1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ONCOLOGIC DRUGS ADVISORY COMMITTEE

Tuesday, July 27, 2004

8:30 a.m.

ACS Conference Room

5630 Fisher Lane

Rockville, Maryland

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PARTICIPANTS

Otis W. Brawley, M.D., Acting Chair

Johanna M. Clifford, M.S., RN, Executive Secretary

MEMBERS

Ronald M. Bukowski, M.D.

Bruce D. Cheson, M.D.

James H. Doroshow, M.D.

Stephen L. George, Ph.D.

Antonio J. Grillo-Lopez, M.D.

Pamela J. Haylock, RN

Maha H.A. Hussain, M.D.

Alexandra M. Levine, M.D.

Joanne E. Mortimer, M.D.

Michael C. Perry, M.D.

Maria Rodriguez, M.D.

CONSULTANT (Voting)

Ralph D\'Agostino, Ph.D.

PATIENT REPRESENTATIVE (Voting)

Sheila Ross

FDA

Martin Cohen, M.D.

Richard Pazdur, M.D.

Robert Temple, M.D.

Yong-Cheng Wang, Ph.D.

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C O N T E N T S

Page No.

Call to Order and Opening Remarks 5

Introduction of Committee 5

Otis Brawley, M.D.

Conflict of Interest Statement 7

Johanna Clifford, M.D., RN

NDA 21-677, Alimta (pemetrexed)

Eli Lilly & Company

Introduction

Richard Pazdur, M.D. 10

Sponsor Presentation

Introduction and Objectives of the Presentation

Paolo Paoletti, M.D. 21

Background on Non-Small Cell Lung Cancer

Second-Line Treatment

Frances Shepherd, M.D. 32

Alimta Development

Roy Herbst, M.D., Ph.D. 40

Clinical Efficacy from the Pivotal Study JMEI

Paul Bunn, M.D. 46

Safety Profile from the Pivotal Study JMEI

Richard Gralia, M.D. 64

Overall Conclusions

Paul Bunn, M.D. 78

FDA Presentation

Clinical Review

Martin H. Cohen, M.D. 86

Statistical Review

Yong-Cheng Wang, Ph.D. 103

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C O N T E N T S (Continued)

Page No.

Open Public Hearing 112

Questions from the Committee 114

ODAC Discussion 195

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P R O C E E D I N G S

Call to Order and Opening Remarks

DR. BRAWLEY: Good morning. I am Otis

Brawley. I am a professor at Winship Cancer

Institute of Emory University. I will be the

Acting Chair of the Oncologic Drugs Advisory

Committee for the day.

I would like to welcome everyone here and

like to start out by coming the meeting to order.

The first order of business will be to

introduce the members of the committee and then we

will have the conflict of interest statement read.

So, if we can start off to my left with

Ms. Sheila Ross, if you would introduce yourself,

and as members introduce themselves, if they could

mention what institution they are from.

Introduction of Committee

MS. ROSS: Thank you. Good morning. My

name is Sheila Ross. I am the Washington

representative for the Alliance for Lung Cancer. I

am here as a patient advocate. I am also a

two-time survivor of non-small cell lung cancer.

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DR. GRILLO-LOPEZ: My name is Antonio

Grillo-Lopez. I am a hematologist/oncologist with

the Neoplastic and Autoimmune Diseases Research

Institute.

MS. HAYLOCK: I am Pamela Haylock. I am

an oncology nurse and a doctoral student at the

University of Texas Medical Branch in Galveston,

and I am the consumer representative.

DR. D\'AGOSTINO: Ralph D\'Agostino from

Boston University, a biostatistician, consultant to

the panel.

DR. GEORGE: Stephen George, also in

biostatistics, Duke University.

DR. LEVINE: Alexandra Levine,

hematology/oncology at University of Southern

California in L.A.

DR. BUKOWSKI: Ronald Bukowski, medical

oncologist, The Cleveland Clinic.

DR. DOROSHOW: Jim Doroshow, medical

oncology, National Cancer Institute.

DR. RODRIGUEZ: Maria Rodriguez,

hematology/oncology at M.D. Anderson Cancer Center

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in Houston.

MS. CLIFFORD: Johanna Clifford, Executive

Secretary to this committee.

DR. HUSSAIN: Maha Hussain, Professor of

Medicine and Urology, University of Michigan.

DR. PERRY: I am Michael Perry from the

University of MIssouri, Ellis Fischel Cancer Center

in Columbia, Missouri, hematology/oncology.

DR. CHESON: Bruce Cheson,

hematology/oncology, Georgetown University,

Lombardi Comprehensive Cancer Center.

DR. WANG: Yong-Cheng Wang, FDA,

statistical reviewer.

DR. PAZDUR: Richard Pazdur, Division

Director, FDA.

DR. BRAWLEY: Thank you.

If Ms. Clifford could read the conflict of

interest statement.

Conflict of Interest Statement

MS. CLIFFORD: Thank you. The following

announcement addresses the issue of conflict of

interest and is made a part of the record to

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preclude even the appearance of such at this

meeting.

Based on the submitted agenda and all

financial interests reported by the committee

participants, it has been determined that all

interests in firms regulated by the Center for Drug

Evaluation and Research present no potential for

appearance of a conflict of interest with the

following exceptions:

Dr. Ronald Bukowski has been granted a

208(b)(3) waiver for consulting with a competitor

on an unrelated matter. He receives less than

10,001 a year.

Dr. Maha Hussain has been granted waivers

under 208(b)(3) and 21 USC 505(n) for owning stock

in two competitors. The stocks are valued from

\$25,001 to \$50,000, and from \$50,001 to \$100,000.

Sheila Ross has been granted a waiver

under 21 USC 505(n) for owning stock in a

competitor, valued between \$5,001 to \$25,000.

Because her stock interests falls below the de

minimis exception allowed under 5 CFR

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2640.202(b)(2), a waiver under 18 USAC 208 is not

required.

A copy of the waiver statements may be

obtained by submitting a written request to the

agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building.

We would also like to note that Dr.

Antonio Grillo-Lopez is participating as the acting

industry representative, acting on behalf of

regulated industry. Dr. Grillo-Lopez is employed

by the Neoplastic and Autoimmune Disease Research

Institute.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

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upon.

Thank you.

DR. BRAWLEY: Thank you, Ms. Clifford.

The committee is gathered today to discuss

the New Drug Application for Alimta or pemetrexed,

an Eli Lilly compound proposed as a single agent

treatment of patients with locally advanced or

metastatic non-small cell lung cancer after prior

chemotherapy.

I would now like to introduce Dr. Richard

Pazdur, Director of the Division of Oncology Drug

Products, Center for Drug Evaluation & Research of

the FDA to give us an introduction.

NDA 21-677, Alimta (pemetrexed)

Eli Lilly & Company

Introduction

Richard Pazdur, M.D.

DR. PAZDUR: Thank you, Otis. It is a

pleasure to be here, and I welcome the

participants, the members of ODAC, as well as the

audience to this most interesting ODAC

presentation.

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I have entitled my comments \"Inferiorities

of Non-Inferiority Trials.\" I will just start off

by saying I was listening to the Democratic

Convention yesterday and Al Gore was talking about

the 2000 election, and he said, \"There are winners,

there are losers, and then there is this third

area,\" and it is kind of this third area, if I

could take some statistical liberties that we are

going to be talking about, and that is this whole

area of non-inferiority, not positive, not

negative, but some assumption of being equal.

I would like to preface today\'s

presentation with a few comments really to focus

your attention on key issues. This NDA highlights

some unique challenges in developing oncology drugs

regarding non-inferiority trial design and

analysis.

Survival as an endpoint for regular

approval has been a well-established endpoint for

clinical benefit and regular approval. In oncology

trials, test drugs have generally demonstrated

survival improvements compared to active controls.

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Alternatively, an effect on the survival

endpoint may be accomplished by demonstrating a

non-inferior survival effect. Non-inferiority

ensures that a survival advantage, the so-called

\"control effect,\" would not be lost by a new agent.

To determine the control effect, external

historical information from multiple control trials

is generally required.

A certain proportion of the control

effect, known as the margin, should be preserved to

demonstrate non-inferiority. The active control in

a non-inferiority trial should have an effect that

is of substantial magnitude and that can be

precisely estimated with estimates relevant to the

setting.

The ICHE9 guidance states that an

acceptable active comparator \"could be a widely

used therapy whose efficacy in the relevant

indication has been clearly established and

quantified in well-designed and well-documented

superiority trials\"\--and I emphasize the plurality

of that word\--\"and which can be reliably expected

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to have similar efficacy in the contemplated active

control trial.\"

The active control, therefore, should be

preferably derived from multiple studies with a

large consistent drug effect suitable for a

convincing meta-analysis to be performed.

Constancy assumptions must be addressed in

designing a non-inferiority trial, ensuring that

the active control effect should be the same as in

the historical controls. These considerations

ensure that the population enrolled in the

historical trials is similar to the population in

the proposed trial with respect to baseline

characteristics, supportive care, additional

available therapies, and observational frequencies.

The primary objective in the present

Alimta trial was not achieved. Neither superiority

nor non-inferiority to docetaxel were adequately

demonstrated.

The FDA believed that Alimta\'s

non-inferiority for overall survival cannot be

demonstrated for two reasons. First, only a single

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small historical study exists to estimate the

docetaxel treatment effect. This study randomized

a total of 104 patients, approximately 50 patients

in each arm, to receive either docetaxel or best

supportive care.

A second study was used in the docetaxel

approval consideration. This study compared

docetaxel to either ifosfamide or vinorelbine.

Neither agent had a demonstrated survival effect in

this setting.

This second trial failed to demonstrate an

overall survival benefit associated with docetaxel,

however, there was an improvement in one-year

survival. Although sufficient data existed to

approve docetaxel in this setting, the FDA believed

that there is not a reliable and reproducible

characterization of the docetaxel effect to use in

a non-inferiority analysis. Constancy assumptions

cannot be verified and interstudy variability is

unknown.

An additional concern is the existence of

crossover in the present study. Over 30 percent of

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patient randomized to receive Alimta subsequently

received docetaxel at disease progression.

Crossover obscures the differences between

treatments, hence, in a superiority trial,

crossover may lead to a false negative conclusion

potentially denying an active drive a marketing

claim.

The use of a time to progression endpoint,

an analysis occurring prior to crossover, may be

preferred in settings where significant crossover

is expected.

In contrast to superiority trials,

crossover in non-inferiority trials may lead to a

false positive conclusion. This crossover

confounds our interpretation of survival since the

observed survival in both arms can theoretically be

attributed to the control drug, in this case

docetaxel.

Similarly, data integrity problems, known

as trial sloppiness, either lack of attention to

details in data collection or execution may obscure

the observation of differences leading to false

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positive non-inferiority trials, hence, the agency

has strongly recommended two trials to support a

non-inferiority claim in an attempt to ascertain a

true effect.

For regular approval of a drug, the

sponsor must demonstrate that the drug is safe and

effective in adequate and well-controlled trials.

The effectiveness must be demonstrated on an

endpoint that the agency believes to represent

clinical benefit, usually survival, disease symptom

amelioration or established surrogates for these.

The sponsor is not obligated to show that

the drug is safer and/or more effective than an

approved drug. Many other therapeutic areas

conduct placebo-controlled trials, drug A versus

placebo, ensuring that superiority can be easily

demonstrated even if a comparator drug is

commercially available.

It is more difficult to demonstrate

superiority in an active control trial, drug A

versus drug B. The test drug must possess the

entire activity of the active control on the

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endpoint plus an incremental addition effect to

demonstrate superiority.

The agency has frequently recommended

add-on trials, A plus B versus B. This design was

used in the approval of Alimta plus cisplatinum in

mesothelioma earlier this year.

In the add-on design, the test drug plus

active control combination is compared to the

active control alone or, alternatively, active

control plus placebo. This design ensures that all

patients receive the active treatment, yet isolates

the test drug\'s effect.

To demonstrate superiority, the test drug

must only possess an incremental advantage over the

active control on the primary endpoint rather than

the control effect plus an increment.

We will be asking the committee to

consider this application for accelerated approval.

For accelerated approval, an improvement over

available therapy must be demonstrated and may

utilize a surrogate endpoint \"reasonably likely to

predict clinical benefit.\"

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A more favorable safety profile could

constitute a \"improvement over available therapy.\"

This decision requires considerable clinical

judgment, and is not merely an exercise in adding

up Grade 3 and 4 toxicities in two columns and

declaring a winner.

The importance of a selected toxicity in

patient management, toxicity duration, and

overlapping toxicity, such as concomitant

neutropenia plus diarrhea, concomitant neutropenia

plus stomatitis may direct your clinical opinion.

With regards to surrogate endpoints for

accelerated approval in this application, the

agency has used response rates of similar magnitude

and duration as demonstrated in this Alimta trial

for past accelerated approvals in similar disease

settings.

In making a regulatory decision, we must

consider all available data, a comprehensive drug

evaluation including past approvals and single-arm

studies. As noted, Alimta in combination with

cisplatinum was approved for a mesothelioma

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indication earlier this year. An improvement in

overall survival advantage was demonstrated, the

first for a drug in this disease.

In contrast to other accelerated approval

applications that commonly use single-arm trials,

the sponsor has provided a large randomized trial.

Randomized trials always provide greater

information.

We have comparative response rate data, we

have comparative toxicity data, and we have the

ability to examine time to event endpoints although

we believe formal, non-inferiority analysis can

neither be performed on TTP nor survival.

The sponsor is conducting large randomized

trials in early lung cancer that can serve as

confirmatory studies for clinical benefit if

accelerated approval is granted. The statistical

analysis and the design of non-inferiority trials

is an evolving field and represents considerable

challenges.

Non-inferiority trials are difficulty.

They take considerable resources in planning,

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designing, and executing trials and usually require

considerable patient resources.

In conclusion, winning is always better

than tieing. The demonstration of superiority is

always better than that of non-inferiority.

Winning moves the field forward by identifying new

agents and treatments.

However, a win may not only be an efficacy

improvement, but may also be a safety improvement

especially in a field such as oncology where

toxicity concerns may dictate treatment choices or

whether a patient even receives any therapy.

However, as we would like you to discuss

later this morning, this regulatory decision must

be carefully weighed against the clinical relevance

of any potential survival loss.

I hope these comments will focus your

attention and deliberations on the essential issues

presented in this application.

Thank you.

DR. BRAWLEY: Thank you, Dr. Pazdur.

Our sponsor presentation will now begin

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and last over the next hour.

If I can introduce Dr. Paolo Paoletti of

Eli Lilly, who will give us the introduction

objectives, and if you would present the presenters

as we move along.

I should add that we are going to hold all

questions until after the open public hearing.

Sponsor Presentation

Introduction and Objectives of the Presentation

Paolo Paoletti, M.D.

DR. PAOLETTI: Good morning. My name is

Paolo Paoletti. I am the Vice President for Lilly

Oncology Clinical Research and Oncology Products.

I want to thank the FDA and the members of the

Advisory Board for allowing Lilly to present the

data on Alimta for the treatment of second-line

non-small cell lung cancer.

\[Slide.\]

Here is the agenda for the Lilly

presentation. I will give a short introduction on

the objectives of the presentation, the historical

context, and the rationale for the design of the

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pivotal registration trial.

Dr. Frances Shepherd, Professor of

Medicine at the University of Toronto, and

President of the International Association for the

Study of Lung Cancer, and also principal

investigator for the Phase III pivotal trial,

Alimta versus docetaxel, will give the ground for

the treatment of second-line non-small cell lung

cancer.

Dr. Roy Herbst, the Chief of Thoracic

Oncology at M.D. Anderson, University of Texas,

will present the development of Alimta after the

pivotal trial JMEI.

Dr. Paul Bunn, Director of the University

of Colorado Cancer Center, past President of ASCO,

and principal investigator for the Phase III trial

Alimta versus docetaxel will present the efficacy

result of the pivotal trial JMEI.

Dr. Richard Gralla, President of the

Multinational Association of Supportive Care, will

report the data on safety profile and patient

reported outcomes for the same trial.

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Finally, Dr. Bunn will give the

conclusion.

\[Slide.\]

Additional experts from other

international academic institutions are here today

to answer your questions, and also experts from

Lilly.

\[Slide.\]

In this slide, you can see the specific

expertise are here to answer to your questions.

\[Slide.\]

The objective of the presentation is to

provide evidence that Alimta is effective and safe.

We intend to show that given the superior

safety results, Alimta has a better risk-to-benefit

profile than docetaxel and provides benefit to

patients with non-small cell lung cancer.

This is supported by, first, Alimta is a

novel and effective agent in non-small cell lung

cancer. Alimta has the same efficacy as docetaxel

when looking at the variety of efficacy endpoint

including survival, time to progressive disease,

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response rate in the entire population of patients.

In addition, this efficacy is consistently

present when looking at the large number of

subgroups. Alimta is estimated to retain 102

percent of docetaxel benefit over best supportive

care.

Alimta is superior to historical best

supportive care. Alimta has an excellent safety

profile and superior safety results when compared

to docetaxel. Therefore, Alimta offers an

effective and safer second-line treatment option

for patients with non-small cell lung cancer.

\[Slide.\]

We propose the following 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, and at the dose of 500 mg/m2 i.v.

with a 10-minute infusion at day 1 of each 21-day

cycle, and to control toxicity, oral folic acid at

the daily dose of 350-1,000 microgram and vitamin

B12 at the dose of 1,000 microgram every 3 cycles

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given IM, dexamethasone 4 mg/bid on day minus 1,

day of the treatment, and day plus 1.

\[Slide.\]

In this slide, I summarize the historical

context and the rationale for the statistical

design when the pivotal trial JMEI was initiated.

Alimta showed consistent activity in

non-small cell lung cancer in seven Phase II trials

as a single agent or in combination with platinum

agents both in first- and second-line.

This activity compares well with data from

other commonly used regimens. Folic acid and B12

interventions significantly improve the safety

profile of Alimta, however, the magnitude of this

intervention was not completely known at the time

of the initiation of the Phase III pivotal trial

JMEI.

It was decided to proceed with the Phase

III trial in second-line to offer a better

alternative treatment.

\[Slide.\]

The trial, as Dr. Pazdur was saying,

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presented several design challenges and

limitations, but we decided to run a head-to-head

trial Alimta versus docetaxel.

We wanted to run a global clinical trial

to support global registration. Best supportive

care in second-line treatment of non-small cell

lung cancer was considered not practical because of

the presence of the docetaxel as an approved agent

in second-line treatment and not feasible in the

United States and in many countries in Europe.

Combination chemotherapy was considered

not appropriate especially in this second-line

setting. Docetaxel was approved in second-line

non-small cell lung cancer primarily based on the

result of the trial TAX 317B where superior

survival over best supportive care was demonstrated

in 55 patients treated at the dose of 75 mg/m2.

Survival was selected as the primary

endpoint, however, we acknowledge the presence of

limited historical data on the effect of docetaxel.

Moreover, a pure equivalency trial would require

more than 4,000 patients.

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\[Slide.\]

The JMEI is a global registration trial,

and we discussed the statistical design with both

FDA and the European Regulatory Agency. Sample

size of 520 patients allows for testing of

superiority. With the assumption of superiority,

this sample would also allow for testing

non-inferiority. The hazard ratio was the basis to

compare treatment arms for survival.

The protocol specified superiority

testing, as well as testing 10 percent fixed margin

for non-inferiority. This margin was agreed upon

with the European Agency. We always believe this

was a very conservative matching. Indeed, the

magnitude of the effect of folic acid

supplementation on toxicity was not known at the

time. Thus, safety advantages of Alimta were not

considered in the definition of this match.

Before unblinding the data, we included

the percent retention method for non-inferiority in

the statistical analysis plan. The FDA suggested

for the evaluation of Alimta the retention of the

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effect of docetaxel, docetaxel versus best

supportive care.

The FDA used this methodology to approve

docetaxel in breast cancer and capecitabine in

colon cancer. Rothmann and co-authors published

percent retention method in January 2003, and the

details of the percent retention analysis were

included in the statistical analysis plan before

unblinding the data and before any analysis was

undertaken.

\[Slide.\]

This slide shows the Alimta lung cancer

submission timeline. The first patient was

enrolled on March 20, 2001. The last patient was

enrolled on February 6, 2001. The Final

Statistical Analysis Plan was approved on January

24, 2003.

Unblinding of the analysis and the data

occurred on January 30, 2003. U.S. fast track

designation for second-line treatment of non-small

cell lung cancer was granted on July 23, 2003.

Non-small cell lung cancer submission was filed in

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November 4, 2003 in the U.S., and in July 2003 for

Europe.

In June 22nd of this year, the European

CHMP, the regulatory agency, gave a positive

opinion for both second-line non-small cell lung

cancer and mesothelioma.

\[Slide.\]

Alimta has already shown to be an active

agent in cancer. In fact, Alimta, in combination

with cisplatin, was approved on February 4, 2004

for the treatment of mesothelioma in the United

States.

This slide shows the survival curve. You

can see that the combination Alimta plus cisplatin

has a median survival of 12.1 months, while

cisplatin alone has a median survival of 9.3

months. The difference was statistically

significant at P of 0.02.

\[Slide.\]

Based on the evidence of the next

presentation, we believe that Alimta merits the

approval for the treatment of second-line non-small

30

cell lung cancer for the following reasons.

