, 1.17)

MTTPD = median time to disease progression

63

Type

No. of Patients in Each Arm (%)

Alimta (N=265)

Docetaxel (N=276)

1 Chemotherapy 126 (47.5) 107 (38.8)Platinum 9 (3.4) 15 (5.4)Docetaxel 85 (32.1) 11 (4.0)Paclitaxel 4 (1.5) 3 (1.1)Vinorelbine 6 (2.3) 25 (9.1)Gemcitabine 17 (6.4) 32 (11.6)Other chemo 22 (8.4) 34 (12.3)Gefitinib 5 (1.9) 21 (7.6)

JMEI: Post Study Chemotherapy Received (RT)

64

JMEI: Survival by Post Study Chemotherapy Group (RT)

Patient PopulationAlimta

(N=265) MSDocetaxel (N=276) MS

No post-study chemo 139 6.2 mo 169 5.0 mo

Any post-study chemo 126 9.8 mo 107 10.8 mo

Post-study docetaxel therapy

85 9.6 mo 11 10.1 mo

Other chemotherapy 41 10.6 mo 96 11.2 mo

65

JMEI: Post Progression Survival

Alimta (N=213)

Docetaxel (N=208)

HR 1.01

95% CI of HR (0.81, 1.27)MST 4.5 mo

MST 4.5 mo

Surv

ival

Dis

tribu

tion

Func

tion

0.00

0.25

0.50

0.75

1.00

Post Progression Survival

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

STRATA: trt_01=Docetaxel trt_01=LY231514

1.00

0.75

0.50

0.25

0.00

Su

rviv

al D

istr

ibu

tio

n F

acto

r

0 1512.5107.552.5 17.5 20

Post Progression Survival

66

JMEI: Response Rates

0

10

20

30

40

50

9.1% (CI 5.9, 13.2) 8.8%

(CI 5.7, 12.8)

45.8%(CI 39.7, 52.1)

46.4%(CI 40.3, 52.5)

Complete and partial response

Stable Disease

Alimta (n=264)

Docetaxel (n=274)

67

Statistically Significant Grade 3/4 CTCToxicities Regardless of Causality (RT)

Percent of Patients

Toxicity Alimta

(N=265)Docetaxel(N=276) p-value

Febrile Neutropenia 1.9 12.7 <0.001

Neutropenia 5.3 40.2 <0.001

Infect w Gr 3/4 Neutropenia

0 5.8 <0.001

Diarrhea 0.4 4.0 0.006

Alopecia (all grades) 11.3 42.4 <0.001

ALT 2.6 0.4 0.034

68

Benefit of Alimta in Second-Line NSCLC

Survival of Alimta compared to docetaxel:

– Overall survival is similar

– Retains 102% of docetaxel benefit (over BSC)

– Internal consistency within subgroups

– No cross-over or other post-study chemotherapy effect

Superior survival to historical BSC

Similar response rate to docetaxel

Similar PFS and TTPD to docetaxel

Superior safety profile to docetaxel

69

Safety Results and Patient Reported Outcomes

Richard J. Gralla, MDPresident, Multinational Association of Supportive

Care in Cancer

JMEI Randomized Trial:Alimta vs Docetaxel in Second-Line

NSCLC

70

Primary Endpoint:

– Survival





– Toxicity


JMEI: Endpoints

71

Patient Reported Outcomes:Evaluation Methods in the JMEI Trial

Lung Cancer Symptom Scale (LCSS)

– Well validated with published psychometrics *

– Patient (9 items) & Observer (6 items) forms– Developed for clinical trials and patient management– Used in many randomized, multicenter trials in lung cancer

Evaluation

– Patients completed the instrument weekly while on trial

– 85% of patients adequately completed the PRO evaluation

* Reference: Hollen et al Cancer, 1994.

72

Maximum Symptom Improvement from Baseline for Patients with CR/PR vs SD vs PD

-5

0

5

10

15

20

25A

no

rex

ia

Fa

tig

ue

Co

ug

h

Dy

sp

ne

a

He

mo

pty

sis

Pa

in

AS

BI

CR/PR (n=42)

SD (n=231)

PD (n=211)

ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004

73

Maximum Symptom Improvement from Baseline for Patients with CR/PR + SD

0

5

10

15

Anorexia Fatigue Cough Dyspnea Hemoptysis Pain ASBI

Pemetrexed (n=133)Docetaxel (n=140)

All between-arm comparisons were not statistically significant

ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004

74

Primary Endpoint:

– Survival





– Toxicity


JMEI: Endpoints

75

Docetaxel Toxicities (75 mg/m2) Regardless of Causality (per Label)*

Toxicity Any Grade 3/4

Neutropenia 84.1 65.3

Febrile Neutropenia - 6.3**

Infection 33.5 10.2

Asthenia 52.8 18.2

Nausea 33.5 5.1

Vomiting 21.6 2.8

Stomatitis 26.1 1.7

Diarrhea 22.7 2.8

Neurosensory 23.3 1.7

Hypersensitivity 5.7 2.8

Fluid Retention 35.5 2.8

Rash 19.9 0.6

Alopecia 56.3 -

* Data combined from TAX 317 and TAX 320

** ANC Grade 4 with fever >38°C with iv antibiotics and/or hospitalization

76

Percent of Patients

EventAlimta


On-study deaths*: Regardless of causality Drug-related

11.71.1

14.5 1.8

NS NS

Patients with 1 or more SAE: Regardless of causality Drug-related

37.410.2

43.523.9

NS<0.001

Patients with 1 or more TEAE: Regardless of causality Drug-related

97.778.1

98.685.9

NS0.025

JMEI: Adverse Events (RT)

* On-study or within 30 days of discontinuation

77

JMEI: Summary of Deaths

On-Study*Deaths Alimta Docetaxel p-value

Study drug related 3 5 0.725

Study disease related 18 26 0.276

Other 10 9 0.818

Total 31 40 0.374

Number of patients

* On-study or within 30 days of discontinuation

78

JMEI: Adverse Events (RT) NCI Common Toxicity Criteria v2 – Example: Neutropenia

Neutrophils/mm3 Risk / Impact

Grade 1 > 1500 < 2000 None

Grade 2 > 1000 < 1500 Very Low

Grade 3 > 500 – 1000 Moderate

Grade 4 < 500 Very High

79

Percent of Patients

Toxicity Alimta


Neutropenia 5.3 40.2 <0.001Febrile Neutropenia

1.9 12.7 <0.001

Infection with Gr 3/4 Neutropenia

0 5.8 <0.001

AnemiaThrombocytopeniaCreatinineALTAST

7.5 1.90.0

2.6 1.1

6.20.70.0

0.4 0.4

0.6100.277

1.0 0.034 0.364

Bilirubin 0.8 0.0 —

JMEI: Grade 3/4 Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)

80

Percent of Patients

ToxicityAlimta

(N=265) Docetaxel

(N=276) p-value

Fatigue 15.8

16.7 0.817

Nausea 3.8

2.5 0.466

Vomiting 1.5 1.4 1.0Stomatitis 1.1 1.1 1.0Diarrhea 0.4 4.0 0.006Neurosensory 7.5 9.8 0.365Hypersensitivity 0.0 1.8 0.062Fluid Retention 0.4 0.4 1.0Rash 0.0 0.0 1.0Alopecia (all grades) 11.3 42.4 <0.001

JMEI: Gr 3/4 Non-Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)

81

Percent of Patients

ToxicityAlimta (N=265)

Docetaxel (N=276) p-value

All Grade 1 26 23.9 0.620

All Grade 2 29.4 25.0 0.288

All Grade 3 18.1 30.4 <0.001

All Grade 4 5.3 34.1 <0.001

JMEI: Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)

82

JMEI: Transfusions and Growth Factors (RT)

Percent of Patients

Alimta (N=265)


Red Blood Cell Transfusions

16.6 11.6 0.108

Erythropoietin 6.8 10.1 0.169

G-CSF/GM-CSF 2.6 19.2 <0.001

83

Percent of Patients

ToxicityAlimta


All Grade 1 95.1 92.0 0.165

All Grade 2 93.6 93.8 >0.999

All Grade 3 60.0 68.1 0.060

All Grade 4 14.3 22.5 0.020

JMEI: Non-Lab Toxicities Regardless of Drug Causality (RT)

84

JMEI: Hospitalizations (RT)

Percent of Patients

Alimta (N=265)


Any Hospitalizations 48.7 52.9 0.345

>1 Hospitalization due to AE 31.7 40.6 0.032

All drug-related hospitalization

Any drug-related hospitalization

Due to febrile neutropenia

7.2

1.5

21.7

13.4

<0.001

<0.001

Due to other drug-related AEs 6.4 10.5 0.092

85

Toxicity-Free (Any Grade 4) Survival Curve

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

Toxicity Free Survival Time (Months)

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5

Alimta (n=265)

Docetaxel (n=276)

MTFS 7.5 months; 1yr TFS 27.8%

MTFS 2.3 months; 1 yr TFS 16.0%

HR 0.5795% CI of HR (0.47, 0.69)