Seven Alimta Phase II studies in

first-and second-line non-small cell lung cancer

show consistent evidence of activity within the

range of activity of other agents currently

available.

From this large Phase III randomized

clinical trial in second-line non-small cell lung

cancer, Alimta showed consistent similar clinical

efficacy when compared to docetaxel in all primary

and secondary endpoints and in all subgroup

analyses.

Alimta is better than historical best

supportive care. Moreover, Alimta is significantly

better for clinically relevant toxicity when

compared to docetaxel.

Only docetaxel is approved for second-line

treatment today, and there is a need for more

second-line treatment option.

\[Slide.\]

Alimta is an effective drug for the

treatment of second-line non-small cell lung

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cancer, and it has a better risk-to-benefit profile

when compared to docetaxel.

As you hear the rest of our presentation

and that from the FDA today, please keep into

consideration the following points:

Docetaxel at the dose of 75 mg has shown

activity across several studies in second-line of

non-small cell lung cancer after the pivotal trial

TAX 317B, however, its use is limited by its

toxicity. The results in 288 patients receiving

docetaxel in the JMEI pivotal trial confirms

docetaxel\'s survival effect.

As I mentioned before, docetaxel was

approved based on limited data, hence, the

imprecision of the effect of docetaxel made

non-inferiority design and related analyses very

challenging.

This context, together with the lack of

feasibility to conduct placebo-controlled trial

once the drug is approved makes further advancement

in drug development very difficult.

Although post-study treatment, inevitable

32

in the United States, may confound survival result,

the analysis from the pivotal trial JMEI suggest

that such a confounding effect is unlikely.

In conclusion, I respectfully request that

the members of this advisory board evaluate the

data in second-line treatment of non-small cell

lung cancer considering the overall efficacy and

safety that will be presented.

Now, Dr. Frances Shepherd will give the

background for the second-line treatment for

non-small cell lung cancer.

Background on Non-Small Cell

Lung Cancer Second-Line Treatment

Frances A. Shepherd, M.D.

DR. SHEPHERD: Thank you very much,

members and guests.

\[Slide.\]

In 1997, the ASCO Guidelines stated that

\"there is no current evidence that either confirms

or refutes that 2nd-line chemotherapy improves

survival in non-small cell lung cancer.\"

This conclusion was reached only seven

33

years ago because, at that time, only single-arm,

Phase II trials were available. However, several

trials of the third-generation agent docetaxel

suggested that this agent might be appropriate to

study further in randomized Phase III trials.

\[Slide.\]

In the first trial initiated, the TAX 317

study, patients previously treated with at least

one platinum-based regimen were stratified based on

their ECOG performance status, 0.1 versus 2, and on

their best response to prior chemotherapy.

They were randomized to receive either

docetaxel 100 mg/m2 or best supportive care.

Routine safety monitoring revealed 5 or 10 percent

early toxic deaths in the chemotherapy arm.

Therefore, after discussion with the principal

investigators and the FDA, the docetaxel dose was

reduced to 75 mg/m2 for the second half of the

study.

The sample size was maintained at 200

patients as originally planned due to the

difficulty in accruing patients to this study

34

because of the best supportive care arm.

\[Slide.\]

The overall response rates to docetaxel

100 and 75 mg/m2 were both 6 percent. Time to

progressive disease was 2.8 months for patients

treated with docetaxel 75 mg compared to only 1.6

months for best supportive care. Median survival

was significantly longer for docetaxel 75 mg

treated patients at 7.5 months compared to only 4.6

months for best supportive care. One-year survival

was 3-fold higher for docetaxel patients.

\[Slide.\]

Survival is shown graphically in this

slide for the second half of the trial at docetaxel

75 mg/m2, the FDA approved dose. Survival was

significantly longer for patients treated with

docetaxel with a log-rank p-value of 0.01.

One-year survival was significantly higher with a

chi-square p-value of 0.003.

\[Slide.\]

This is a very important slide to

concentrate on. In this trial, patients must have

35

received one platinum-containing regimen, but could

have received more than one regimen before entering

the trial.

As you can see from this slide, the

numbers of patients unfortunately are small, and

these must be considered exploratory subset

analyses, however, they suggest that patients

treated with docetaxel after two or more regimens

derived absolutely no survival benefit from the

treatment as compared to best supportive care

alone.

The entire survival benefit of the trial

came from the administration of docetaxel in the

true or strictly defined second-line setting.

\[Slide.\]

The second large trial was the TAX 320

trial and was performed in the United States where

a best supportive care trial could not be

conducted.

In this trial, patients were stratified by

their best response to platinum-based therapy and

performance status, and were randomized to receive

36

docetaxel 100 mg/m2 or docetaxel 75 mg/m2, or a

comparator of vinorelbine or ifosfamide. This was

largely vinorelbine.

\[Slide.\]

The overall response rate was 11 percent

for patients treated with docetaxel 100 mg, and 7

percent for patients in the 75 mg group. Both of

these response rates were significantly higher than

the 1 percent response rate noted in the control

group with p-values of 0.001 and 0.036.

There was no difference in median or

overall survival among the three treatment arms,

however, the one-year survival rate of 32 percent

for patients treated with docetaxel 75 mg, the

FDA-approved dose, was significantly better than

the 19 percent one-year survival rate of patients

treated with vinorelbine or ifosfamide. Chi square

p-value for this is 0.05.

\[Slide.\]

This is shown graphically on this slide

where you will see the survival curve separating in

the latter part.

37

\[Slide.\]

The FDA-approved label for docetaxel 75 mg

reports Grade 3/4 neutropenia of 65.3 percent,

Grade 3/4 infection of 10.2 percent, and using a

very stringent definition, febrile neutropenia rate

of 6.3 percent.

Although Grade 3 and 4 diarrhea and

neurotoxicity are rare at this dose of docetaxel,

lesser grades of both of these toxicities may be

distressing to patients. Similarly, alopecia,

although never life-threatening, may have a major

negative emotional impact on both men and women.

\[Slide.\]

Quality of life and symptom control was

measured in both the TAX 317 and 320 trials. Pain

was significantly better controlled in the 317

trial, and this was not because of increased opioid

use. You can see from this slide that opioid use

was the same at study entry in both arms of the

trial, however, significantly fewer patients

treated with docetaxel required additional opioids

and significantly fewer patients required the

38

introduction of new opioids.

\[Slide.\]

Weight loss was measured closely, and you

will see that in the TAX 317B trial, 25 percent of

patients treated with best supportive care had

weight loss greater than 10 percent compared to

only 2 percent of patients treated with docetaxel.

Weight loss greater than 10 percent was seen in

only 5 percent of patients treated with docetaxel

75 mg/m2 in the 320 trial compared to 8 percent for

vinorelbine patients.

\[Slide.\]

Treatment was not at the expense of

quality of life or performance status. Indeed,

performance status improved during the study for

patients treated with docetaxel whether measured at

initiation, across the cycles, or at the last

treatment.

\[Slide.\]

In summary, these landmark trials showed

that second-line chemotherapy prolonged survival in

non-small cell lung cancer. It also improved

39

symptom control and does not have a negative effect

on quality of life or performance status.

These trials led to the approval of

docetaxel 75 mg/m2 for the second-line treatment of

non-small cell lung cancer in 1999.

\[Slide.\]

In 2003, the revised ASCO evidence-based

guidelines recommended docetaxel for patients with

non-small cell lung cancer who have progressed on

first-line platinum-based therapy.

\[Slide.\]

In summary, the body of evidence shows

that patients derive benefit from second-line

treatment of non-small cell lung cancer with

docetaxel. However, better tolerated or more

effective alternatives are needed.

Finally, docetaxel is being used more

frequently in the first-line setting and no options

are currently available for patients who are

treated first-line with docetaxel-containing

regimens.

As docetaxel is the only approved agent

40

for the second-line treatment of non-small cell

lung cancer, additional options are required.

Dr. Roy Herbst will now discuss the

development of Alimta.

Alimta Development

Roy Herbst, M.D., Ph.D.

DR. HERBST: Good morning, panel members

and guests. My name is Roy Herbst from the M.D.

Anderson Cancer Center. Our group and myself

personally have worked with this drug both in the

front and second-line setting in non-small cell

lung cancer.

\[Slide.\]

My purpose this morning is to provide some

background information regarding this novel

antifolate and to share supporting evidence that

Alimta has activity in patients with non-small cell

lung cancer, as well as providing clinical benefit.

\[Slide.\]

First, a word about the structure. As you

can see, Alimta is very similar to folic acid, but

really it is quite a unique and novel compound.

41

You can see two circles areas on the slide. The

N-10 nitrogen has been replaced by a methylene

group, and most importantly, the pyrrolo-pyrimidine

ring circled makes this structurally different from

other antifolates. That is important because it

gives it some very unique qualities as I will talk

about in the next slide.

\[Slide.\]

Shown here is the mechanism of action of

this drug, which is a multi-targeted antifolate.

As shown in the left, the Alimta enters the cell by

reduced folate carriers. Once inside the cell, it

is polyglutamated. This potentially allows it to

be stored in the cell for higher intracellular

concentration.

You can then see that it blocks three

different enzymes involved in folate

metabolism - TS, DHFR, and GARFT. There is also the

potential for this drug to be active in MTAP \[ph\]

efficient cells. This makes it potentially more

active, as well, at any cell that might upregulate

any one of these different enzymes.

42

\[Slide.\]

Activity has been across a wide spectrum

of tumor models. Today, we will focus on lung

cancer. Here, you can see four non-small cell lung

cancer cell lines with activity in the nanomolar

range. There is also evidence here of a lung

cancer xenograph, and you can see the drug is quite

active, as well.

\[Slide.\]

What about clinical experience? First,

the front-line experience. Shown here are two

studies that looked at Alimta before vitamin

supplementation in patient with non-small cell lung

cancer, compared to several studies with docetaxel

also in the front-line setting.

The important thing to notice here is that

the activity, both based on response rates in the

20 percent range and the median survivals, from 7

to 9 months, is quite consistent with what one

would expect for docetaxel or, in fact, most of the

third-generation chemotherapeutics that we now use

for non-small cell lung cancer.

43

\[Slide.\]

Activity has also been seen, and quite

favorable toxicity, in combination with platinum,

which, of course, is the way we treat lung cancer

in the front-line setting.

Shown here are four studies, two using

cisplatinum, two using carboplatinum, and again you

can see in these Phase II studies, response rates

that are quite similar to other agents in this

setting, in one case in the 40 percent range,

median survivals between 8 and 10 months, in fact,

13.5 months in our M.D. Anderson study, and one-year

survivals are quite good. This drug clearly

has activity with platinum in the front-line

setting of lung cancer, as well.

\[Slide.\]

Going into the randomized trial that you

are about to hear about, this was the Phase II

experience, the study from Smit and colleagues, 79

patients. This is a refractory group of patients

with non-small cell lung cancer. One hundred

percent of these patients were refractory within

44

three months, and importantly, it\'s an especially

bad group because 66 percent were refractory within

one month.

You can see that this drug demonstrates a

clear response rate of 8.9 percent with a median

survival of 5.7 months, and a one-year survival of

23 percent. There is clearly activity based on

this trial in the second-line setting, and we will

hear more about this, of course, today.

\[Slide.\]

Now, what about safety? As with most

antifolates, the primary toxicity of this drug is

hematologic. Early data showed that high

homocysteine levels, a surrogate for functional

folate or B12 deficiency, correlated with high

levels of toxicity.

So, a decision in development was made

early on to supplement all patients with folic acid

and vitamin B12 when they received this drug. This

resulted in decreased toxicity with no detrimental

effect on efficacy.

\[Slide.\]

45

I show one slide here. This is basically

showing a group of patients, 246, without vitamin

B12 and folate supplementations, single agent

administration, or 220, who did receive

supplementation.

Shown on the left are all the toxicities

lumped together that I am going to show in this

slide. You can see in the white before, and in the

green after, with a significant improvement.

Then, breaking that up into the top three,

you can see Grade 4 neutropenia is significantly

reduced, Grade 3/4 diarrhea also significantly

reduced, and at least in this Phase II experience,

you can see toxic death rate is zero, and then we

are seeing when the supplementation was given.

\[Slide.\]

So, in summary, Alimta has shown activity

in non-small cell lung cancer as a single agent,

both in the first- and second-line setting, in

combination with platinum agents in the first line.

The safety has been well characterized.

The toxicity is significantly reduced after adding

46

folic acid and B12, and a very low incidence of

neutropenia, febrile neutropenia, and other

non-hematologic toxicities.

I can personally say, both for my group

and myself, this has been our experience, as well.

Based on these results, a pivotal Phase

III study in the treatment of second-line non-small

cell lung cancer was indicated, and Dr. Paul Bunn

will now present those data.

Thank you.

Clinical Efficacy from the Pivotal Study JMEI

Paul Bunn, M.D.

DR. BUNN: Good morning, Dr. Brawley, ODAC

members, and guests.

\[Slide.\]

As one of the principal investigators, I

will review the results of the pivotal trial JMEI,

which was a head-to-head comparison of Alimta to

docetaxel in the second line treatment of patients

with advanced non-small cell lung cancer.

\[Slide.\]

I will begin this presentation with the

47

study design and patient demographics. The results

of the primary endpoint survival will be given with

a detailed discussion of the survival result and

comparison with docetaxel and historical best

supportive care with and without adjustment in a

Cox model.

Following this discussion, I will review

the results of the secondary efficacy endpoints and

a brief discussion of the effect of third line

therapy. Because efficacy cannot be considered in

the absence of toxicity, I will give a brief

overview of toxicity, and then Dr. Gralla will

review the safety results and patient reported

outcomes in detail. Then, I will wrap up with a

few concluding remarks.

\[Slide.\]

After stratification for known prognostic

factors including performance status and stage, as

well as other possible prognostic factors listed,

patient were randomized to Alimta 500 mg/m2 I.V.

day 1 every 21 days or docetaxel 75 mg/m2 day 1

every 21 days.

48

The 283 patients randomized to Alimta

received B12 and folic acid supplementation and

dexamethasone was given to prevent skin rash.

The 288 patients randomized to receive

docetaxel received dexamethasone according to the

label.

\[Slide.\]

The primary study endpoint was survival.

This survival endpoint is expressed as a hazard

ratio of Alimta to docetaxel with a 95 percent

confidence interval.

Secondary endpoints included

progression-free survival, time to tumor

progression, response rate toxicity and patient

reported outcomes as measured by the Lung Cancer

Symptom Scale.

\[Slide.\]

Of course, these endpoints were assessed

in one of two populations, intention to treat and

randomized and treated. The primary endpoint

survival, as well as all other time to event

variables were assessed on an intent to treat

49

population. This population included all

randomized patients regardless of therapy.

The toxicity endpoints were evaluated on

randomized and treated population. This group

included randomized patients who received at least

one dose of treatment.

\[Slide.\]

Important inclusion and exclusion criteria

included histologic or cytologic diagnosis of Stage

III or IV non-small cell lung cancer. All patients

had progressed after at least one prior

chemotherapy treatment, but not more than one prior

chemotherapy treatment for metastatic disease.

Prior adjuvant and neoadjuvant therapy was allowed.

Patients had performance status 0 to 2 and

adequate organ function. Active brain metastases,

severe peripheral neuropathy or significant weight

loss were not allowed. Uncontrolled pleural

effusions and prior docetaxel was not allowed.

Prior paclitaxel was allowed and prior platinum was

not required.

\[Slide.\]

50

The most important prognostic variables,

performance status and stage, were well balanced

between the arms. The less important variables,

such as age and gender, there were minor but

nonsignificant differences. Histology and

pre-treatment homocysteine levels were well

balanced.

\[Slide.\]

There were no differences in the fraction

of patients responding to initial chemotherapy or

the fraction with early relapse after prior

treatment.

The two groups had no relevant differences

in prior chemotherapy in terms of taxane or

platinum exposure.

\[Slide.\]

In both groups, dose intensity was well

preserved with a similar number of patients

receiving at least 4 cycles of therapy and a median

of 4 cycles of therapy in both arms. The percent

of the planned dose intensity and dose delays were

similar. There was a significant increase in dose

51

reductions in the docetaxel arm.

\[Slide.\]

Of course, survival is so important in the

primary endpoint and the unadjusted Kaplan-Meier

survival curves for Alimta and docetaxel were

overlapping and crossed several times. The median

survival times are 8.3 months and 7.9 months,

favoring Alimta.

The one-year survival rates was 29.7

percent in both arms. The unadjusted hazard ratio

was 0.99 in favor of Alimta. The 95 percent

confidence interval was 0.82 to 1.2. This hazard

ratio and confidence interval did not show

superiority, nor rule out a 10 percent margin.

\[Slide.\]

In order to more fully understand the

survival implications of Alimta relative to both

docetaxel and to best supportive care, the data

must be put in the context of this and other

studies.

Percent retention analysis is a means of

estimating the amount of benefit of docetaxel over

52

best supportive care that is retained by Alimta.

This analysis, as you have heard from Dr. Paoletti,

was not in the original protocol, but was

prespecified in the statistical analysis plan prior

to unblinding and prior to data analysis.

The retention analysis was based on the

results of TAX 317B, which was docetaxel 75 mg/m2

versus best supportive care. This analysis takes

into account variability within the studies and

allows for comparison of Alimta to best supportive

care.

An important assumption of the percent

retention analysis is comparability of populations

and results between TAX 317 and JMEI. This allows

for the assumption that if the best supportive care

arm were to be included in JMEI, its survival curve

would have been similar to that seen in TAX 317.

\[Slide.\]

For the most important prognostic factor,

such as performance status and stage, populations

in TAX 317 and JMEI were very similar. There were

less important factors, such as age and gender,

53

there were minor differences, but overall, the

pre-treatment characteristics make the populations

appear comparable.

\[Slide.\]

Looking at the outcome of the 75 mg/m2

docetaxel arms in both TAX 317B and in JMEI, shown

here, shows the results are very similar. The

Kaplan-Meier survival estimate of docetaxel 75

mg/m2 from TAX 317 is shown in green and JMEI in

blue. This outcome confirms the finding of TAX

317B for docetaxel.

\[Slide.\]

Once the populations are shown to be

comparable, then the percent retention analysis

allows for comparison of survival between TAX 317B

and JMEI.

Superimposing the Alimta result of JMEI,

which is the yellow curve I just added, it is

evident the result is similar to docetaxel 75 mg/m2

from both 317B, the prior study, and the current

study JMEI. This finding shows that Alimta is

equivalent to docetaxel 75 mg/m2.

54

Now, adding in the best supportive care

result, in white, strongly suggests the superiority

of Alimta to best supportive care. The hazard

ratio of Alimta to best supportive care is 0.55

with a 95 percent confidence interval that does not

overlap 1, 0.33 to 0.9, the p-value is 0.019.

\[Slide.\]

Another way to understand the survival

results, which are real, and the confidence

interval around these results is to compare hazard

ratio and confidence interval in the trial results.

Shown in yellow are the actual study

results showing an unadjusted 0.99 hazard ratio, a

95 percent confidence interval of 0.82 to 1.2. For

reference, the percent retention of docetaxel\'s

benefit over best supportive care is shown below

the line.

For the actual data, the hazard rate of

0.99 represents retention of 102 percent of

docetaxel\'s benefit over best supportive care. A

hazard ratio of 0.82 represents 150 percent

retention, and so forth.

55

If we want to determine whether Alimta has

benefit over best supportive care, we can calculate

the hazard ratio if the percent retention were

zero, indicating that best supportive care and

Alimta were the same. In this case, the hazard

ratio of Alimta to docetaxel would be 1.33.

Since the upper limit of the hazard ratio

was 1.2, we can be quite confident that Alimta is

better than best supportive care.

If we want to determine the hazard ratio

if Alimta retained at least 50 percent of the

benefit of docetaxel, the hazard ratio would need

to be less than 1.21 for 95 percent confidence, and

again this criteria was met.

If the upper limit of the 95 percent

confidence interval was less than 1.11, then,

Alimta would have been within 10 percent of

docetaxel as originally requested by the European

Regulatory Group. As shown, it did not reach this

value. However, after reviewing the totality of

the evidence, the European Authorities have

recommended approval.

56

Alimta would have been declared superior

to docetaxel if the upper limit of the 95 percent

confidence interval had been less than 1. The

result did not reach this threshold of superiority.

\[Slide.\]

Since not receiving therapy can affect

non-inferiority analyses, the ICH Guidelines

recommend that analyses of non-inferiority

performed percent retention calculations on both an

ITT, as well as the randomized and treated RT

population.

This table shows the calculation from both

populations. For the ITT population, Alimta

retained 52 to 150 percent with a p-value for 50

percent retention of 0.047.

For the RT population, Alimta retained 58

to 168 percent with a p-value for 50 percent

retention of 0.036.

These data support retention of docetaxel

survival benefit by Alimta.

\[Slide.\]

As a prespecified secondary analysis, a

57

Cox multivariate regression analysis was performed

with these 7 prespecified prognostic factors in the

model. These factors included stage, performance

status, time since last therapy, response to prior

therapy, prior taxane, prior platinum, and number

of prior chemotherapies.

\[Slide.\]

The results from this model showed that

three factors predictive for survival - Performance

Status 2, time since last chemotherapy less than 3

months, and Stage IV, all predictive for a worse

survival outcome.

\[Slide.\]

This slide shows the adjusted survival

hazard ratio on a similar number line. The actual

data is represented in yellow. The hazard ratio

was 0.93 with a 95 percent confidence interval of

0.76 to 1.13. The p-value for the 10 percent fixed

margin was p equals 0.051.

The difference between the upper limit of

the confidence interval 1.13, and the prespecified

10 percent fixed margin 1.11, translates into

58

approximately 3.6 days difference.

\[Slide.\]

This slide demonstrates subgroup analyses

unadjusted and adjusted for known or potentially

important prognostic factors for JMEI.

In most instances, relative subgroups,

there were no appreciable treatment effect

differences. For Performance Status 2 patients,

the hazard ratio favored Alimta, but in this case,

the sample was small, and the result was not

statistically significant.

For no prior platinum, the apparent

differences in the adjusted hazard disappeared when

imbalances important to other factors were taken

into account.

These data provide confidence that the

observed results were consistent across all

subgroups and that the results could not be

explained by a large benefit within any particular

subgroup.

\[Slide.\]

We will now review the secondary endpoints

59

of progression-free survival, time to progression,

tumor response, and toxicity. In addition, I will

provide an exploratory data on possible confounding

effect of post-study chemotherapy.

\[Slide.\]

Shown is the Kaplan-Meier estimate for

progression-free survival in intent to treat

population. It difficult to see that there is two

curves here because they are so overlapping, but

there are two distinct curves with a median

progression-free survival of 2.9 months in both

arms.

The hazard ratio was 0.97, slightly

favoring Alimta, with a 95 percent confidence

interval of 0.82 to 1.16.

\[Slide.\]

This is the Kaplan-Meier estimate of the

time to tumor progression for JMEI. Again, the

curves overlap considerably with a median time to

tumor progression of 3.4 and 3.5 months for Alimta

and docetaxel respectively.

The hazard ratio was again 0.97, with

60

confidence intervals of 0.8 to 1.17.

\[Slide.\]

A review of chemotherapy given after this

study showed that more patients on Alimta received

any chemotherapy. Not surprisingly, docetaxel,

which is the only approved drug, was given more

frequently after progression on Alimta despite the

evidence you have heard that it provides no benefit

in this setting.

Receipt of docetaxel does represent a

crossover of sorts. As expected, patients on

docetaxel received more gemcitabine, more

vinorelbine, and more gefitinib, as well as more

other chemotherapy.

Of course, you will recall that gefitinib

is the only agent for which there is any evidence

for survival effect in third-line non-small cell

lung cancer.

\[Slide.\]

To further understand the post-study

treatment effect, an analysis was performed to look

at the type of post-study therapy and its potential

61

effect on survival. Of course, all of these are

retrospective and are subject to great bias, which

we can discuss later.

Patients who received post-study therapy

lived longer than those who did not, not

surprisingly, regardless of the nature of that

therapy or the study arm.

Patients on Alimta who received

post-therapy docetaxel did numerically worse than

those who received other post-treatment study, such

as gemcitabine or vinorelbine.

Patients on the docetaxel arm who received

post-therapy docetaxel actually had numerically

better survival than those receiving docetaxel

after Alimta. This post hoc analysis does not

suggest any crossover effect or post-study effect

of docetaxel treatment.

\[Slide.\]

In fact, this slide shows the distribution

of survival after progressive disease by treatment

arm, Alimta versus docetaxel. A higher proportion

of patients on the Alimta arm received docetaxel,

62

and a higher proportion of patients on docetaxel

received other therapies.

The median survival was 4.5 months in both

arm. This comparison suggests there is no

difference between salvage therapies in the two

arms.

Assuming that patients with progressive

disease have similar prognoses in the groups, this

comparison implies the crossover to docetaxel in

the Alimta arm did not affect any conclusion

regarding survival.

\[Slide.\]

Investigators determined the best response

in the study according to South West Oncology Group

criteria. The response rate between the arms was

virtually identical, 9.1 for Alimta and 8.8 for

docetaxel, respectively.

Stable disease was seen in about 46

percent of patients on each arm. These data are

consistent with the previously published data using

both docetaxel and Alimta in this setting.

Because all efficacy parameters were

63

equivalent, much of the clinical benefit of Alimta

relates to toxicity, so the toxicity analysis, of

course, becomes important.

\[Slide.\]

This table provides a brief overview of

significant toxicity differences regardless of

causality. Alimta was associated with significantly

less Grade 3/4 neutropenia, less febrile

neutropenia, less infection with neutropenia, and

less diarrhea.

There were also significantly less

clinically relevant alopecia of all grades.

Alimta treatment was associated with

significantly more ALT elevations, 2.6 percent

versus 0.4 percent.

\[Slide.\]

In conclusion, the results of JMEI

demonstrate that Alimta afford efficacy benefits

for patients with non-small cell lung cancer

undergoing treatment after progression with prior

chemotherapy.

The survival result is similar to that of

64

docetaxel with a hazard ratio of 0.99. This hazard

ratio translates into 102 percent retention of

docetaxel\'s benefit over best supportive care.

The results are internally consistent

across subgroups. In JMEI, there is no evidence of

an effective crossover or other post-study

chemotherapy effect.

The survival results robustly support

Alimta\'s superiority to historical best supportive

care.

In addition to the survival endpoint, all

secondary endpoints, including response, time to

progression, progression-free survival affirm

Alimta\'s activity and benefit to this group of

patients.

Finally, the safety profile of Alimta,

which Dr. Gralla will review in detail, is clearly

superior to docetaxel.

Now, I would like to invite Dr. Richard

Gralla to review symptom and safety results from

Study JMEI.

Safety Profile from the Pivotal Study JMEI

65

Richard Gralla, M.D.

DR. GRALLA: Thank you, Dr. Bunn, and good

morning.

\[Slide.\]

In considering second-line treatment in

any patient with advanced lung cancer, both

physicians and patients also regard the safety or

toxicity of an agent with great concern.

At the same time, all wish to preserve the

efficacy benefits of treatment including symptom

control and to do so with fewer potential risks

from treatment.

\[Slide.\]

Recognizing that significant patient

reported outcome advantages, including pain

control, were seen with the docetaxel when compared

with supportive care, as Dr. Shepherd discussed

with TAX 317 trial, it was important to assess

prospectively this efficacy parameter in the

current trial.

The study was designed to evaluate the

impact of symptoms as measured by the average

66

symptom burden parameter of the LCSS instrument.

Dr. Bunn outlined briefly the significantly lower

toxicity profile with Alimta, which I will discuss

in greater detail in a few minutes, but it is

crucial to ascertain that the safety advantages

were not achieved at the expense of the decrease in

symptom control as expressed by patients.

\[Slide.\]

PRO, or patient reported outcome

evaluations, are best conducted when using

previously validated instruments. The LCSS has good

published psychometric properties and was selected

for prospective use in this trial for several

reasons.

It is demonstrated high patient and

observer acceptability, it was designed

specifically for randomized comparative clinical

trials, and was used in the docetaxel TAX 317 and

320 trials.

Patients completed the instrument weekly,

allowing 85 percent of the patients to be included

in the PRO evaluation.

67

Two major questions are associated with

PRO evaluation. First, are the quality of life

instruments used sensitive enough to reflect

changes that patients experience, and, second, is

there value in receiving second-line chemotherapy

in terms of symptom relief and quality of life

advantages?

Does the magnitude of response, major

response versus stable disease versus progressive

disease predict the degree of benefit expressed by

patients?

\[Slide.\]

This slide shows the patient reported

results displayed by the objective response

category achieved. For this analysis, the results

of both the Alimta and docetaxel arms were

combined.

As can be seen, major response was

associated with the greatest patient expressed

benefit, the green bars, while a lesser impact, but

still a positive result, was reported by those

patients in whom stable disease, the magenta bars,

68

was their best response.

Of note is the fact that over 50 percent

of patients had either a major response or stable

disease in this trial, and that these groups

reported symptomatic benefits as seen on the slide.

In light of the PRO benefits overall in

the trial, and with the significantly lower

toxicity on the Alimta arm, it is important to see

that the response related symptomatic benefits were

preserved with the less toxic Alimta regimen.

\[Slide.\]

This slide shows the evaluations for

patients by randomized treatment arm and examines

the results seen in those patients with major

response or stable disease.

The bar graphs represent the six general

and thoracic symptoms evaluated in the LCSS and the

average symptom burden index, or ASBI. It is clear

that these results show similar symptom

amelioration for each treatment arm in these lung

cancer related symptom areas.

\[Slide.\]

69

In all new agent evaluation, efficacy and

safety are the main considerations. Given the

similar efficacy endpoints in terms of survival,

response, and patient reported outcomes found with

both agents in this large randomized trial, safety

issues are of marked importance when considering

therapeutic index differences between the agents.

To place the overall safety profiles for

second-line treatment in context, it is useful to

review briefly the safety findings of the currently

available second-line agent docetaxel.

\[Slide.\]

The docetaxel arms at 75 mg/m2 from the

TAX 317 and 320 trials, which Dr. Shepherd outlined

in her presentation, are seen on this slide.

When one concentrates on marked

toxicities, as expressed as a percentage of

patients experiencing Grade 3 or 4 levels of

toxicity, it is clear that neutropenia is the

primary concern occurring in the majority of

patients. In fact, as originally designed, the

amount of docetaxel given in TAX 317 had to be

70

lowered during the study to 75 mg/m2 because of

undue toxicity.

Nonetheless, even at this dose, nearly

two-thirds of patients still experienced marked or

severe neutropenia. Physicians remain particularly

concerned with the high degree of this potentially

life-threatening toxicity.

While patients and physicians appreciate

the modest benefits of docetaxel, concerns with

neutropenia and its complications have led to the

frequent need for growth factor injections and

alterations of doses and schedules.

\[Slide.\]

An overall view of the safety in the JMEI

trial is seen in this slide. The table shows the

incidence of the most serious toxicity, death,

serious adverse events or SAEs, and finally, any

adverse event called the treatment emergent adverse

event, or TEAE.

As can be see for any of these parameters,

a higher rate of adverse events was found in this

study with the docetaxel arm.

71

When one looks at either the serious

adverse events affecting a minority of patients, or

the treatment emergent adverse events affecting

most patients, significant differences favoring the

Alimta arm are found when the results are evaluated

for events that are drug related.

\[Slide.\]

Of course, the toxicity outcome of

greatest concern with any drug is death. As seen

in this slide, while the number of deaths during

the study are relatively similar between the two

treatment arms, fewer deaths are seen in total on

the Alimta arm, and in the important categories of

study drug related deaths and lung cancer related

deaths.

\[Slide.\]

When examining adverse events, any

toxicity can be relevant, but major toxicity, that

is, Grade 3 and 4, is of greatest concern and

deserves our focus.

Clearly, an approach that lessens toxicity

from the marked Grade 3 and 4 categories to Grades

72

1 and 2 would have the same overall toxicity

percentage, but by lessening the severity would be

a major benefit. All drugs have side effects, the

severity of these side effects is a crucial issue

in patient management and in the assessment of

toxicity in this trial.

\[Slide.\]

This slide is the first of several

summarizing laboratory-based major toxicities from

the current Alimta versus docetaxel randomized

trial as displayed as Grade 3 and 4 level of

toxicity.

As expected, the most commonly occurring

laboratory-measured side effect was neutropenia.

Of note is the finding that there was a markedly

different occurrence of this toxicity depending on

the treatment arm.

Not only was there a highly significantly

different rate of neutropenia, favoring those

patients randomly assigned to Alimta, but the

related life-threatening toxicity of febrile

neutropenia occurred far less often in the

73

Alimta-treated patients affecting fewer than 2

percent.

Not surprisingly, documented infection

rates were lower in those patients receiving Alimta

with no occurrences found on this arm of the trial.

Now, stepping away from the statistical

analysis at this point and placing it in a clinical

context, these results mean that 1 of every 8

patients in this study, randomized to docetaxel,

had febrile neutropenia, while this

life-threatening toxicity occurred in less than 1

of every 50 patients on Alimta.

The only laboratory area in which a

significantly higher side effect rate was seen with

the Alimta, was in the hepatic transaminase ALT.

Fortunately, this degree of elevation was uncommon,

occurring in fewer than 3 percent of patients.

\[Slide.\]

In general, rates of non-laboratory side

effects were relatively low in this study.

Nonetheless, the distressing but not

life-threatening side effect alopecia occurred far

74

less often in patients receiving Alimta.

Additionally, a significantly different

rate of serious diarrhea was found again favoring

Alimta.

Thus, when considering both laboratory and

non-laboratory events, threatening overlapping

toxicities, such as neutropenia and diarrhea, were

significantly reduced by the use of Alimta.

\[Slide.\]

When one looks at the occurrence of all

serious laboratory toxicities, that is, Grade 3 and

4, by treatment regimen, it is clear that Grade 3

toxicities occurred in only about half as many

patients randomly assigned to the Alimta arm, and

that Grade 4 toxicities were markedly lower in

patients on that arm.

\[Slide.\]

During the trial, anemia was reported by

about 7 percent of patients on either arm of the

study. This could be related to the chemotherapy

or to anemia associated with the lung cancer

itself. Overall, physicians elected to transfuse

75

or to give erythropoietin to between 22 percent and

24 percent of patients with no significant

differences between treatment arms.

With markedly lower drug-induced

neutrophil counts on the docetaxel arm, 7 times as

many of these patients were given

granulocyte-stimulating growth factors, again a

highly significant difference.

\[Slide.\]

The advantages in non-laboratory

toxicities are perhaps best illustrated when

looking at serious toxicities of any cause. The

more minor toxicity grades 1 an 2 are similar

between the treatment arms, however, when one

reviews the more serious toxicity grades, important

differences are clear.

Grade 3 toxicity rates approach

statistical significance. In Grade 4, the most

marked toxicity category, a third fewer patients on

the Alimta arm had this rate of serious toxicity a

statistically significant difference between the

treatment arms.

76

\[Slide.\]

It can be useful to review briefly

hospitalization patterns. As seen in this slide,

hospitalizations due to adverse events of all

causes were significantly lower in patients on the

Alimta arm.

The driving factor behind this rate

involved the significantly fewer hospitalizations

for the life-threatening complication of febrile

neutropenia. Paradoxically, the number of days in

hospital was modestly greater in the Alimta arm.

This imbalance was due entirely to non-drug-related

factors, that is, longer hospitalizations for

social considerations and for management of

complications of the metastatic lung cancer, not

for drug-related issues.

In particular, it is the appropriate

concern with the risk of major toxicity that limits

the willingness of physicians to advise second-line

docetaxel despite demonstrated survival and

symptomatic gains from the TAX 317 study as

outlined by Dr. Shepherd.

77

Many individuals involved in new agent

investigation have struggled to display clearly

this balance between toxicity and benefit, or at

least ways of showing the overall effect of major

toxicity rates on survival.

\[Slide.\]

This slide demonstrates one attempt to do

this. It is interesting to look at the experiences

of all patients on this large Alimta versus

docetaxel trial with regard to the time of

survival, which was free of serious Grade 4

toxicity.

As is seen in terms of the remaining

period of survival, patients randomized to the

Alimta arm spent two to three times as long without

this degree of serious toxicity when compared with

those on docetaxel.

This analysis helps to demonstrate the

impact of the more favorable toxicity profile of

Alimta when compared with docetaxel.

\[Slide.\]

We conclude that this large multi-center

78

trial demonstrated several major advantages for the

group randomized to Alimta with the real but

limited benefits found in second-line treatment of

non-small cell lung cancer. A decrease in the risk

of treatment is an important advantage for Alimta.

These significant benefits were found in

the key areas of decreased neutropenia and febrile

neutropenia, less risk of alopecia and diarrhea,

and few drug-related deaths and serious adverse

events overall.

From a safety and patient reported

outcomes perspective, Alimta is a useful and safe

treatment option for patients with non-small cell

lung cancer who are candidates for second-line

chemotherapy.

The toxicity advantages associated with

Alimta with similar symptomatic and quality of life

benefits are of great value to patients. The PRO

and toxicity evaluations, coupled with the other

major endpoints, help to support the finding that

Alimta treatment is safer without any compromise in

survival response or palliative outcomes.

79

I would like now to call on Dr. Bunn to

summarize these results and to put them into the

context of current treatment.

Overall Conclusions

Paul Bunn, M.D.

DR. BUNN: In the past three talks, we

have reviewed the relevant data supporting Alimta

for the treatment of advanced non-small cell lung

cancer after prior chemotherapy. I would like to

take a few minutes to summarize the salient issues

in your review. I also appreciated Dr. Pazdur\'s

overview of the issues before you and just make a

few comments as I go through my presentation.

Of course, you are here to provide your

advice to the agency. Your advice is largely going

to depend on how much you think about safety and

about efficacy, and your confidence in the safety

and the efficacy relate to survival, they relate to

patient-reported outcomes, and they relate to

safety, and we must consider not only the JMEI

trial, but what is known in the literature, as Dr.

Pazdur alluded to before and how confident are we

80

about what best supportive care does and how

confident are we about what docetaxel does and how

many trials are there.

\[Slide.\]

From this presentation, Alimta clearly

provides a new, a safe and clearly an effective

treatment option for patients with advanced

non-small cell lung cancer in the second-line

setting.

This is important as advances in

treatment, patients with lung cancer are living

longer and they are living better. As a result,

more of these patients are candidates for

second-line therapy.

At present, they have only one approved

option, docetaxel. As noted, docetaxel\'s use is

limited by its significant toxicities and also its

use in the first-line setting.

\[Slide.\]

What about safety? Alimta is clearly

safer than docetaxel with respect to any clinically

relevant toxicity. Its advantage, of course, is

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most marked in the reduction of febrile

neutropenia, from 12.6 percent to 1.9 percent.

A secondary benefit that results from this

is a concomitant reduction in the use of G and

GM-CSF, fewer visits to the clinic for neutropenia,

fewer hospitalizations for neutropenia.

However, not all the benefit is isolated

to reduction in neutropenia. There was also a

significant reduction in Grade 3/4 diarrhea and a

reduction in alopecia, a side effect particularly

important to patients.

Finally, there was a 3-fold reduction in

hospitalization for drug-related adverse events.

\[Slide.\]

How confident can we be in the safety

profile of Alimta? Shown here are the safety

results of Alimta in JMEI and in the safety

database of all other Phase II monotherapy of

Alimta with vitamins.

Of note is the consistent results of

Alimta in febrile neutropenia, in diarrhea and

alopecia, that were all lower than docetaxel in

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JMEI.

\[Slide.\]

On looking at the direct pivotal trial

evidence for survival benefit from JMEI, Alimta has

comparable activity with a hazard ratio of 0.99.

Median survivals are essentially the same.

One-year survival rates were identical and there

was internal consistency across all groups.

When indirectly compared to best

supportive care, Alimta preserved at least 50

percent of docetaxel\'s benefit over best supportive

care.

With respect to non-inferiority analyses,

the 1.11 fixed margin was not met statistically,

and many p-values can be calculated different

methods, however, we can be confident that Alimta

retains docetaxel survival advantage over best

supportive care, not only from comparison to TAX

317B, but also comparison to other historical best

supportive care trials and the consistency of

Alimta\'s survival result across all first- and

second-line trials that you have heard.

83

\[Slide.\]

Reviewing all secondary endpoints, the

following conclusions can be made from a direct

comparison to docetaxel from JMAI.

The time to progression is identical

almost. Progression-free survival was the same,

and the response rate was very similar. Over 50

percent of all patients on each arm showed improved

or stable symptoms.

Indirectly, the response rates of median

time to progression for Alimta are consistent

across all trials and show relevant activity in all

non-small cell lung cancer either in the first line

or second line, and these endpoints are superior to

historical best supportive care. So, this is what

Dr. Pazdur was talking about.

How do clinicians review efficacy of a

compound, and how can we tell if one seems similar

to another? It is helpful if there are multiple

randomized trials.

Fortunately, there are five randomized

trials of docetaxel in the second-line setting, and

84

those five randomized trials are shown here.

\[Slide.\]

Obviously, a meta-analysis has not been

done because some of these are recent, but these

are the five randomized trials using docetaxel 75

mg/m2 in one arm. These consistent results with

median survivals of 6 to 8 months in all trials

give us confidence about the effect of docetaxel.

In each of these five studies, docetaxel

75 mg/m2 was numerically superior to the

comparator. Note that two of these trials, the

comparator was docetaxel 100 mg/m2 with the worst

outcome. That is the reason there are not A versus

A + B trials in the second-line setting. Just a

little bit of extra neutropenia made survival worst

in these patients, and it does limit our ability to

develop new agents, because the A + A + B design is

very difficult in this setting.

If one were to review, then, the best

supportive care results from available second-line

randomized trials, once again we see consistent

results. Median survival in the best supportive

85

care arms was 4.5 and 5.5 months.