86

JMEI: Safety Conclusions

From a safety standpoint, Alimta represents a superior treatment option in the second line treatment of NSCLC

— Significantly less neutropenia and febrile neutropenia*

— Significantly less alopecia and diarrhea*

— Significantly fewer drug-related serious adverse events*

— Fewer on-study deaths

— Significantly fewer hospitalizations due to adverse events

— Less use of supportive care

* p < 0.006

87

Overall Conclusions

Paul A. Bunn, Jr., MD

Grohne/Stapp Prof. & Director, University of Colorado Cancer Center Exec. Director, International Association for the Study of Lung Cancer

88

Treatment Options in Second-Line NSCLC

Alimta provides a safe and effective 2nd-line option for NSCLC patients and this

is especially important because:

Advanced stage NSCLC patients are living longer and better lives, therefore more receive 2nd-line therapy

Docetaxel is the only approved compound for 2nd-line NSCLC

Docetaxel safety profile limits its use in 2nd-line

89

Evidence for Clinical Benefit of Alimta in 2nd-Line NSCLC (RT): Safety

Alimta(N=265)

Docetaxel(N=276)

Febrile Neutropenia 1.9% 12.7%

G-CSF/GM-CSF 2.6% 19.2%

Grade 3/4 Diarrhea 0.4% 4.0%

Alopecia (all grades) 11.3% 42.4%

Drug-induced AE hospitalization

7.2% 21.7%

Alimta is safer with respect to clinically important toxicities

90

Toxicity Comparison of Safety Database for Single

Agent Alimta* Regardless of Drug Causality

Other Alimta SA** (N=207)

JMEI(N=265)

Gr. 3/4 Neutropenia 14.0 5.3

Febrile Neutropenia 1.8 1.9

Gr. 3/4 Platelets 3.7 1.9

Gr. 3/4 Anemia 2.4 7.5

Alopecia (any grade) 11.6 11.3

Gr. 3/4 Diarrhea 3.0 0.4

Toxic Deaths 0 1.1

* With vitamin supplementation

** Single Agent

91

Direct Comparison to Docetaxel

– HR=0.99 (0.93 adjusted)

– Median Survival (8.3 mo vs 7.9 mo)

– One-Year Survival (29.7% vs 29.7%)

– Internal consistency of subgroups

Indirect Comparison to BSC

– Preserves at least 50% of docetaxel’s benefit over BSC

– Superior to historical BSC

– Consistent Alimta survival results across 1st and 2nd line trials

Evidence for Clinical Benefit of Alimta in 2nd Line NSCLC: Survival

92

Evidence for Clinical Benefit of Alimta in 2nd Line NSCLC: Response, TTP

Direct Comparison vs. docetaxel Time to Tumor Progression (3.4 mo vs 3.5 mo) Progression-Free Survival (2.9 mo vs 2.9 mo) Response Rate (9.1% vs 8.8%) Over 50% of Alimta and docetaxel patients had improved

or stable symptoms

Indirect Comparison to BSC Comparable Overall response rates and median time to

progression between Alimta trials Superior response rates and TTPD

93

Consistency of Survival Results in Randomized Studies in 2nd-Line NSCLC

0

8

Me

dia

n S

urv

iva

l (m

o)

Do

c 7

5 m

g/m

2

Do

c 7

5 m

g/m

2

Do

c 7

5 m

q 2

1d

Do

c 75

mg

/m2

Do

c 7

5 m

q 2

1d

Do

c 3

3.3m

w

Do

c 3

6m

w

Vin

/Ifo

s

Ali

mta

50

0 m

g/m

2 q

21

d

TAX 317BN=104

TAX 320N=248

GridelliN=220

CampsN=254

JMEIN=571

JBR21N=364

BS

C

Erl

oti

nib

150

mg

q d

P

lac

eb

o a

nd

BS

C

Alimta produces survival equivalent to the best docetaxel results and superior to BSC

4

2

6

94

Alimta Clinical Benefit

Alimta merits full approval as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy based on:

– Superior PFS and survival compared to BSC

– Similar OR, PFS and survival compared to docetaxel

– Superior safety profile as compared with docetaxel.

Making available a safer effective treatment will improve the physicians’ ability to make treatment decisions for patients with this devastating disease.

1 Presentation to the Oncologic Drugs Advisory Committee Paolo Paoletti, MD Vice President Clinical...

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Transcript of 1 Presentation to the Oncologic Drugs Advisory Committee Paolo Paoletti, MD Vice President Clinical...