The BR21 slide results that are shown on

this slide is limited to those patients who got

second-line therapy, as that trial also included

some third-line patients.

These survival rates with the best

supportive care are clearly inferior to docetaxel.

Finally, when one reviews the median survival for

Alimta in this context, the similar outcomes of

docetaxel and the superiority to best supportive

care is obvious.

\[Slide.\]

In summary, Alimta merits full approval as

a single agent for the treatment of patients with

locally advanced or metastatic non-small cell lung

cancer after prior chemotherapy.

There are many agents that have received

full approval that you know about, sometimes based

only on response rate. Here, we have data and

efficacy on response rate, progression-free

survival, and survival, as well as patient reported

outcomes.

86

Alimta has a superior response rate,

progression-free survival, and survival compared to

best supportive care. Alimta has similar response

rate, progression-free survival, and survival

compared to docetaxel.

The safety profile of Alimta is clearly

superior to docetaxel. There are many second-line

lung cancer patients. They deserve to be offered

the safest and most effective treatment that

physicians have available.

Approval of this drug will make a safe and

effective agent available for patients with this

devastating disease.

Thank you for your attention.

DR. BRAWLEY: Thank you, Drs. Bunn,

Gralla, Herbst, Shepherd, and Paoletti, and your

support staffs for preparing the presentation.

We would now like to move to the FDA

presentation, the clinical review and the

statistical review.

The clinical review will be given by Dr.

Martin Cohen.

87

FDA Presentation

Clinical Review

Martin H. Cohen, M.D.

DR. COHEN: Good morning. My name is

Martin Cohen and I am going to present the FDA

clinical review of Alimta, also known as pemetrexed

and LY231514.

My review will be followed by the FDA

statistical review by Dr. Wang.

\[Slide.\]

The proposed indication for Alimta is as a

single agent for the treatment of patients with

locally advanced or metastatic non-small cell lung

cancer after prior chemotherapy.

\[Slide.\]

A single study was submitted comparing

treatment with Alimta to treatment with docetaxel.

The stratification factors were performance status,

disease stage, number of prior regimens, response

to the last prior chemotherapy, whether or not the

patient received prior platinum or paclitaxel

therapy, homocysteine levels, and treatment site.

88

\[Slide.\]

I would like to comment on the

determination of baseline homocysteine values.

Elevated pre-treatment homocysteine values have

previously been shown to be an excellent predictor

of Alimta treatment toxicity and that reduction of

those elevated homocysteine levels with folic acid

and vitamin B12 was accompanied by a significant

reduction in Alimta toxicity.

Whether vitamin supplementation would also

decrease docetaxel toxicity is unknown. There is

no reason, however, not to expect a toxicity

reduction similar to that observed with Alimta.

\[Slide.\]

Since docetaxel is the comparator in the

Alimta trial, this slide summarizes the clinical

materials that were submitted for approval of

docetaxel as second-line non-small cell lung

treatment.

The first study listed on this slide, as

previously discussed, was reported by Dr. Shepherd

and colleagues. In this study, patients with

89

performance status zero to 2, who had failed one or

more platinum-based chemotherapy regimens, were

initially randomized to receive docetaxel 100 mg/m2

or best supportive care.

Because of early toxic deaths, the

protocol was amended to reduce the docetaxel dose

to 75 mg/m2. After this amendment, there were 55

patients who received docetaxel 75 mg/m2 and 49

patients who received best supportive care.

Docetaxel treatment gave a response rate

of 5.5 percent. The median survival was 7.5 months

for docetaxel versus 4.6 months for best supportive

care. The difference in overall survival was

statistically significant at a p-value of 0.01, and

one-year survival was 37 percent versus 12 percent,

and that also was statistically significant.

The second study on the slide was reported

by Fosella and colleagues. This was a randomized

trial comparing docetaxel 100 mg/m2 or docetaxel 75

mg/m2 to a physician\'s choice of either vinorelbine

or ifosfamide.

The study population had a higher percent

90

of Stage IV patients and more patients who had

received two or more prior chemotherapy regimens

than did the Shepherd study. The docetaxel 100

mg/m2 dose was again associated with early toxic

deaths and will not be discussed further.

The 75 mg/m2 docetaxel-treated patients

had a response rate of 5.7 percent versus 0.8

percent for the physician\'s choice arm. The median

survivals were 5.7 to 5.6 months, and the one-year

survivals were 30 percent versus 20 percent.

The difference in overall survival between

the two treatment groups was not statistically

significant. The p-value for the one-year survival

difference was 0.025.

\[Slide.\]

Alimta drug administration is shown on

this slide. Alimta 500 mg/m2 was administered

intravenously over 10 minutes on day 1 of a 21-day

treatment cycle.

Patients receiving Alimta, as mentioned

previously, also received folic acid, vitamin B12,

and dexamethasone at the doses and schedules listed

91

on the slide.

Folic acid and vitamin B12 were

administered for the purpose of reducing blood

homocysteine levels so as to ameliorate Alimta

toxicity. Dexamethasone was given to prevent or

decrease the occurrence of skin rash.

\[Slide.\]

Docetaxel drug administration is shown on

this slide. Docetaxel 75 mg/m2 was administered

intravenously over 60 minutes on day 1 of a 21-day

treatment cycle.

Dexamethasone in the doses scheduled

listed on the slide was given as prophylaxis

against fluid retention and hypersensitivity

reactions.

\[Slide.\]

There were 135 investigational sites in 23

countries that participated in this study, and

approximately 21 percent of the study population

came from United States institutions.

\[Slide.\]

This slide demonstrates selected patient

92

characteristics. As shown the two treatment groups

were comparable for performance status, prior

chemotherapy regimens, prior platinum and

paclitaxel therapy.

Approximately 30 percent of patients in

each treatment group had an elevated baseline

homocysteine level.

\[Slide.\]

This slide shows efficacy endpoints. The

primary endpoint was overall survival, and the FDA

survival analysis will be discussed in the

following FDA presentation.

Secondary efficacy endpoints included

response rate and duration, time to progression,

progression free survival, and lung cancer systems

as measured by the Lung Cancer Symptom Scale.

Because progression free survival results

mirror time to progression, only the former will be

discussed on the subsequent slide. Similarly,

because no differences were identified between the

two patient groups in any of the Lung Cancer

Symptom Scales, symptom burden will also not be

93

further discussed.

\[Slide.\]

Alimta treatment resulted in 1 complete

response and 23 partial responses, for an overall

response rate of 9.1 percent. Docetaxel treatment

resulted in no complete responses and 24 partial

responses, for a response rate of 8.8 percent.

The overlapping 95 percent confidence

limits of the two response rates are listed.

Median response durations were 4.6 months for

Alimta and 5.3 months for docetaxel.

\[Slide.\]

This slide shows time to progression for

both the intent to treat, or ITT patient

population, and the randomized treated, or RT

patient population.

As indicated, time to progression was

similar for Alimta and for docetaxel treatment

groups whether one compares results for either the

ITT or RT population groups. For the ITT

population, there was a slight advantage of median

time to progression favoring Alimta, whereas, for

94

the RT population, there was a slight advantage

favoring docetaxel.

\[Slide.\]

Now, we get to one of the more

controversial aspects of this review, the issue of

post-study chemotherapy. The patient population

analyzed in this slide is the randomized and

treated population.

At the time of disease progression,

patients were allowed to receive post-study

chemotherapy. This slide lists the drugs that were

most frequently used. As indicated on this slide,

126 or 48 percent of Alimta-treated patients and

107 or 39 percent of docetaxel-treated patients

received post-study chemotherapy.

Of possible importance to a

non-inferiority survival analysis, 85 or 32 percent

of Alimta-treated patients crossed over to

docetaxel treatment. Patients on the docetaxel arm

were not permitted to cross over to Alimta, and

they received a variety of other drugs including

those listed on this slide.

95

\[Slide.\]

This slide shows the median survival of

randomized treated populations who received or did

not receive post-study chemotherapy.

139 Alimta patients did not receive

post-study chemotherapy and 169 docetaxel-treated

patients did not receive post-study chemotherapy.

The 30 patient difference between the two treatment

arms might be important, because patients on both

study arms who did not receive post-study

chemotherapy had shorter median survivals, 6.2

months for Alimta patients and 5.0 months for

docetaxel patients than patients who did receive

post-study chemotherapy, as summarized in the last

two lines on this slide.

\[Slide.\]

Because this slide demonstrates that

post-study chemotherapy improved survival, it is

important to look at patients who did not receive

post-study chemotherapy. The presumption might be

made that these patients were too sick to receive

treatment, and that is why they had a worse

96

survival.

This does not appear to be the case,

however. This slide shows the last recorded

performance status of patients who did not receive

post-study chemotherapy. Again, there were 139

Alimta-treated patients and 169 docetaxel-treated

patients.

As is evident from this slide, the large

majority of patients who did not receive post-study

chemotherapy were performance status zero or 1 at

their last study visit, and conceivably, could have

received additional treatment.

\[Slide.\]

In our previous look at this slide, we

were concerned with patient who did not receive

post-study chemotherapy. We are now concerned with

patients who were treated.

While it appears that all treatments,

including post-study docetaxel or post-study other

chemotherapy, gave comparable survival results, it

must be remembered that these are not randomized

patients and that prognostic features of each group

97

may be very different.

Thus, post-study chemotherapy treatment

may well have been of more benefit than post-study

docetaxel treatment may well have been more

beneficial than other post-study chemotherapy

treatment.

\[Slide.\]

Turning now to safety considerations, this

slide shows patient exposure to treatment. The

median number of cycles we see by patients on each

treatment arm was 4, and there was no striking

difference in the percent of planned dose intensity

received by patients on either treatment arm.

\[Slide.\]

This slide summarizes all toxicities

experienced by study patients regardless of

causality based on their CTC grade. As evidence

from this slide, there was no difference between

Alimta and docetaxel for Grade 1 and Grade 2

toxicities. For Grade 3 toxicity, Grade 4

toxicity, and Grade 3 or 4 toxicity, Alimta was

significantly less toxic than docetaxel.

98

Alimta\'s safety advantage for Grade 3 or 4

toxicity comes primarily from less neutropenia,

less febrile neutropenia, and less infection

accompanying neutropenia.

\[Slide.\]

Looking specifically at neutropenia, this

slide shows Grade 3 to 4 neutropenia accompanied

with fever or with infection. Thirty-six or 13

percent of docetaxel-treated patients had febrile

neutropenia versus 5 or 2 percent of Alimta-treated

patients.

Also, indicated on this slide, documented

infection in the setting of neutropenia occurred in

5.8 percent versus zero percent of docetaxel and

Alimta-treated patients, respectively.

\[Slide.\]

Therefore, if one now looks at all

toxicities regardless of causality excluding white

blood cell events, such as decreased leukocytes and

lymphocytes, neutrophils, granulocytes, infections,

febrile neutropenia, or other white blood cell

related events, there is no longer a significant

99

difference between Alimta and docetaxel treatment.

For Grade 3 or 4 toxicity, for example,

the p-value is 0.781.

\[Slide.\]

CTC Grade 3 or 4 adverse events regardless

of causality are listed on this slide. As

indicated, alopecia and diarrhea occurred

significantly more often with docetaxel treatment

than with Alimta treatment.

Grade 3 to 4 diarrhea occurred at 4

percent of docetaxel-treated patients versus 0.4

percent of Alimta-treated patients.

There was no statistically significant

difference in the occurrence of the other listed

toxicities - fatigue, nausea, vomiting, stomatitis,

pulmonary toxicity, or neurosensory toxicity.

\[Slide.\]

Turning now to treatment emergent adverse

events, of TEAEs, this slide shows all treatment

emergent adverse events regardless of causality for

which there was a statistically significant

difference between treatment groups based on an

100

uncorrected p-value of less than 0.001.

As shown, nausea, weight loss, increase in

hepatic enzymes, the alanine and aspartate amino

transferases, and decrease in creatinine clearance

were all more frequent in Alimta-treated patients.

Alopecia was worse in docetaxel-treated patients.

\[Slide.\]

This slide shows all treatment emergent

adverse events regardless of causality for which

there was a statistically significant difference

between treatment groups and an uncorrected p less

than 0.05 value.

Myalgias, arthralgias, neurotoxicity, and

diarrhea were all more common in docetaxel-treated

patients, while constipation, fatigue, and skin

rash were more common in Alimta-treated patients.

\[Slide.\]

Hospitalizations present a mixed picture.

Docetaxel-treated patients had somewhat more

hospital admissions, 364 versus 337, but

Alimta-treated patients spent somewhat more time in

the hospital, 1,722 days versus 1,410 days for

101

docetaxel-treated patients.

\[Slide.\]

As regards efficacy conclusions, you will

hear the opinion of the FDA statisticians regarding

survival subsequently.

Whatever your views on the relative merits

of the survival analyses, however, the fact is that

post-study chemotherapy confounds the survival

analyses.

With regards to post-study chemotherapy,

there are two issues. The first issue is the

crossover of 85 Alimta-treated patients to

docetaxel treatment. While median survival of

these patient is similar to the median survival of

patients receiving other chemotherapy regimens,

such survival analyses do not take into account

possible prognostic differences between the various

treatment groups.

The second issue is that patients who did

not receive post-study chemotherapy had a shorter

survival than those who did receive such treatment.

There were 30 more docetaxel-treated patient than

102

Alimta-treated patients who did not receive

post-study chemotherapy.

The large majority of untreated patients

had a performance status of zero or 1 at the time

of progression, and could conceivably have received

additional treatment.

Alimta did show evidence of activity,

however, in that it produced a response rate of 9.1

percent.

\[Slide.\]

The toxicity spectrum of docetaxel clearly

differs from that of Alimta, and this slide

summarizes the differences between the two drugs.

Docetaxel produces more neutropenia and

neutropenic complications, including febrile

neutropenia, infections, and need for

colony-stimulating factors. It also causes more

neurotoxicity, myalgias, alopecia, and diarrhea.

Alimta, on the other hand, produces more

thrombocytopenia, more skin rash, more nausea and

vomiting, more elevations of hepatic enzymes, a

decrease in creatinine clearance, and more weight

103

loss than does docetaxel treatment.

An important point on this slide is that

folic acid and vitamin B12 supplements presumably

by reducing elevated homocysteine levels have been

shown to ameliorate Alimta toxicity. Whether such

supplements, which were not given to

docetaxel-treated patients, would ameliorate

docetaxel toxicity is not known.

Thank you for your attention.

DR. BRAWLEY: Thank you, Dr. Cohen.

Dr. Yong-Cheng Wang.

Statistical Review

Yong-Cheng Wang, Ph.D.

DR. WANG: Thank you, Dr. Cohen.

Good morning. I am Yong-Cheng Wang, the

statistical reviewer for the application being

discussed today. In this presentation, I will

present the results of efficacy analysis of Study

JMEI.

\[Slide.\]

Here is the outline of my presentation.

The results of protocol specified primary endpoint

104

analyses. Post-hoc 50 percent of retention non-inferiority

analyses, which was submitted in the

NDA.

The critical issues in Study JMEI. The

results of secondary endpoint analyses. Efficacy

conclusions will be given at the end of this

presentation.

\[Slide.\]

The protocol specified two study

objectives, superiority hypothesis and fixed margin

non-inferiority hypothesis.

In the superiority hypothesis, the goal is

to demonstrate that Alimta is more effective than

docetaxel.

In the fixed margin non-inferiority

hypothesis, the goal is to demonstrate that Alimta

is not worse than docetaxel by 11 percent clinical

benefit, or in other words, that non-inferiority

margin is fixed at 1.11.

The fixed margin of 1.11 was specified at

the recommendation of EMEA, and was not based on

any historical trial data. However, from our

105

calculation, this margin is close to FDA/CBER

technology.

\[Slide.\]

Here are the results of primary endpoint

overall survival analysis for the intent to treat

population. For the overall survival, the median

survival is 8.3 months for the Alimta group and 7.9

months for docetaxel group.

The study failed to demonstrate superior

efficacy of Alimta to docetaxel with a log-rank

p-value of 0.93. It also failed to demonstrate

non-inferiority based on the fixed margin

non-inferiority test. The p-value is 0.256.

Based on the Cox regression model, the HR

of Alimta versus docetaxel is 0.99 with 95 percent

confidence interval 0.82 to 1.2. The

non-inferiority margin 1.11 is less than the upper

limit 1.2.

\[Slide.\]

For the randomized and treated population,

the results are similar to ITT population as

presented in the previous slide.

106

\[Slide.\]

The sponsor also included a post hoc

non-inferiority hypothesis of 50 percent of

retention of docetaxel effect in the NDA

submission.

In this hypothesis, the goal is to

demonstrate that at least 50 percent of docetaxel

effect will be retained by Alimta. In the current

study, we have serious reservation about this

analysis as presented in the next few slides.

\[Slide.\]

There are two major critical issues in

Study JMEI. First, the docetaxel effect is

estimated from only one small historical trial,

therefore, we cannot assure the ability to repeat

the results.

Also, we cannot reliably assess the

magnitude of the docetaxel effect.

Second, the survival results are

confounded by crossover of Alimta to docetaxel.

\[Slide.\]

I will now go over the details of these

107

critical issues. The historical trial which is

used for the estimation of the docetaxel effect is

TAX 317. As presented here, this is a very small

trial, total of 104 patients were enrolled with 55

patients in the docetaxel arm and 49 patients in

the best supportive care arm.

So, the estimate of the docetaxel effect

is not reliable and not robust. Since this is the

only one historical trial used for the estimation

of docetaxel effect, the constancy assumption that

docetaxel effect in Study JMEI is the same as in

the historical trail cannot be verified.

It should also be noted that these results

are in the ITT population only, and we do not have

results based on the randomized and treated

population.

\[Slide.\]

This slide shows the critical issue of

treatment crossover of Alimta to docetaxel. There

are more than 30 percent patients who crossed over

from Alimta group to docetaxel group. Therefore,

the survival results are confounded.

108

\[Slide.\]

I will now present the results of

secondary endpoints analysis.

\[Slide.\]

This slide shows the results of survival

rate analysis. For the 6 month, Alimta has a

slightly higher relative risk than docetaxel in the

survival rate.

For the 12, 18, and 24 months, Alimta has

a slightly lower relative risk than docetaxel for

the survival rate.

\[Slide.\]

This slide shows the results of time to

progressive disease. Alimta is not significantly

superior to docetaxel for the time to progressive

disease in the ITT population.

\[Slide.\]

This slide shows the results of

progression-free survival. These results are

similar to the time to progressive disease.

\[Slide.\]

This slide shows the results of response

109

rate analysis. Alimta is not significantly

superior to docetaxel with respect to tumor

response. The results of symptom improvement

analysis are not present either, as there was

missing data. Results were based on a subset of

patients in this open label study.

It should be noted that even though

p-values have been presented for all the secondary

endpoint analysis, these values are not

interpretable, and none of them are adjusted for

multiplicity.

Efficacy conclusions. Based on the

overall survival analysis, a single, randomized,

open-label, multi-center study JMEI in advanced

non-small cell lung cancer patients treated with

Alimta versus docetaxel failed to demonstrate

superior efficacy of Alimta to docetaxel.

It also failed to demonstrate

non-inferiority compared to docetaxel.

\[Slide.\]

The estimate of docetaxel effect based on

only one small historical trial is not reliable and

110

not robust.

In the presence of treatment crossover

from Alimta to docetaxel, the survival results are

confounded and non-inferiority analysis is very

difficult to interpret.

Therefore, the result of 50 percent

retention non-inferiority analysis is not

interpretable.

Thank you for your attention.

DR. BRAWLEY: Thank you.

As we move forward, I would like to ask

Dr. Pazdur if he wants the current questions,

Question No. 1 and Question No. 2, and you would

like a vote on Question No. 1 and Question No. 2.

Thank you very much.

At this point, it is 10:31. I would

propose that we go to break until 10:45. I would

ask the members to be back in their seats at 10:45.

I think we can finish a little earlier today than

is currently posted.

\[Break.\]

DR. BRAWLEY: As we come to order, this is

111

the section for open public discussion. I

understand there is one discussant. I need to say

the following:

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. To

ensure such transparency at the open public hearing

session of the Advisory Committee meeting, FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its product, and, if

known, its direct competitors.

For example, this financial information

may include the sponsor\'s payment of your travel,

lodging, or other expenses in connection with your

attendance at the meeting.

Likewise, FDA encourages you at the

beginning of your statement to advise the committee

112

if you do not have any such financial

relationships. If you choose not to address this

issue of financial relationships at the beginning

of your statement, it will not preclude you from

speaking.

I am sorry. That is an official sort of

thing that has to be read into the record.

MS. POLLACK: I understand.

Open Public Hearing

DR. BRAWLEY: If you can introduce

yourself and begin your statement.

MS. POLLACK: Certainly. Good morning.

My name is Michelle Pollack and I am the Director

of Marketing and Development for the Wellness

Community, an international non-profit organization

that provides support, education, and hope to

people affected by cancer.

For the record, the Wellness Community

receives unrestricted educational funding from Eli

Lilly, however, we received no funding or

compensation for my presence here today.

The Wellness Community offers free

113

programs including professionally led support

groups, educational seminars, nutritional

workshops, exercise and mind-body programs, among

others.

Our mission is to help people living with

cancer regain a sense of control over their lives,

feel less isolated, and restore their hope for the

future regardless of the stage of their disease.

Last year, we provided support services to

more than 30,000 people with cancer including

people with locally advanced or metastatic

non-small cell lung cancer. Through the virtual

Wellness Community on-line, we were able to reach

even more people.

At the Wellness Community, we have learned

a great deal from those we support and we believe

in the importance and value of an educated and

empowered patient. Since people with cancer often

feel stigmatized, alone, and overwhelmed with

grief, they feel stronger and more hopeful when

they have more treatment options available to them.

With an estimated 174,000 new diagnoses of

114

lung cancer in 2004 in the United States alone,

with 80 percent of those non-small cell lung

cancer, there is no doubt that we are in need of

improved treatments, more manageable and tolerable

side effects, and greater accessibility to those

treatments.

We have the opportunity to expand the

chances that these families have for a better life

with new treatment options, and we feel very

strongly about supporting that opportunity.

Today, I ask you to carefully consider the

plight of people with locally advanced or

metastatic non-small cell lung cancer and empathize

with the range of daily physiological and

psychosocial issues that they face.

Please take a leadership role in approving

a broader range of treatments and then encourage

patients to be informed, empowered, and optimistic

about the possibility of longer, healthier lives.

Thank you.

DR. BRAWLEY: Thank you, Ms. Pollack.

I believe there is no other speakers for

115

the open public hearing, am I correct? Hearing

none, then, we are going to move on.

I would like to ask the committee to

address any questions to either the sponsor or the

FDA.

Dr. D\'Agostino.

Questions from the Committee

DR. D\'AGOSTINO: If I read correctly the

way the FDA has put the questions to us, the

discussion really gets onto secondary events and

toxicity, and so forth, but there is a couple of

comments in the front statement of the FDA about

the ability with the one small historical study to

actually estimate survival and also the crossovers.

I know they were mentioned in the

discussion of the sponsor, but I think it would be

useful to hear a response from Lilly in terms of

those two questions, so that we discuss them and

put them aside, or discuss them and think they are

important.

DR. PAOLETTI: No crossover is inevitable

in a situation like that especially in the United

116

States. I will ask Dr. Frances Shepherd to review

the historical context of third-line treatment in

lung cancer to answer the question in this way.

Then, I will ask Dr. Bunn to respond to the

question in terms of what we have observed in our

data, and, finally, Dr. Scott Emerson from a

statistical point of view to address this issue.

DR. SHEPHERD: Yes, we really do not feel

that there was a significant effect on survival

from crossover. If we could have the first slide

projected, please.

You may be uncomfortable with the survival

that was achieved with docetaxel in the TAX 317 or

the TAX 320 trials. There have been several

studies that have followed after that of docetaxel

75 mg/m2, and as Dr. Bunn showed you, every single

one of those studies had a median survival in a

very tight range that was similar to the TAX 317

trial.

So, we now have at least five randomized

trials of docetaxel showing where the median

survival is expected to be in this clinical

117

scenario.

With respect to the best supportive care

arm, we have fewer studies, and there has been no

study in the third-line setting of chemotherapy.

Looking at this slide, though, a

retrospective study was done by the M.D. Anderson

and Institute Gustaf Ruce \[ph\] looking at 700

patients who had had first-line and second-line

chemotherapy. Of those, 43 were treated with

third-line.

The response rate was a mere 2.3 percent,

and the median survival was less than four months.

When you look on the other side of the slide, this

is the subset analysis from the TAX 317 study.

This is the only randomized data that exist that

compare third-line chemotherapy to best supportive

care. We do not underestimate the small sample

size here. These are exploratory analyses, but

there is nothing in this curve that would suggest

that third-line chemotherapy contributes to

survival.

Next slide, please.

118

I am going to show you the survival curve

from the BR21 trial, No. 568. This is the survival

curve in the BR21 trial, which was a trial of

placebo and best supportive care versus erlotinib

in the second- and third-line setting. Erlotinib

showed a significant survival advantage.

I show this to you for two reasons. One,

to show you that the survival of the untreated

group, the median survival was 4.5 months, almost

identical to the best supportive care group of the

TAX 317 trial.

So, we have a supporting trial that

provides a similar survival advantage or

disadvantage with no treatment. So, it gives us a

little bit more confidence that the best supportive

care group in TAX 317 was exactly what we would

expect to see in larger populations.

Now, in actual fact, if you look

carefully, more patients on the docetaxel arm

received Iressa, a drug very similar to Tarceva, in

the third-line setting. So, in actual fact, the

only treatment that has been shown to prolong

119

survival in the third-line setting is an EGFR

inhibitor and more patients on the docetaxel arm,

four times as many patients on the docetaxel arm

actually received that kind of treatment.

So, if anything, that would have favored

docetaxel and not Alimta.

DR. BUNN: Not only do we wish that we had

more treatments in the third-line setting to make

people live longer, but when we look at the

analysis, it is not, I don\'t think, appropriate to

say that the third-line treatment made people live

longer in the study.

People who got chemotherapy in the

third-line did live longer, but that is just a

prognostic group. That is like saying responders

live longer than aggressive disease. That doesn\'t

mean that the treatment made them live longer.

But we looked very hard to try to sort out

whether there was any evidence that third-line

treatment did anything here to the best of our

ability.

So, you see here on the top of this curve

120

is the overall survival results, and presumably,

the third-line therapy is given after some period

of time, and if it had an effect, the curves might

look different at the end.

I think it is easy to say, in the survival

curve, there is no difference in the beginning,

there is also no difference at the end.

If there had been a difference in

progression, the time of progression, it might have

favored one group, and on the lower left you see

that the time to progressive disease was identical

in the two things.

Finally, if there was an effect post

study, the post-study survival is shown in the

lower right curve, as I showed before, and there

was absolutely no evidence, not even a hint that

there was some survival effect in the post-study

groups.

Obviously, post hoc analyses like this are

difficult, and there are many statistical issues.

I am going to ask the statistician to get up, from

a clinical point, no matter how we looked at this,

121

we couldn\'t find any evidence that there was an

effect of post-study treatment that was different

between the groups.

DR. PAOLETTI: Dr. Emerson, please.

DR. EMERSON: Scott Emerson from the

University of Washington. Slide 64, please. This

is a slide, that this is now the fourth time we

have seen this in some version, and as Dr. Bunn

remarked earlier, this is a very biased

presentation, this is not really a very informative

presentation at all, and I would just like to point

out what we can say from this and what we can\'t say

from this.

We certainly can say that those people who

survived long enough to get post-study chemo,

survived longer than those who didn\'t survive

longer to get post-study chemo.

The grouping is true, that there is longer

survival among those who got post-study chemo, but

that is not quite as strong as what Dr. Cohen said

when he said that the post-study chemo made you

live longer.

122

So, to address that, if I could have the

slide 669. We did an analysis that tried to

compare apples more with apples. Let\'s compare

those people who got post-study chemotherapy at a

certain point in time with other people who had

also survived that long, so we will assign your

group as to whether you got post-study chemo

according to the time that you are on the study.

So, this time-variant covariate analysis

allows us to compare Alimta to docetaxel, keeping

that post-study chemo variable constant across the

groups being compare.

It also allows us to estimate the effect

of post-study chemotherapy. Let me qualify what

that effect is. It allows me to estimate the

difference in survival among those who got post-study

chemotherapy to the survival among those who

didn\'t.

I am not going to claim that this is truly

a cause and effect, because, of course, this isn\'t

randomized. There was a lot of physician

discretion that went into this.

123

But from this analysis, if I look among

patients who had no post-study chemotherapy at any

time during the study\--and again I would have

switched them to another group if they had\--the

Alimta to docetaxel hazard ratio is actually 0.84,

it is looking a stronger effect than we saw when we

just did the intention to treat or RT analyses.

If we look at the effect of post-study

chemotherapy, now I am just going to look at among

those patients alive at any given time, on the

docetaxel arm, who are getting post-study

chemotherapy compared to those on the docetaxel arm

that aren\'t getting post-study chemotherapy at that

same time, the hazard ratio is 1.12. This estimate

suggests there is a 12 percent increased risk of

death if you get post-study chemotherapy.

On the Alimta arm, it is far more

striking. There is a 58 percent higher chance of

death among those subjects on the Alimta arm who

are getting post-study chemotherapy relative to

those who don\'t.

So, this nonrandomized comparison, which I

124

don\'t really believe is the effect of post-study

chemotherapy, but this analysis would suggest quite

the contrary to what was worried about, was that

the post-study chemotherapy is responsible for the

better survival is actually if we took this at face

value, you would say if we could just write in the

indication that you don\'t do any post-study

chemotherapy, we are doing better than docetaxel.

I don\'t believe that, because I truly

believe that physicians are pretty smart.

Can we go back to slide 64 for a moment.

What we see here is that 139 subjects had

no post-study chemotherapy on Alimta and 169

subjects on docetaxel. My personal belief would be

that physicians, faced with a progression or a

patient who is failing on Alimta, would recognize

that docetaxel has been approved for second-line

therapy and those patients should really give that

chance.

I think that physicians are pretty able to

recognize when patients are in trouble, that they

are on a path towards worse and worse conditions,

125

and I personally believe that that is the primary

effect that we are seeing with that greater rate.

Patients on docetaxel could not be

switched to another therapy if, in fact, they were

already experiencing a fair amount of toxicity.

You wouldn\'t want to try them again on that

chemotherapy. We may just be seeing physician

behavior, so again, I am not claiming that that

higher post-study therapy is there, but I am

claiming that we don\'t have any evidence to suggest

in this data that there is an added benefit of

post-study chemotherapy to improve survival.

Lastly, if I could see slide 20, just to

make a point again that Dr. Shepherd made, and that

is this concept that in this study, the patients

receiving that third-line chemotherapy were not

randomized, but in TAX 317, they were randomized.

It is a subgroup analysis, but when we did

a randomization based on that, we clearly saw no

benefit. That would be presumption, that if we had

done randomization to third-line therapy, that this

would likely have been the case and that we

126

wouldn\'t have seen that added risk.

DR. PAOLETTI: Dr. D\'Agostino, should we

answer your second question, or do you want to

continue on this issue?

DR. D\'AGOSTINO: It is up to the Chair.

DR. BRAWLEY: Go ahead with the second

question.

DR. D\'AGOSTINO: You don\'t want to ask

questions on what they just presented?

DR. BRAWLEY: Does anyone have questions

on what was just presented?

DR. D\'AGOSTINO: I have a question.

DR. BRAWLEY: Oh, go ahead, I am sorry. I

misunderstood you.

DR. D\'AGOSTINO: What if Alimta was not

effective at all, and it was just the

post-chemotherapy of the crossover that gave these

individuals an increased survival? I don\'t think

there is an interpretation that they just gave us,

but there is another interpretation that is just as

viable, that the crossover is adding quite a bit to

the\--it\'s not the third line\--it\'s the second-line

127

treatment.

The other thing is that I am concerned

with really Dr. Cohen\'s presentation where he

showed that those who didn\'t get the added

chemotherapy on the prognosis basis looked pretty

good, and it is hard for to me to understand that

the third line isn\'t helpful, yet, the ones who

didn\'t get any added to their line, that some are

crossovers, some aren\'t doing as well.

I don\'t really want to make a big

statistic discussion out of it, because I agree 100

percent that we are beyond statistics, it is just

that it does raise a question about how to deal

with this type of data.

DR. EMERSON: Could I address your second

question just slightly. Performance status, we got

identical results essentially in the time variant

covariate, if I adjusted for a time variant

performance status, as well, in this trial.

DR. PAOLETTI: As regards the question

about efficacy, it\'s a point like progression-free

survival, time to progression of disease where

128

there is no effect of crossover, the results are

identical, as well as response rate.

Dr. Bunn.

DR. BUNN: I think if Alimta had no effect

in the early analysis for time to progression, we

would have seen a difference, and we would have

seen a survival difference if it didn\'t have any

effect. We probably would have seen a response

rate different, and we probably would have seen a

patient reported outcome difference if it didn\'t

have any effect.

DR. D\'AGOSTINO: I mean that was an

extreme statement I made. The point is that it may

be it is not as effective as, and it is the added

boost of the chemotherapy, the second- or the

third-line chemotherapy that makes the difference.

I don\'t see how you can sort that out from the

data.

DR. BUNN: I would just like to comment

about, you know, giving third-line therapy. You

know, we are oncologists and we generally like to

offer therapy where it might be effective, and I

129

think that most of our patients would prefer to get

treatment where it would be effective.

There does come a time when neither the

patient nor the physician is anxious to give

chemotherapy. Usually, that is in people who are

quite ill. Sometimes they are ill and show up as a

performance status, but sometimes they have been

beat up by chemotherapy and they don\'t have

sufficient blood counts, or they have neuropathy,

or they have many other things that would preclude.

It is hard to imagine, to me, that the

physicians would have a bias in the third-line

setting about treating or not treating patients.

As a doctor, I find that hard to believe.

DR. D\'AGOSTINO: I didn\'t say anything

about bias.

DR. PAOLETTI: Dr. Shepherd.

DR. SHEPHERD: Just one further point. I

think the point that Dr. Cohen made showing us how

many good performance status patients do not get

chemotherapy underlines the belief of the lung

cancer treating oncologist that third-line

130

chemotherapy is not beneficial.

When you have no evidence from historical

data to suggest a survival benefit, when you have a

response rate less than 3 percent, the potential

for toxicity is higher than the potential for

benefit, so clinical practice on the whole is not

to offer chemotherapy.

You don\'t want to make a performance

status zero or 1 patient, performance status 3 or 4

with toxicity, if you don\'t have a good chance of

benefit.

DR. NGUYEN: Maybe another clarification

on this point. Binh Nguyen, Eli Lilly, Oncology

Platform Team.

I would like to address Dr. D\'Agostino\'s

questions. 471, please. Out of those performance

status that were shown by Dr. Cohen, actually, the

patient who would perform zero and 1 and alive at

one month after discontinuation is only half, so

not all those 139, 169 could receive chemotherapy,

so you have to take that into consideration and

look at the difference between the two arms. A

131

drop now is not 30 patients, it is only 12

patients.

So, it is obvious these patients actually

die very quickly, that is why they couldn\'t receive

post-chemotherapy even thought they had a

performance status of zero and 1. I think these

data are very important.

DR. D\'AGOSTINO: I think this is the type

of discussion I was hoping to hear in terms of

responses, why are they looking so good, are they

really dying or not dying. The group actually

again, even though there is this discussion that we

heard, the ones who did not get the second shot out

at the third-line chemotherapy do not do as well,

and it is just not clear to me yet that there is an

obvious reason that one can see on that.

DR. BRAWLEY: Dr. D\'Agostino, did you have

a second question?

DR. D\'AGOSTINO: I asked a second

question. That was about the sample size.

DR. BRAWLEY: Dr. Mortimer.

DR. PAOLETTI: Actually, you were

132

referring to the non-inferiority design, et cetera.

Again, we acknowledge that the historical data at

the beginning, when we designed this trial, were

limited to the TAX 317.

However, as Dr. Bunn was showing at the

conclusion of his presentation, additional

historical data, additional data were growing

during all this year, and most importantly, the

results from our trial in 288 patients are

confirming the performance of the TAX 317.

I would like to ask Dr. Don Berry to

answer the question from a statistical point of

view.

DR. BRAWLEY: I think we need to move on.

DR. MORTIMER: I have two sort of

questions. One relates to a comment Dr. Shepherd

just made. I mean is it possible to ferret out the

patients who were on the docetaxel arm who might

have actually refused therapy because of the risk

of hospitalization since they were hospitalized

more often.

Secondly, is there a difference in

133

patterns of relapse in these arms, specifically,

brain metastases?

DR. PAOLETTI: Not to my knowledge, but I

will ask\--no, actually.

DR. BRAWLEY: Dr. Perry.

DR. PERRY: Thank you. I have a question

for Dr. Pazdur. Did the study proponents run this

proposal through the FDA, was it approved by the

FDA before it was actually set into place?

DR. PAZDUR: I would have to check if it

had a special protocol assessment. Obviously, it

was discussed with the sponsor, the design of the

trial. Whether or not there was a special protocol

assessment, I would have to check on that.

DR. PERRY: The issue to me is there is a

lot of criticism of the protocol design,

particularly about the crossover, and if the

sponsor got approval from the FDA first, I think it

is a little unfair to come around post hoc and say,

well, you didn\'t allow for the crossover, which I

don\'t think is valid in the first place, but I

would like from my own point of view whether the

134

FDA really approved this.

DR. TEMPLE: Can I just comment a little.

Nobody is criticizing the crossover, it is

completely unavoidable when the other drug is

available. The only question is what impact it has

on the somewhat marginal equivalence studies,

that\'s all.

The point was I think this should be

emphasized, if there is even a modest effect, one

that you would have difficulty detecting in a

clinical trial in that setting, it could have an

effect on the equivalence margin. That is really

the main point of what Dr. Cohen was saying.

I don\'t think we have reason to dispute

any of the analyses that were done. You can\'t

prove there is an effect. That would be very

difficult because the effect at best is small, but

taken in the context of the whole non-inferiority

design, there could be questions about whether that

undermines it some. I think that is the point.

But it is not that anybody did the wrong thing or

that we think they did.

135

DR. SRIDHARA: This is Rajeshwari

Sridhara. I am the Team Leader for Statistics.

Regarding your question regarding protocol design,

et cetera, our understanding was that they would do

a superiority and fixed margin analysis, and, yes,

we knew that there would be crossover, but in

superiority trials, this is not an issue.

When it is non-inferiority and when they

are crossing over to the same control as they are

testing, the question arises are we comparing

control to control or are we comparing treatment to

control. That is the importance of crossover that

we are talking here.

DR. PAOLETTI: Just for clarity, we did

have a special protocol assessment.

DR. PERRY: Thank you. I have another

question, Dr. Brawley, if I am permitted.

This is for Dr. Cohen. You made a comment

that the B12 folate supplementation might have had

an effect if it were given to the people on the

docetaxel trial.

Is there any evidence anywhere in medical

136

oncology that vitamin B12 folate supplementation

decreases toxicity in any group of compounds other

than the folates?

DR. COHEN: Well, this was pretreatment

elevation of homocysteine, so it had nothing to do

with giving an antifolate. This was baseline. But

to answer your question, no, there is no evidence

that this effect would be seen with other drugs,

but there is no reason to exclude that possibility

either.

DR. PERRY: Well, yes, I think there is

every reason to exclude it. I mean it hasn\'t been

done, but I mean you could say that these people

didn\'t get yogurt either, and that didn\'t have an

effect. I think that is really an invalid point to

bring up.

It is the antifolates that have the

vitamin B12 supplementation effect, not the

taxanes, not the alkylating agents, not any other

class of drugs.

DR. COHEN: I guess we disagree.

DR. PERRY: I would be happy if you could

137

show me any evidence anywhere in the medical

literature that supplementation with vitamin B12

and folate affected the toxicity profile of any

group of drugs.

DR. COHEN: I wasn\'t involved with this

study at the end of Phase II meetings, it was

another medical officer, but it is my belief that

the sponsor was asked to give vitamin

supplementation to the docetaxel group also, and

they chose not to.

DR. PERRY: I can understand that because

there is no evidence that it works.

DR. TEMPLE: For what it is worth, in the

mesothelioma\--correct me if this is wrong\--but we

believe that in the mesothelioma trial of the same

drug, it was given to both groups. Is that not

correct?

DR. PAOLETTI: Yes, it was given to the

both groups, but the trial was a single arm,

randomized trial, so when we have to modify the

protocol\--single, blind, sorry\--randomized trial,

and you have to amend the protocol to reduce

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toxicity, we were obliged to give the drug.

DR. TEMPLE: So, it was just for blinding.

DR. PAOLETTI: For blinding, correct.

DR. TEMPLE: There is a certain advantage

when you don\'t have information to exercise the

caution of giving it to both groups, but we don\'t

think there is evidence that it would help the\--

DR. PAOLETTI: I just would like to remind

you that the patients were stratified by

nutritional status as measured by homocysteine, so

at least the nutritional status would balance, and

we did look also about the toxicity by homocysteine

levels, and there was no difference in the

docetaxel arm.

DR. BRAWLEY: Dr. Levine.

DR. LEVINE: I would agree with Mike

related to the B12 and folic acid. It doesn\'t

really make sense to me that it would have any

ability to ameliorate the toxicity on the docetaxel

arm.

My question relates to some of the

toxicity issues in terms of hospitalization. I

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think the data is quite compelling related to the

increased risk of neutropenia and febrile

neutropenia and infection with the docetaxel arm.

What I don\'t understand is the hospitalization.

The numbers of hospitalizations were also decreased

with the study drug, but not the number of days.

My question relates to why. I subtracted

the social days and I subtracted the protocol

treatment days, but even then it is a little bit

higher on the study drug, it is 1,199 versus 1,147.

Do you have days in U.S. patients or what

explains that?

DR. PAOLETTI: Dr. Gralla will answer to

your question.

DR. GRALLA: I think I had the same issue

and wanted to look at the data and it is kind of

confusing, but let me just go through with you how

I looked at it, and I looked at it exactly the same

way you suggested, and Dr. Cohen also looked at the

patients treated in U.S. and Canada, North America,

the 21 percent versus the other three continents.

What you find is if you look at those 21

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percent treated in the U.S. and Canada, where you

don\'t have those confounding issues of social

admissions and protocol admissions, that what you

have is a higher number of patients admitted for

drug-related reasons for docetaxel, and what you

have is the same number of patients admitted in

North America for non-drug related issues, exactly

what you would expect, that because of the febrile

neutropenia, you would expect to see more patients

admitted with docetaxel for drug-related reasons,

but you would expect to see the same for non-drug.

Then, you go to the other three continents

and what you see in the other three continents is

again for drug-related issues, you find fewer

admissions on Alimta, but for non-drug related

issues, there is an imbalance.

This relates to about 4 percent of all the

patients on the protocol all together, and what you

have are more patients admitted for disease

progression reasons, for complications, so these

are for cord compression, limb pain, pleural

effusion, COPD reasons, and for whatever reasons

141

that are not clear, and there is no evidence that

it is due to drug toxicity, you have longer

hospital stays, and some of these hospital stays

are 30 to 60 days, and you find three to four weeks

for pleural effusion drainage.

So, for whatever reason, and some of the

countries lack hospice, there is this imbalance,

but it is not in drug related issues, it\'s in these

non-drug related areas, and I think again, the 4

percent of patients that amount to all this excess,

that this is just a fluke bad luck result, because

there is no other explanation that I can find,

spending a good amount of time looking at these

data.

DR. BRAWLEY: Ms. Ross.

MS. ROSS: Thank you. First of all, I

would like to thank Mike for bringing up the

clarification about the B12 effects on antifolates.

I really had to do something else from your remark,

Dr. Cohen, and I am glad it was clarified.

I want to ask two questions, two questions

that will help me understand better as a patient

142

advocate what FDA is really saying, if you will

bear with me.

FDA is taking the position that the

sponsor has not proven non-inferiority. Is FDA

then taking the position that the drug is inferior,

that Alimta is inferior?

DR. PAZDUR: No, basically, what we are

looking for in a non-inferiority design is an

effect on survival. One could win on survival

either by an improvement in survival or

non-inferiority.

What we are saying here is because of our

concerns of crossover because of the lack of a

really good historical database, the analysis of

non-inferiority may be in question. We are not

saying that it is an inferior drug. We are saying

basically that we have concerns that an effect on

survival may not have been convincingly

demonstrated, and for regular approval of a drug,

one has to have confidence of an effect on a

clinically meaningful endpoint, such as survival.

That is the issue.

143

MS. ROSS: Thank you for that

clarification.

DR. TEMPLE: Can I just take half a minute

to describe the non-inferiority problem?

\[Laughter.\]

DR. TEMPLE: Okay, maybe two minutes.

In situations where you cannot treat

people, your only choice is to be better than the

standard therapy or to show that you are not worse

by more than certain amounts. So, we call these

non-inferiority studies, but that is a misnomer.

They are really not too much inferiority studies,

and not too much means you have preserved a

reasonable fraction of the known effect of the

control agent. That is what you do.

The simplest way, and the last one that I

must say I have been able to understand fully,

because statistics takes over after that, is this.

You make an estimate of what your effect is of the

control from the historical experience.

So, we have that study. It is a small

study and it clearly showed an effect of docetaxel,

144

but because it was small, the confidence interval

was wide and the 95 percent confidence interval for

how much better was that it was only 12 percent

better than the control.

So, one way of estimating the absolutely

known effect of the control agent is it has 12

percent on survival. For reasons I will explain,

people consider that too conservative, but let me

start there.

If that is what you believe, then, you

want your comparison of the new drug with the

control drug to rule out a difference of more than

12 percent, because if it was more than 12 percent,

then, there would be no effect of the new drug at

all. In fact, given that we are talking about

lethal disease, we often ask that some fraction of

that effect be preserved.

So, if you thought the effect of the

control is 12 percent, you might ask that you rule

out a difference of more than 6 percent, and if you

did that, then, you would say you have shown

non-inferiority. That is what it means.

145

Now, the trouble with that is that if you

take the worst case for the control agent, that is,

that the effect is only 12 percent, when the point

estimate of the effect was more like 40 percent,

that is a very conservative choice, and it makes it

very difficult.

Ruling out a difference of 6 percent or

even 12 percent is a very hard thing to do. You

would need a study that is very, very large. So, a

lot of people have been working on more

conservative\--or less conservative, if you like,

less conservative ways to do these studies, and

they are statistically complicated, but at least

one of them, and the one that was used by Lilly,

involves\--sorry, I have one other thing to tell

you.

We also calculate that when you use this

12 percent value or something like that, you have

got a study that gives you an equivalent of a p of

0.003, which is more than we usually demand. So,

people have thought about how we could come up with

an analysis that is closer to what we usually want,

146

you know, a p of 0.05.

One method of doing that was developed by

Mark Rothmann who works here, and that is what

Lilly used. Basically, he calculates an interval

that is different from the 95 percent confidence

interval, that, if used, will preserve a p-value of

something roughly equivalent to 0.05.

I understand from a conversation at the

break that when Lilly did that, they used something

like a 65 percent confidence interval. Now, if you

do that, instead of having a 12 percent effect of

the drug, you have something larger. I am just

making it up, but say it is 25 percent effect or 30

percent, I don\'t know, I didn\'t get that number

although I gather it has been submitted to us.

When you do that, ruling out a difference

of 30 percent in this study, you can see the study

did rule out a difference of 30 percent because the

upper bound of the worseness was I think 18 percent

or 20 percent.

So, depending on what you think and what

you are willing to say the effect of the control

147

agent is, you succeed or fail in your

non-inferiority study. The difficulty is there is

not a lot of agreement, it is very complicated.

Most clinicians can\'t understand what is going on,

they depend entirely on the mathematics of it,

which is always a problem for me, I like to

understand.

But anyway, that is what we are talking

about, and that is what all these discussions of

methods have been about. The 11 percent that they

tried to do and failed sort of corresponds to that

initial 95 percent confidence interval lower bound,

and that is highly conservative, and they didn\'t

win on that, but they may have won\--that is what

the debate is about\--on a less conservative attempt

to show that you have preserved a reasonable

fraction of the effect of the control agent.

I don\'t know if that helps or not.

MS. ROSS: Could I beg your indulgence and

ask one other question on that point?

DR. TEMPLE: Yes, but you have got to give

me another 30 seconds.

148

MS. ROSS: Thank goodness Dr. Fleming is

not here.

\[Laughter.\]

DR. TEMPLE: He would have said the same

thing I said.

MS. ROSS: Suppose we turn the tables.

Suppose Alimta were the already approved drug for

second-line treatment for non-small cell lung

cancer, and it was docetaxel that was here seeking

approval.

Based on the numbers that you have seen,

would docetaxel have been able to demonstrate

non-inferiority to your satisfaction?

DR. TEMPLE: Well, you have to tell me how

big the effect of Alimta was, so I can create an

appropriate non-inferiority margin given the new

equivalence of the measured results here, you might

that if you knew the Alimta effect size very well,

this might have been successful, but a lot depends

on how well you know the control drug effect.

In this case, you had quite a dramatic

effect in the small study, meaning that the

149

confidence interval is rather large even though the

effect was very impressive in that small study.

So, if Alimta had a big 250-patient study,

a 40 percent reduction, and the confidence interval

was very narrow, a study like this might

persuasively show equivalence or non-inferiority.

MS. ROSS: For docetaxel.

DR. TEMPLE: Yes. I should say one other

thing. We recognize this is a huge problem because

calculating\--first of all, you want drugs that

might be a little safer, and at the same time, you

want to be sure that they still have the desired

effect.

I know everybody looks at those

Kaplan-Meier curves and they look at them and they

say how could there be any difference. The trouble

is the effects on the Kaplan-Meier curve of the

drugs that are effective are very modest, and there

could be a difference or, you know, that is what is

being debated, and you wouldn\'t want that

difference, you wouldn\'t want to lose the effect

even if it\'s small, but it poses a tremendous

150

problem for manufacturers who want to show

non-inferiority. It is very hard.

DR. BRAWLEY: Ms. Ross, we have the

additional problem, you know, we just heard a

wonderful statistics lecture, and thank you for

giving us the lecture without confusing us, but you

can have a situation where\--let me just as a simple

country doctor sort of thing.

You can have a drug that has a 20 percent

response rate in a disease, but has terrible

toxicities, and there are certain patients who

might look at those toxicities and say, hey, I will

take a drug that has a 15 percent response rate

with a lot less toxicity.

The problem we have is where do we go from

there, because that might actually be what we have

been presented with here. I made up the numbers,

they are not applicable to this issue.

MS. ROSS: But I think your point is

exactly what we are looking at here. We have two

drugs very similar in effect. Whether the hair

splitting on proof of non-inferiority goes one side

151

or the other, the difference is in toxicity.

As has been pointed out several times,

there is only one drug approved right now for

second-line chemotherapy for non-small cell lung

cancer, and if that is going to make a difference

in infection and neutropenia and in hair loss, I

mean this is a very big deal. You all kind of

glossed over the hair loss thing, but you have a

patient who is very sick with lung cancer, not

losing their hair makes a big difference in their

attitude and general feeling of wellness.

DR. TEMPLE: But presumably, you would

still want to be sure that it had the effect you

were using it for, you wouldn\'t want to lose it

all.

MS. ROSS: Well, according to all the

charts I saw, it is very similar.

DR. TEMPLE: Well, that is the point, that

is necessary.

MS. ROSS: It is very similar, but it has

less toxicity. Well, certainly I would go for that

drug, and I hope my doctor would, too.

152

DR. TEMPLE: Right, as long as you are

reasonably sure that it has that effect. That is

what we would all say.

MS. ROSS: Reasonably sure that it has an

effect.

DR. TEMPLE: The desired effect on the

tumor and on survival.

MS. ROSS: Someday we are going to be

sitting around this table talking about drugs that

increase survival by two or three years. We are

not there yet.

DR. TEMPLE: No, we are not.

MS. ROSS: We are only talking about

months in any event, and if you have a drug that

gives you less side effects and does the same

thing, I think that the lung cancer patients

deserve that option, and I would argue for full

approval for this drug. It is not fair they only

have one now. This is a horrible disease.

DR. BRAWLEY: We will get to the questions

in a little bit.

Dr. D\'Agostino, I know you wanted to ask a

153

question, but I think Dr. Paoletti and his group

have a rebuttal to the previous question.

DR. PAOLETTI: Yes, if we may have our

additional 30 seconds to discuss about the issue,

and I will give to Dr. Berry and then Dr. Bunn to

comment on that.

DR. BERRY: Donald Berry from M.D.

Anderson.

This is related to Dr. Temple\'s discussion

and also to Dr. D\'Agostino\' second question. If I

could have slide 450, please.

This shows better, I think, the confidence

interval that we have been discussing that goes

from 0.82 to 1.20, and it puts in perspective the

fact that Ms. Joss was just talking about, it looks

similar. The similarity has much greater

likelihood than the N\'s of the confidence interval.

We are talking about a ratio of 5 or so here in

terms of degree of likelihood, so it is much more

likely that the survival is the same in both than

that you are the N\'s of those intervals.

451, please. this shows the confidence

154

interval, actually, the 90 percent confidence

interval for the hazard ratio for the comparison

docetaxel to best supportive care. The 95 percent

confidence interval goes down to 0.35 and up to

0.88. The 0.88 is the 12 percent or the 1 minus 12

percent that Dr. Temple mentioned.

Again, this confidence interval is a good

deal wider although it looks the same from the

previous picture, and that reflects the fact that

this study was about one-fifth the size of the

previous study.

Slide 565, please. The concern about only

one small historical study concerns me as to how we

are going to do this. I mean I agree with Dr.

Temple that we are not there yet in terms of

understanding everything about non-inferiority

trials, but what this means is that there is only

one trial comparing best supportive care to

docetaxel, and there won\'t be any more.

That means that to show a benefit, we

would have to have enormous trials. If we had many

large trials, an infinite number of patients, we

155

would still not be able to show, on the basis of

the comparison with the historical data, that the

drug is equivalent to a preserves a benefit that

docetaxel has even\--and this gets to Ms. Ross\'s

point\--even docetaxel itself couldn\'t be shown to

be non-inferiority to itself.

The precision of the trial, the previous

trial, is, of course, not very great. The number

of patients, as pointed out by everyone, is 104.

There is great imprecision, and that limits any

comparison, but the Rothmann analysis and other

reasonable analyses account for that imprecision.

Even though the study is small, it is possible to

make the comparison.

What are we left with in terms of showing

non-inferiority? The FDA is taking away historical

study comparisons, and that means we would have to

show a comparison\--the \"we\" being the medical

community\--would have to show a comparison with

docetaxel itself, which would mean thousands or 4

or 5,000 patient trials, and that is not in the

best interest of patients.

156

DR. PAOLETTI: Dr. Bunn.

DR. BUNN: Some people aren\'t going to

believe this, but I actually have empathy for Dr.

Pazdur and Dr. Temple. I think that they are

trying to do the best things, as well. They also

have regulatory issues, and one of their regulatory

issues is there has to be adequate and

well-controlled trials.

Many times in the past, historical

controls serve as adequate and well-controlled

trials, many, many precedents for that, and one of

the issues is not only how comfortable are you with

this one trial, okay, but do you have any

historical data that gives you confidence, as well.

Oftentimes, you know, Gleevec, you have a response

rate, when you are expecting none, you get 60, you

know, that is an adequate and well-controlled

trial.

If we could have slide 560, the slide says

that docetaxel evidence, you know, we have a number

of historical studies that not only discuss

survival, but also discuss response rates and

157

progression-free survival, as well as patient

reported outcomes.

There are patients who get placebo or best

supportive care who have objective responses, and

that is, of course, their pneumonia getting better,

and we can quantify that because there have been

randomized trials against best supportive care, and

they all show a response rate of 1 percent or less,

indicating that 1 percent of the time or less, you

have a pneumonia that gets better with antibiotics,

and you think that the drug did something.

But we have lots of trials to show that

both Alimta and docetaxel cause response, and we

can compare that to best supportive care. We also

know from the randomized trials that the median

time to progression is very short with best

supportive care, and we can be relatively confident

that that interval is much longer in patients who

get some therapy that has an effect.

I am not the best supportive care guy, but

there are backup slides, I don\'t think we need

them, to show the same for patient reported

158

outcomes. I personally believe that another way to

look at this is are we confident that there is an

effect of the drug from historical trials, not just

TAX 317B.

DR. BRAWLEY: Thank you.

Dr. D\'Agostino.

DR. D\'AGOSTINO: The comments I wanted to

make and the question fits in very well with this.

I think that no matter how you look at the

studies, at a study that was presented, there is

this problem of the crossover and what does it lead

to. We don\'t know how, we are going back and

forth, but we really don\'t know how to handle it,

and it is there, and it is not a criticism of the

design, it is a fact of reality.

The comment about the non-inferiority and

the problem there is that we don\'t, as a committee,

want to set a precedent, that we somehow or other

feel that one small study will do the job, and the

concern that the FDA has, if I understand it

correctly, is that one small study has a lot of

variability, and they are still not convinced that

159

maybe we have adjusted enough for it, and maybe the

statistical analysis for the straight-out approval

is questionable.

But I thought I heard at the beginning of

the presentation that was made by the FDA, that

this was under the accelerated approval type of

mode, and the accelerated approval type of mode

takes us to a different level of sort of approval

process.

Could you go over that?

DR. PAZDUR: First of all, there are

several issues that I want to address here because

I think when we brought\--our purpose in bringing

this application, it really reflects a lot of the

problems that we have been having with

non-inferiority analysis.

By no means do I want anybody to walk away

with the feeling that we are saying that this drug

is inactive. I think we feel very comfortable in

some of the surrogate endpoints, response rates. I

made the statement that we have accepted similar

response rates for accelerated approval, to take a

160

careful look. It is not just adding up the numbers

of toxicity, it is really clinically getting down

and seeing what are the real advantages of this

drug.

But accelerated approval, because we do

have this issue, are we dealing with a true effect

on survival, do we want a regular approval of this

drug, and have we adequately demonstrated that

effect.

If we really haven\'t, then, obviously,

that produces precedents which we may not want to

get into. We do have accelerated approval that

will allow us, number one, if the drug has an

advantage over available therapy and toxicity,

could be that, and has a demonstrated effect on a

surrogate endpoint that is reasonably likely to

predict clinical benefit, such as response rate,

that we could move for approval in that situation.

So, that was the avenue that we were

taking because of the concern that we had for what

is the effect, has this been clearly demonstrated

on survival. But I think there are big issues here

161

that this application brings forward for the whole

area of oncology and how to develop drugs in this

non-inferiority aspect.

Many other therapeutic areas can use

placebo-controlled trials. In oncology, that is

tremendously difficult to do, hence, we are stuck

either with superiority trials A versus B, where

you have to show not only the benefit of your drug,

incremental benefit, but the entire effect of the

other drug to win, or you could do an add-on trial

to demonstrate an incremental benefit, but then you

have to have a situation where you could combine

the two drugs together.

The other area is we have an issue of

crossover, and that is going to be with us. You

know, we totally realize that if there is a

commercial drug out there that you are comparing it

to, a large number of people are going to be

getting that drug at the time of disease crossover,

and that does pose a problem to looking at

non-inferiority analysis.

The issues of what constitutes an adequate

162

database is very difficult. If you look at our

previous non-inferiority approval that we did on

non-inferiority, and with capecitabine several

years ago, we had approximately 10 studies which

isolated the effect of 5FU-leucovorin versus 5FU.

That luxury of having multiple trials was done

because there wasn\'t any drug activity or

meaningful drug activity for almost three decades

in metastatic colon carcinoma.

We aren\'t going to have that again, and

thank God, because that obviously is not

identifying active drugs, so these are essential

problems that we are going to have to face with

non-inferiority, and that is why we brought this

application to bear.

How do we handle this if we can\'t really

determine a true treatment effect to preserve, how

do we address the issue of crossover, and the

accelerated approval program does give us the

option of dealing with this problem from a

regulatory framework if the drug really has a

meaningful reason to be approved here, i.e., a

163

toxicity reduction.

DR. TEMPLE: Could I just add one thing?

In oncology anyway, the studies people do to

confirm clinical benefit are often in a different

stage of the disease. It would not be unusual,

having given accelerated approval for second-line

therapy, to reach the conclusion the drug is

effective in this disease based on first-line

studies which, as you know, are ongoing.

DR. D\'AGOSTINO: What I wanted to follow

up, we have some impressive data on the toxicities,

as was pointed out, and you talk about looking at

some of the time to progression of the disease and

progression-free intervals, tumor response, the

secondary variables.

Are we going to get caught in the dilemma

that when you start looking at those variables,

they show acceptance of a null hypothesis of

equality, they don\'t show superiority, they don\'t

show non-inferiority, so are you leading us in a

path, or are we leading ourselves in a path that is

really not going to resolve the issue of how to put

164

this data together outside of the toxicity, I

think, which is quite superior.

DR. PAOLETTI: In designing and asking the

questions, I think we outlined the problems here,

how can we really address those problems. Here

again, we would like to, when we get to the

questions, talk about full approval of this drug

also, so we are not just looking at accelerated

approval here, and we would be happy with the

conversation that has gone on to take a look at

that question.

But here again, you know, these are very

difficult problems to grapple with, how do we deal

with them is very difficult to do, and I don\'t

think there is a clear answer here.

DR. BRAWLEY: Dr. Cheson, then, Dr.

George.

DR. CHESON: Since we are at least in part

looking at this drug for consideration for

accelerated approval, one of the requirements for

this that Dr. Temple alluded to is that there be a

program ongoing for confirmatory trials that will

165

address the safety and efficacy of this particular

agent.

I am a lymphoma doc, so I don\'t really

follow this lung cancer stuff, and I was wondering

what sorts of trials are ongoing that may help

resolve this issue, that can be done in the

foreseeable future?

DR. PAZDUR: I believe there are at least

three, and probably Paolo can address those, I did

mention that in our introductory comments.

DR. PAOLETTI: Yes, we have one ongoing

trial in second-line lung cancer, again an

randomized trial, and we have two planned and one

ready to start, again randomized trial in

front-line lung cancer, where Alimta is combined

with a platinum agent.

DR. BRAWLEY: Dr. George, then Ms. Ross.

DR. GEORGE: One quick question or one

point on the accelerated approval issue. I have

heard you say before, Rick, that accelerated

approval is not a second-class approval, that is,

it has to have the same level of evidence as you

166

would for full approval. It just means little

different things.

That is not really why I raised my hand,

but I felt we might want to discuss that some if we

get to that point.

What I wanted to do is address a couple of

quick points about the historical data and point

out that I think it may be less reliable even than

we have been talking about.

A couple of things. One is a minor sort

of technical point that perhaps can be cleared up

quickly. I was just reading the methods in the

paper that reports the results, and it says there

that survival time is censored with any subsequent

chemotherapy, so that, in effect, crossovers would

be censored, which would be kind of a bizarre thing

to do, I think, in the statistical approach here.

We can argue about what it means to cross

over and the effect on survival, but you don\'t

usually censor it. That may be a misprint in the

paper or misstatement, because I know it wasn\'t

done here, but it does relate to how you\--what you

167

are using as the historical control.

There was a 100 mg dose to start off, and

that was on roughly the first half of the patients,

and one interesting thing, and then they switched

to 75 at the recommendation of the Data Safety

Monitoring Board for the second half of the trial.

If you look closely at what the results

were in the first half and the second half, let\'s

just say look at the best supportive care in the

100 group, that is, the concurrent randomized group

at that point, and look at what happened. There

was no direct comparison, but eyeball it, compare

that to the subsequent best supportive care in the

75 mg part of the trial, you will see that the best

supportive care results got worse in the second

half of the trial, maybe not significantly worse

you can\'t do the test easily, just eyeball it, but

clearly, if, say, the best supportive care group

happened to be reversed, that is, the ones that got

it in the first half or the ones you were actually

looking at in the second half, your effect size,

you estimate would be smaller, still with the same

168

kind of imprecision, but require then more

difficulty in proving that you had non-inferiority.

So, I think this doesn\'t prove anything

directly except that one small trial does create

problems, and it may be even worse than has been

indicated here.

DR. PAZDUR: To address Dr. George\'s

question about secondhand approvals and level of

confidence in the data, and I mentioned this in my

introductory comments, most of the times when we

are looking with this committee and also, if we

take regulatory actions, without the committee\'s

input, we have been looking at single-arm trials

usually of 100 patients.

As I pointed out, even though this trial

failed its primary endpoints, randomized trials

always give you more information. We have

randomized response rate information, we have

randomized toxicity data. We can take a look

albeit not through any formal non-inferiority

mechanism, but at time to event and points, such as

time to progression and survival.

169

Although we cannot with precision state

what that non-inferiority is, I think we get some

degree of confidence in making a regulatory

decision here. We also have another approval of

this drug and an unrelated disease albeit in

mesothelioma, the first drug to have a survival

effect in this disease.

We have Phase II trials that show activity

also of this disease.

DR. BRAWLEY: I think we are morphing from

questions to discussion here.

Dr Paoletti, do you have something

specific?

DR. PAOLETTI: I think that Dr. Shepherd

has something specific.

DR. SHEPHERD: I have to bear the

responsibility, of course, for the TAX 317 trial.

These little shoulders, though, have done a lot of

best supportive care in placebo trials for this

august group, which really cannot be done in the

United States, and I would just like to remind you

of that.

170

These are extremely difficult trials to

do, and we unfortunately have to live with the

trials that we have. Yes, the TAX 317 trial wasn\'t

analyzes with censoring, and, yes, I recognize that

there were differences in the survival of the best

supportive care group in the second part of the

trial, but I feel more comfortable with the

follow-on of our BR21 trial that compared placebo

to erlotinib in which once again we saw a no

treatment survival that was really almost identical

to the survival of the second half, not the first

half, but the second half of the TAX 317 trial.

So, I think we can be comfortable with

many hundreds of patients in the BR21 trial, what

happens with no treatment, and I think that that

supports the observations that we had in the TAX

317 trial.

DR. PAZDUR: To follow up on Dr.

Shepherd\'s comment, we are aware there is a great

deal of difficulty in dealing with placebo-controlled

trials, A versus placebo. Those are

being down outside of the United States primarily.

171

Alternatively, I think we need to keep in mind, as

a field, that also then starts posing problems of

constancy, what are the qualities of those patients

going on, what are the supportive care, all Stage

IV lung cancer metastatic disease is not the same

once chemotherapy has started, may differ

tremendously whether you are talking about Boston

or Bosnia.

DR. SHEPHERD: Well, I can tell you that

there is not a great difference between Boston and

Toronto, and that when we looked actually at the

Canadian patients in the NCI trial, which was an

international trials, when we looked at Canada

versus the rest of the world, it was actually a

similar result.

DR. PAZDUR: I am just bringing that up as

future concerns.

DR. SHEPHERD: I think polymorphisms and

many other things may come into play when we are

looking at different patient populations.

DR. BRAWLEY: Dr. Temple, you had a follow

up?

172

DR. TEMPLE: Yes, I mean I know sometimes

there is no choice because all you can do is

compare one study with another, but if Dr. George

points out that the first half of the study and the

second half of the study are different, it is not

that reassuring to learn that some other study was

more like one-half than the other.

DR. BRAWLEY: Ms. Ross, you had a

question?

MS. ROSS: I think I might have forgotten

what the question was. I just want to

again\--indulge me as the patient advocate here, I

am not a scientist\--if FDA is not really sure and

confident in the design of the non-inferiority

trials, and if they approve that design for this

sponsor to go forward, then, that question is moot.

I mean they have done what they are supposed to do.

The question then becomes even if you are

not satisfied, even if we accept you are not

satisfied, doesn\'t the question then revolve around

the risk-benefit ratio to the patient? Doesn\'t

that take precedence at that point?

173

DR. BRAWLEY: Dr. Temple.

DR. TEMPLE: Well, we often agree with

companies about a study design, but what determines

whether data supporting approval arise from that

design is the results.

So, there was hope that Alimta would

actually be better. That was one of the hoped-for

results. Had that occurred, we probably wouldn\'t

even have brought it here.

It also is possible, I mean the best way

to be non-inferior is to be slightly better, so

that you are kind of leaning in a favorable

direction, but don\'t quite show superiority.

Had that occurred, I mean it was a tiny

bit better on median, but not better on hazard

ratio, had that occurred, that would also be a

relatively easy case. What you have got here is

where they are sort of even when you looked at

hazard ratios, and so we are expressing

reservations about whether\--not a conclusion, we

are going to listen\--we are expressing reservations

about whether the Alimta has been shown to preserve

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the modest but real survival effect of the control

agent, which is still important.

MS. ROSS: Granted that is important, but

even if you accept that there are going to be

continued questions about that, what then is the

next criteria?

DR. TEMPLE: The design really isn\'t the

problem, the results are the issue. Nobody thinks

it is a badly designed study, and as we have said

repeatedly, the crossover is inevitable and

unavoidable. Nobody doubts that anyone would not

do that.

MS. ROSS: Right. So, then, what becomes

the next criteria is my question.

DR. TEMPLE: That is sort of what we are

asking about. If people were persuaded that the

questions we have raised are not sufficient to

raise doubts about whether it is, in fact,

effective in the non-inferiority sense, then, it

could be considered for full approval.

One of the options, though, created in, I

don\'t know, 1996 or thereabouts, for diseases like

175

cancer was that if you have a surrogate you think

is reasonable, and response rate has been

considered a reasonable surrogate for clinical

benefit, we can approve a drug if it has some

advantage over other therapy even though true

clinical benefit has not yet been demonstrated if

we believe, for example, that it was clearly less

toxic. That is what accelerated approval is for.

Accelerated approval is full approval, but

on a condition that further studies be done, but

the drug is sold and marketed, and so on.

MS. ROSS: There are other implications to

accelerated approval versus full approval, too.

Some of them put the patient in a very difficult

position.

DR. TEMPLE: Say why?

MS. ROSS: There are other implications of

accelerated approval versus full approval. I know

you don\'t want to get into this today, but one of

the implications is whether or not it is going to

be covered.

DR. TEMPLE: I don\'t have the impression

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that that is usually not covered. I know there has

been discussions of some of those things. A lot of

cancer drugs have been approved initially under the

accelerated approval rule.

DR. PAZDUR: But I don\'t think we can go

down that path and make any regulatory decision

based on coverage, I am going to make that clear

for all of the committee members and any voting or

any decisionmaking that you make. That is a

separate issue, can change today, can change

tomorrow, can change every five minutes.

DR. BRAWLEY: But I should point out that

most of the accelerated approval\--at least all the

accelerated approval drugs that I know of are

covered by insurances including Medicare.

Dr. Bukowski.

DR. BUKOWSKI: There was mention made of

another second-line trial with Alimta in lung

cancer. Could you clarify or tell us what that

trial consists of?

DR. PAOLETTI: Yes. This trial is ongoing

and we are comparing two dose of Alimta, the 500

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dose with a higher dose.

DR. BRAWLEY: Dr. D\'Agostino.

DR. D\'AGOSTINO: Just to go back, if I

understand the question that was being raised, I

mean in terms of my understanding of the approval

process, if we are stuck on whether or not there is

sufficient data for approval, we can\'t jump over it

and use a different criteria, so I think we have to

face the question do we think that there is enough

data from this non-inferiority trial, and I think

the questions about the historical database and the

crossover still linger with us, and so the switch

to the accelerated approval, which is quite viable

here, and the data seems to line up quite nicely

for that, I think is something that would be the

switch as opposed to a risk-benefit and glossing

over the non-inferiority trials discussion and

problems.

DR. PAOLETTI: Dr. Shepherd, do you want

to comment?

DR. SHEPHERD: I think that many of us

feel that full approval is appropriate, but since

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we have raised the issue of accelerated approval,

there is another part of accelerated approval, and

that is the unmet need.

We have an increasing population of

patients who are receiving docetaxel first line.

Its level of activity in the second line has led to

randomized trials in the first line showing

superiority, so docetaxel is being moved more and

more into the first line in advanced disease, and

the first line administered concurrently in locally

advanced disease.

It has never been the practice with

non-small cell lung cancer to re-treat patients in

the second-line setting with the same agent. So,

that leaves an increasing population of patients

for whom there will be no approved second-line

therapy.

DR. PAZDUR: Could I just interrupt you?

I really don\'t follow your logic here, because if

you are arguing accelerated approval versus full

approval, the drug is available.

DR. SHEPHERD: Yes, well, I don\'t want to

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either, and as a Canadian, I shouldn\'t be getting

into reimbursement, but it is my understanding that

it may not be reimbursed for non-indicated, not

approved indications.

DR. BRAWLEY: I am going to take the

Chair\'s prerogative here.

DR. SHEPHERD: And there is also the group

with neuropathy that can\'t have the drug.

DR. BRAWLEY: I am hearing a lot of

statements about reimbursement that I know are

contrary to what I know to be true.

So, why don\'t we stop talking about

reimbursement all together and let\'s get back to

talking about the drug.

Dr. Levine.

DR. LEVINE: I have a very simplistic

question to the statisticians. Because of the

issues and difficulties with the crossover, what is

scientifically wrong with just looking at data in

those individuals who did not get further

treatment? So, the study drug was 6.2 months

versus 5 months in the docetaxel.

180

The time to tumor progression was the

same, the response rate is the same, and if you

just stop it at the end of all treatment, it seems

to be quite equivalent. That is not hazard ratios,

and so forth, but what is wrong with my thinking?

DR. BRAWLEY: Dr. Yong-Cheng Wang.

DR. WANG: That is a subgroup analysis.

It doesn\'t show the whole population. So, subgroup

analysis, the p-value is not interpretable.

DR. D\'AGOSTINO: You have destroyed the

randomization by doing that, so then from that

point on, it is subgroup or it\'s sort of trying to

intuit, and that is exactly nicely presented by

Lilly in terms of trying to give us a feel for

that, but as everybody is saying, we can\'t

interpret the p-values anymore.

DR. BRAWLEY: Dr. Emerson.

DR. EMERSON: I would agree with the

aspect of the subgroup analysis for several of your

points, but not all of them. The aspect of looking

at time to progression and defining progression as

getting the same line there, but that is still a

181

randomized comparison, and there was equivalence on

that endpoint.

For what it is worth, the subgroup

analysis in which you say that you are just going

to look at the group that never got the post-study

chemotherapy is covered by that time-variant

covariate analysis, and it was just looking at that

0.84 has a ratio that was in favor of Alimta, but

again, the bias that creeps into that subset

selection is too great.

DR. BRAWLEY: It\'s about noontime right

now or five past noon. We have morphed into

discussion away from questions. Are there any

members of the committee with questions or things

that they would like to discuss?

Yes, Ms. Haylock.

MS. HAYLOCK: You talked about different

endpoints, and I was wondering where the issue of

morbidity and mortality in terms of the symptoms\--I

think Dr. Levine mentioned the neutropenia, and I

am thinking of the kinds of things that actually

cause lung cancer patients to die, that may not be

182

directly related to tumor, but are related to the

side effects of treatment, so I am wondering how

you factor in the significance of the side effect

profile of this drug versus the docetaxel.

DR. PAZDUR: Obviously, any regulatory

decision is based on a risk-benefit analysis, but

particularly in this situation, and the reason as

we morph into the questions will be, the first

question is asking does this drug have a more

favorable toxicity profile.

The reason behind that from a regulatory

point of view, in order to have an accelerated

approval, you have to be better than available

therapy, hence, a more favorable toxicity profile

would encounter that requirement.

DR. BRAWLEY: Dr. Cheson.

DR. CHESON: I guess it\'s along the same

lines. I would not like us to set a precedent for

approving drugs vis-a-vis efficacy that don\'t meet

either the primary or secondary endpoints.

We have had drugs in recent history that

didn\'t meet the primary, met the secondary, and

183

didn\'t get approved, but as you said, its safety in

this case may be the more compelling aspect of this

drug, and I think that it is fairly impressive that

it is safer, but I am certainly not convinced about

any of the other endpoints, and I wouldn\'t like us

to set that precedent or else we ought to start

rethinking some other drugs.

DR. PAZDUR: So, Bruce, what you are

saying is that no drug should be approved unless it

meets its primary endpoint, and perhaps we should

just refuse to file those applications?

DR. CHESON: No, I am saying if it doesn\'t

meet the primary or the secondary endpoint of

efficacy, then, it needs something else. In this

case, it\'s the safety endpoint.

DR. PAZDUR: Don\'t throw the baby out with

the bath water here, folks, okay? I think we have

to take a look at how difficult doing clinical

trials in oncology are, and I mentioned this

before, that many areas do placebo-controlled

trials. We can\'t do them especially in this

situation where there is already approved drugs.

184

But this application is usually giving us

more information than we get with a standard

single-arm trial. Here, we have comparative

toxicity data, we have comparative response rates.

We could look, albeit we can\'t do formal non-inferiority

analysis, at least a feeling of what is

going on with time to progression endpoints far

more superior than the standard single-arm trial

that we get with an accelerated approval in a very

refractory disease population.

DR. TEMPLE: Just one word about

accelerated approval. When the whole idea was

proposed, it recognized that by relying on a

surrogate endpoint, quote, \"reasonably likely to

predict clinical benefit,\" there was a finite but

real risk that you would eventually discover that

there was not a clinical benefit.

So, that was considered an acceptable risk

if you were getting something in return, and the

something you could be getting in return is ability

to treat a stage of disease that has no other

treatment. That is the more usual one that comes

185

to the committee. But there is nothing

incompatible with the idea that you would do it

because you find a less toxic way of treating the

same condition.

But there is clearly the possibility that

we are going to turn out to be wrong, that it

really will not have a benefit. You know, you have

some track record with Alimta, so you are not too

worried about that, we are not supposed to be too

worried about that, but it could be. I mean that

is part of the deal.

DR. BRAWLEY: Dr. Hussain.

DR. HUSSAIN: I have a comment and a

question. The question is first. Was there a

global quality of life tool done other than the

symptoms and the lung cancer specific? That was

one question, because I don\'t think we saw that

global data, so that was one.

But if you don\'t mind while you are

getting ready, I have a question to Dr. Pazdur and

the group there.

I am looking at slide 35, and slide 35

186

talks about first-line monotherapy of Alimta, and

talking about Alimta and docetaxel efficacy Phase

II trials. There is really nothing in that slide

that tells me a Phase III comparison should have

been powered to look at a survival advantage.

Understanding these are all Phase II data,

the responses are all over the place, overlapping,

median survivals are overlapping, and that perhaps

in avoiding problems like that, when you start in

the beginning is look at the drug and see does this

drug have any chance of proving superiority, and if

it\'s not, then, that would be an unrealistic

primary endpoint, and then power it for survival,

but use a clinical benefit primary endpoint - is

the patient going to live better, is their quality

of life better, something meaningful, so that we

don\'t end up in the predicament every single time

you have very, very modest at best drugs.

DR. GRALLA: I would like to answer the

global quality of life issue. I didn\'t present it

for sake of time, but the LCSS, which is a

validated instrument, includes quality of life

187

analysis, et cetera, did look at three summative

items - global quality of life expressed by the

patients, patient-expressed symptom distress, not

just the symptoms, but how it affected them, and

then their activity level or functional ability.

These were absolutely rock-on identical

for each of the two arms of the study. Of course,

as Dr. Shepherd presented to us from 317, there

were significant advantages in performance status

and already in ease of pain control that had come

from the earlier placebo-controlled trial.

But actually, the symptom benefits that

were seen here are greater and were slightly

misrepresented unfortunately, with all due respect

from the FDA presentation. It was stated that

there was more weight loss for the group that got

Alimta. This is, unfortunately, incorrect. This

is not from the document, and is not correct.

The amount of weight loss of any grade of

weight loss is 8.3 percent on the Alimta and 7.2 on

docetaxel, exactly the same.

Could I see a slide that looks at severe

188

weight loss, which is more important? This is

taken also, I borrowed it from Dr. Shepherd. If you

look at the lefthand side of these bar graphs, we

are looking at weight loss of more than 10 percent,

which as Ms. Haylock has said, what are the

toxicities that really, or the symptoms, or the

problems that really threaten patients\' lives, and

a marked degree of weight loss does.

Again, all degree of weight loss was not

different between the two, that is an incorrect

statement.

If we look here, in TAX 317, the study

that Dr. Shepherd talked about, and she presented

the lefthand side of this slide, you can see that

25 percent of the patients getting just supportive

care had a greater than 10 percent weight loss as

opposed to 2 percent getting the docetaxel.

In this trial, the JMEI trial, which again

is much larger, you had preservation of the lack of

weight loss on the docetaxel arm, only 0.4 percent

of patients had more than 10 percent, and you have

the identical finding with the Alimta.

189

So, you have this finding of weight loss,

a very important and easy to measure finding, and

when you get into the PROs, you have patients

expressing the same degree of quality of life,

global quality of life and symptom distress.

DR. BRAWLEY: Thank you.

DR. EMERSON: The question about powering

the study for survival versus for the secondary

endpoints. If I could see slide 54. The key point

I am trying to make here, of course, is that we

have one hazard ratio here, and the confidence

interval for that hazard ratio, and the question of

superiority, non-inferiority, harm, or whatever, it

is just a question of where we are along this

number line in terms of the Alimta to docetaxel

comparison.

So, in effect, when you are asking, well,

we don\'t power the study for superiority, we power

the study to be able to look at the secondary

endpoints and be able to ensure that we still have

reasonable comparability on survival. That really

is the non-inferiority question.

190

The non-inferiority question is saying we

are really going to be looking at some other

endpoint, and we would like to make certain that

our confidence interval is narrow enough to say

that we are reasonably close.

Now, in this study, and if you will for a

moment concede that it is somewhat relevant to the

comparison to TAX 317, but I will come back to that

in a second, if I could see slide 671.

This is the idea that in TAX 317, the

hazard ratio was 0.56, the confidence interval was

0.35 to 0.88 over best supportive care. If we take

the idea that what we had was two independent

clinical trials and combining the estimates across

those trials, from JMEI and using the TAX 317 data,

we now estimate that the hazard ratio is 0.55

comparing Alimta to best supportive care, and the

confidence interval is 0.33 and 0.90.

Why I just want to point this out is if

that sample size in JMEI had become infinite with

this particular hazard ratio estimate, the best we

could have gotten is to that 0.35, 0.88.

191

So, everything revolves around the

comparability of the TAX 317 and the JMEI docetaxel

arms, which as we pointed out, had very similar

baseline characteristics, very similar survival,

and the major issue was the crossover study, which

the best estimate we have is that there was no

advantage due to the additional post-study

chemotherapy.

DR. BRAWLEY: Dr. Temple.

DR. TEMPLE: Am I wrong in thinking that

that analysis presumes that the docetaxel has an

identical effect in both trials?

DR. EMERSON: No, you are not at all

wrong. That analysis assumes that there is a

comparable effect between the two. The percent

retention analysis can be interpreted as a

sensitivity analysis, that that might not be true.

DR. TEMPLE: But the critical assumption

that the same exact effect showed up both times is

the problem. That is why people do things like

taking the 95 percent lower confidence interval.

DR. EMERSON: Except the percent retention

192

analysis can be interpreted as what contamination

you might have a subpopulation in the JMEI study,

in which the docetaxel effect was nonexistent,

imagine the docetaxel was as good as placebo, and

that interpretation placed on this Rothmann

analysis, the percent retention, has an

interpretation that says if you mixed up to 50

percent of patients in which docetaxel truly had no

effect, but the other 50 percent docetaxel had the

same effect that it had in the TAX 317 study, that

this study would still support the idea that Alimta

was\--

DR. TEMPLE: But I wasn\'t asking about the

Rothmann analysis, I was asking about the two

numbers you put up, which make an assumption that

few would believe is credible. That\'s all.

DR. BRAWLEY: This is how we are going to

proceed. It is almost 12:20. Dr. D\'Agostino has

asked for the floor, I am going to give it to him.

Then, I am going to ask if any other members of the

committee would like to ask a question or make a

statement.

193

Then, perhaps we will take a 10-minute

break in lieu of going to lunch, and come back and

morph into your questions.

Dr. D\'Agostino.

DR. D\'AGOSTINO: I will make it real fast.

I wish Scott had not presented those last two

slides, because that could have led us to three or

four hours of discussion.

The question I really wanted to ask, and

maybe we could take it up after the break, is I

want to make sure we have some guidance in terms of

it we go the accelerated approval, that we pick out

variables that have this clinical benefit, because

I am concerned that the data may or may not show

that now. We can hold that.

DR. BRAWLEY: Well, the questions that we

are asked don\'t discuss accelerated approval or

approval, correct?

DR. PAZDUR: They do in a sense. First of

all, the first question is based on a favorable

toxicity profile. We have to answer that to do an

accelerated approval because it has to have

194

advantage over available therapy.

The second question is given that, and

given the uncertainty on the survival endpoint, an

effect on the survival endpoint, do the surrogate

endpoints of progression-free survival or

predominantly response rate constitute an evidence

for approval. That is where we are going.

The third question that I would like to

ask, considering the considerable comments that

have been made, was with the data presented and

aware of the confounding effects that we have

discussed with crossover, and also the single trial

and estimation of the effect size being questioned,

are people convinced of an effect on survival that

would warrant full approval.

So, let\'s go a three-question approach

here. The first two questions obviously are the

accelerated approval, the last one, full approval.

DR. BRAWLEY: Any other questions from the

committee members?

MS. ROSS: Just an observation, those are

pretty loaded questions.

195

DR. BRAWLEY: Dr. Bukowski.

DR. BUKOWSKI: Dr. Gralla, can you clarify

just for my edification Lung Cancer Symptom Index

and the overall quality of life? They were similar

between the two arms, Alimta and docetaxel, there

were no differences between the arms?

DR. GRALLA: Correct.

DR. BRAWLEY: Anything else?

\[No response.\]

DR. BRAWLEY: With that, I have 12:22. I

hate to do it this way, but let\'s get back together

at 12:35 to tackle the FDA\'s questions.

\[Break.\]

ODAC Discussion

DR. BRAWLEY: If we can come back to

order.

After this morning\'s presentations and the

questions and discussion, we now have three

questions in front of us. How we will work this is

I will read the question, the questions are also up

on the board here. We will have some discussion

about each question, and then we will vote on the

196

question.

The first question is: Do you believe

Alimta has a more favorable toxicity profile than

docetaxel?

Any discuss on this issue? Yes, sir.

DR. GEORGE: Just a quick question.

Because the weight loss issue came up, there seemed

to be a difference between the FDA analysis and the

sponsor.

Dr. Cohen, you didn\'t respond to that. Do

you have anything?

DR. COHEN: I think that what I stated was

correct and that the sponsor\'s summary documents

and briefing documents I think would bear out that

there is more weight loss associated with the

Alimta than there is with docetaxel.

DR. BRAWLEY: Please identify yourself.

DR. NGUYEN: Binh Nguyen from Lilly.

Actually, in the briefing document on page

112 for the sponsor, the Table 5.1, the weight

decreases 8.3 percent versus 7.2 percent, and I

think that\--I don\'t know exactly what the other

197

numbers come from.

DR. PERRY: I think the weight loss issue

here is a real red herring. You have to remember

that the people on the docetaxel arm got an

enormous, bigger dose of decadron, which causes

fluid retention, and therefore artificial weight

gain. We are talking about 16 times the normal

dose of prednisone equivalent that one makes per

day versus 8 time in the Alimta arm.

DR. PAZDUR: Potentially, the fluid

retention of the drug itself.

DR. PERRY: My point is I don\'t think

weight loss is something we can measure, and if we

have lean body estimates by radioactive potassium

estimates, we could calculate whether this is real

or not, but in the absence of it, I don\'t think

weight loss is something we can discuss reasonably.

I do think that there is less neutropenia

on the Alimta arm, so I think the answer to this

question is yes.

DR. BRAWLEY: Any other discussion?

Dr. Levine.

198

DR. LEVINE: I would just like to make the

point related to the corticosteroid, as well. The

Alimta arm had greater rash and also greater nausea

and vomiting, but the increased dose of steroids in

the docetaxel arm could account for that

conceivably as an anti-nausea drug, for example.

DR. BRAWLEY: Ms. Ross.

MS. ROSS: Thank you. I just want to make

sure that everyone on the panel did have a chance

to look at the letter you should have received in

your packets from an actual lung cancer patient on

Alimta.

She is not your typical patient because

she has made it her business to find out everything

that can be found out about the trials, drugs, lung

cancer. In fact, she has her own on-line web site

for this.

She makes it very, very clear that Alimta

is far superior to docetaxel as far as side

effects, delivery time is only 10 minutes versus

hours, no neutropenia. She goes on and on, but I

should definitely take a look at that letter

199

because it speaks to an actual experience, and not

a number.

This is what I heard, too, from the many

patients I polled on various lung cancer e-mail

lists on the web.

DR. BRAWLEY: Thank you.

Any other comments from committee members?

\[No response.\]

DR. BRAWLEY: If we can go to the vote.

The question: Do you believe Alimta has a

more favorable toxicity profile than docetaxel?

Dr. Cheson, if we can start with you.

DR. CHESON: Yes.

DR. PERRY: Yes.

DR. HUSSAIN: Yes.

DR. BRAWLEY: Yes.

DR. MORTIMER: Yes.

DR. RODRIGUEZ: Yes.

DR. DOROSHOW: Yes.

DR. BUKOWSKI: Yes.

DR. LEVINE: Yes.

DR. GEORGE: Yes.

200

DR. D\'AGOSTINO: Yes.

MS. HAYLOCK: Yes.

MS. ROSS: Yes.

DR. GRILLO-LOPEZ: I don\'t have a vote,

but if I had a vote, I would say yes.

DR. BRAWLEY: 13 to nothing yes, I believe

is the answer. We have unanimity amongst the

counters. That is a good thing.

Question No. 2: If the answer is yes,

does the more favorable Alimta toxicity profile

with supporting efficacy data on tumor response and

PFS outweigh the uncertainty regarding loss of

docetaxel survival effect by using Alimta?

Any discussion to the question? Does

everybody understand what the question is?

MS. ROSS: I would like clarification,

please.

DR. BRAWLEY: Dr. Pazdur.

DR. PAZDUR: Well, we have discussed and

in the preamble to these questions, we have laid

out that there have been or can be problems with

the analysis of non-inferiority here. There are

201

problems with crossover that we have discussed.

There are also issues in establishing historical

data to measure the control effect.

Given these problems, there has to be some

uncertainty about that effect. Given the

information that you have on hand about the

surrogate endpoints, that has to be weighed against

this uncertainty here.

DR. TEMPLE: But if you are a person who

doesn\'t believe there is any uncertainty, then, the

answer could be yes for that reason. It is only if

you do believe there is some uncertainty that this

question is more interesting. But if you don\'t

think there is a problem, then, your answer would,

of course, be yes.

DR. BRAWLEY: Is there any further

discussion? PFS, for those in the audience, is

performance status? No, progression free survival.

I am sorry, progression free survival.

DR. D\'AGOSTINO: Now, we are not talking

about superiority on this. No. Thank you.

DR. GEORGE: I guess that is similar to my

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question. Does outweigh mean in the sense of being

able to give accelerated approval?

DR. PAZDUR: This is an accelerated

approval question.

DR. BRAWLEY: Ms. Ross.

MS. ROSS: Sorry to belabor this, but

isn\'t the question assuming that we feel that there

is uncertainty?

DR. PAZDUR: That is what Dr. Temple just

mentioned, if you don\'t have any uncertainty.

DR. TEMPLE: If you believe the benefit in

terms of toxicity outweighs whatever uncertainty

there is, from zero to a lot, then, the answer is

yes. But if you have no uncertainty, then, it

obviously outweighs it.

MS. ROSS: And it is still yes.

DR. GRILLO-LOPEZ: I would like to ask for

clarification since it looks like we are going to

be voting accelerated approval or full approval.

Since we have been today using the verb to morph,

when does an accelerated approval morph into full

approval?

203

DR. PAZDUR: When the sponsor completes

usually the clinical trials that will confirm

clinical benefit, and as pointed out, the sponsor

has several trials that are ongoing. We had a

meeting in March of 2003 to address this area. We

wanted for sponsors that are going to receive

accelerated approval for these trials to be

ongoing, so we feel comfortable with this. It will

be reflected in labeling also.

DR. BRAWLEY: Ms. Ross.

MS. ROSS: How long will it take the

company to complete these additional trials?

DR. PAZDUR: The company will have to

answer that question.

DR. PAOLETTI: The Phase III trials are

ongoing, and at least for the first trial, one

year, one year in-house, and then the other more,

because you need to wait for survival. Probably we

are talking between 2 to 4 years.

DR. PAZDUR: Sheila, the regulations

stipulate that the sponsor should be doing these

trials with \"due diligence,\" so that would be left

204

up to the interpretation depending on the

complexity of the trials, et cetera, that would

enter into a completion date.

MS. ROSS: Thank you, Dr. Pazdur, I

appreciate that, but I think the point here to keep

in mind is that accelerated approval would be a

further delay of 2 to 4 years.

DR. PAZDUR: No, the drug is approved, the

drug is on the market being sold under accelerated

approval.

DR. TEMPLE: That is why it is called

accelerated.

DR. PAZDUR: It\'s approved.

MS. ROSS: You are not requiring them to

complete the trials?

DR. PAZDUR: They are doing the trials.

When those trials are approved, then, the

accelerated approval will be converted to full

approval, but the drug is on the market, they are

charging for the drug. There is some limitations

that they have to check advertising with D.D. Mack.

There is a line stating in the indication that full

205

clinical benefit has not been established, but

other than that, they are free to market the drug

appropriately.

DR. BRAWLEY: Perhaps it would be useful

if you were to name a couple of drugs that are

currently on the market with accelerated approval.

DR. PAZDUR: Iressa is one, Velcade is

one. We have many drugs, I just can\'t remember off

the top of my head.

DR. TEMPLE: All the best drugs.

DR. PAZDUR: Bob said all the best drugs.

MS. ROSS: Thank you.

DR. PAZDUR: Remember, this drug also has

full approval for mesothelioma.

DR. BRAWLEY: All right. Does the Alimta

toxicity profile with supporting efficacy data on

tumor response and progression-free survival

outweigh the uncertainty regarding loss of

docetaxel survival effect by using Alimta?

Let\'s start with Ms. Ross.

MS. ROSS: Yes.

DR. GRILLO-LOPEZ: If I were voting, I

206

would vote yes, but I would not have that vote

interpreted as any way affecting a future vote on

full approval.

DR. PAZDUR: We recognize that, and here

again, obviously, if you vote on accelerated

approval, that does not mean you could not vote for

full approval. These are not mutually exclusive.

MS. HAYLOCK: Yes.

DR. D\'AGOSTINO: Yes.

DR. GEORGE: Yes.

DR. LEVINE: Yes.

DR. BUKOWSKI: Yes.

DR. DOROSHOW: Yes.

DR. RODRIGUEZ: Yes.

DR. MORTIMER: Yes.

DR. BRAWLEY: Yes.

DR. HUSSAIN: Yes.

DR. PERRY: Yes.

DR. CHESON: Yeah. That is a yes with not

much enthusiasm.

DR. PAZDUR: Is that a hanging chad?

\[Laughter.\]

207

DR. BRAWLEY: Thirteen to nothing yes.

The third question: Given the potential

confounding effects of crossover and problems in

estimating the control effect, is there a

convincing effect on survival to warrant regular

approval?

Dr. Hussain.

DR. HUSSAIN: So, Dr. Pazdur, could you

please clarify what you mean by a convincing effect

on survival, because if there was no difference in

survival, what effect are we supposed to assess?

DR. PAZDUR: The effect. Remember we said

that effect on the endpoint of survival can be two

ways. One can see an improvement in survival or a

non-inferiority effect on survival, and that would

demonstrate with a reasonable amount of

certainty\--and I am using that word

clinically\--that a control effect has been

preserved, that the effectiveness in your mind from

a clinical judgment, that effect of docetaxel is

preserved.

DR. BRAWLEY: Can we move on to

208

discussion?

Dr. D\'Agostino.

DR. D\'AGOSTINO: If we vote yes, then, we

are saying that our doubts or the doubts that exist

in this historical database in terms of its

stability and precision is really not a concern to

us. It is quite a precedent to move in this

direction.

DR. BRAWLEY: Anyone else?

DR. PAZDUR: Most of the data, and perhaps

the statisticians would like to comment on this in

the statistical area, point to multiple trials

having to be done to determine a control effect, to

ensure issues of reproducibility, ascertainment of

differences in patients, et cetera, that might be

preserved.

Obviously, you don\'t need that, but it

does set a different precedent in the sense that we

have a very small trial here of only 50 patients in

each arm.

DR. BRAWLEY: Yes, sir.

DR. GRILLO-LOPEZ: I actually sympathize

209

with the FDA in that I do understand the regulatory

constraints that you have. On the other hand, I

think that this may be a good precedent to set

because as an oncology community, shouldn\'t we be

seeking the earliest possible approval of drugs

that do have clinical activity and efficacy even

though it might not be as huge as we would like to

see it.

But if that is accompanied by an

acceptable lower toxicity profile, what harm is

there in giving full approval to such drugs, that

will then be made available to the oncology

community, the cooperative groups, academic

institutions, et cetera, to do the necessary

combination studies to then find out what optimal

combination they might best work under, and believe

me, if they don\'t work, they will go down the

drain. People will just not prescribe and use

them.

DR. PAZDUR: Let me just clarify. When a

drug receives accelerated approval, it is on the

market, folks, okay. People could be doing

210

combinations, they could be charging for this drug.

This is not a substandard approval here that we are

talking about.

Studies go on with these drugs as they

would if it were a regular approval.

DR. TEMPLE: Ordinarily, except for the

case of accelerated approval, you are supposed to

be able to conclude that the drug provides a

clinical benefit. You know, you could ask why is

the law written that way. Maybe you should just

say it doesn\'t hurt you, and you should approve it

if it doesn\'t hurt you enough, but that isn\'t what

the law says. It says you have to have evidence of

clinical benefit.

So, you know, you can think of that as a

regulatory problem. Personally, I would think most

people using drugs would want to know that the drug

has a favorable effect, too, but whichever one it

is, that is the difference.

Accelerated approval allows reliance on a

surrogate for a benefit, and we obviously, based on

our past history, and this committee, based on its

211

past history, believe that a response rate in a

condition where there isn\'t anything else or the

other things are bad, is a reasonable basis for

accelerated approval. Nobody is really disputing

that.

We are pretty happy with the outcome

although it is worth noting the Europeans don\'t

believe that is correct, and don\'t do that for the

most part.

But the question posed here is can you go

beyond that and say based on the data, that you are

satisfied that it has some survival effect, such as

the one equivalent to the control group or close to

it.

DR. BRAWLEY: Dr. Levine.

DR. LEVINE: Just to clarify the meaning

of Question 3, if we have already answered as we

have on 1 and 2, and we answer no on 3, does that

mean that you automatically are going toward

accelerated approval?

DR. PAZDUR: Correct.

DR. LEVINE: Thank you.

212

DR. BRAWLEY: Dr. D\'Agostino.

DR. D\'AGOSTINO: Two comments. One, I

didn\'t pick up on Dr. Pazdur\'s comment about in

many of the non-inferiority trial settings, we

tried to get an awful lot of historical database or

large historical database, and tried to come to

precise estimates of what the placebo or what the

non-drug effect is, we don\'t really have that here.

The other comment is that there is a term

they use in this field of non-inferiority trials of

biocreep is if you allow this to sort of sneak in

with a small database, then, the next one uses even

a smaller database because it not pegged on this

one here, so there is a real concern. It is not

just a matter of being a cruel statistician.

DR. BRAWLEY: Ms. Ross.

MS. ROSS: Well, you could say that is why

we are here. But I just want to make sure I

understand. Maybe I should address this to the

Chair, so I won\'t put anybody at FDA on the spot.

I would like to know what is the down side

to accelerated approval vis-a-vis full approval?

213

DR. BRAWLEY: Well, I am going to answer

the question since it was addressed to me, and

then, Dr. Pazdur, you can tell me if I misstated

this.

If it is accelerated approval, the company

will be allowed to market the drug for its intended

purpose that it was approved for, just as if it

were a regular approval. If there is accelerated

approval, the company takes what I will call a

solemn vow that they will continue to do research,

to do further development on the drug to prove

survival advantage.

In terms of the availability of the drug

to the public, there is no difference between the

two. The real difference is with regular approval,

the company does not have the government telling

them that they have to continue doing work to

develop the drug to truly determine if the drug has

the benefit that we believe that it has.

Did I misstate that?

DR. PAZDUR: Pretty good, but the correct

question, what is the up side of full approval?

214

You know, glasses are half-empty and half-full,

Sheila. The up side is that the American public

will have the confidence after these confirmatory

studies are done that this is a real drug, the FDA

will be monitoring whether these studies are done

with \"due diligence,\" and after the July meeting,

we have been doing that with a greater degree of

intensity.

So, there are advantages here that make

sponsors be accountable to complete these studies.

Yes, they could say they are going to do them, and,

you know, a handshake rather than yes, you must do

it, and we must see these study reports, we will be

watching out for them.

I view this as an advantage, not

necessarily a disadvantage or a down side. The

only minor things, as I said, some of the marketing

materials have to be looked at by our advertising

department, and secondly, there is this line in the

indication that states the clinical benefit has not

been demonstrated.

DR. BRAWLEY: Yes. Keep in mind we are

215

giving advice to the FDA, we are not actually

voting that the drug should be approved in any

particular way. We are just giving advice to the

FDA.

Is there a drug that has had accelerated

approval and then has been removed? Dr. Bunn has

been very patient.

DR. BUNN: I just want to clarify. For

full approval, you have to prove a drug is safe and

efficacious. You don\'t have to prove it is not

inferior to something else. There is nothing in

the regulation that has anything to do with

non-inferiority. You have to prove it\'s safe and

efficacious.

The clinical efficacy that is well

accepted has been survival and patient reported

outcomes, progression-free survival and response

have usually been used as a surrogate. So, if you

believe that there is a survival advantage over

best supportive care or if you believe the patient

reported outcome benefits over best supportive

care, then, you could vote for full approval, that

216

it is safe and efficacious.

If you are uncertain about survival in

patient reported outcomes, if you are quite certain

about safety response rate and progression-free

survival, then, you would vote for accelerated

approval.

DR. PAZDUR: I think we have to take a

look at exactly what safe and effective means and

what effective means. It means that you have an

effect on survival here in the situation that we

are talking about.

As I stated before, the agency has looked

at survival as clinical benefit. So, that

endpoint, you have to demonstrate an effect on.

Now, most of the times we look at

superiority trials, so there is no question you are

better. Here, we have to say that you are

non-inferior, so we are looking at a

non-inferiority effect on that endpoint, and hence,

we are talking about not losing a control effect

here, part of the control effect.

DR. TEMPLE: Non-inferiority is the second

217

way to prove that you have an effect. You do that

by gaining the ability to attribute the effect of

the control to your drug by showing you are not too

much worse.

If we were really insisting on a

comparative efficacy requirement, we would have a

much tighter demand for data. You wouldn\'t allow

the new drug to be 50 percent worse on an important

endpoint like survival. You would say 10 percent

worse or 20 percent worse, which is, in fact, how

antibiotics work. They have to rule out a

difference that is considered clinically

meaningful, and it is often quite small, 10

percent, something like that.

This is not comparability of

effectiveness, it is non-inferiority as evidence

that you have some effect, reasonable retention of

the effect, 50 percent. It is not a very demanding

standard.

DR. BRAWLEY: Ms. Haylock

MS. HAYLOCK: The concern about the

history of the previous studies that were done, did

218

I mishear or am I correct that you said that that

is the history, and you can\'t really go back and

change that, nor can those studies be redone? So,

for research, how does the company go about

rectifying that or dealing with that question?

DR. PAZDUR: This is a problem, and that

is why we are bringing this to this committee, and

I think that this is going to be perhaps even an

increasing problem with time. I made the reference

to the fluorinated pyrimidines in the approval of

capecitabine where we had 30 years of people doing

5FU-leucovorin versus 5FU, because nothing else was

going on in the field.

That probably fortunately, won\'t be

happening because we have a better and more

aggressive environment in drug development now with

newer agents and looking at different combinations.

So, that may be a problem. You can have,

and perhaps Bob wants to talk about it, you know, a

single study if it was a very large study and we

would provide a different statistical approach to

that.

219

DR. TEMPLE: I just wanted to observe this

is a general problem. There are very few people in

which anybody would let you do a placebo-controlled, long-

term, lipid-lowering study

anymore. You could do add-on studies, add

something new to something that existed before,

because that hasn\'t been tested, but wherever there

is established therapy, people are properly

reluctant to leave\--for a life-threatening

disease\--people are quite properly reluctant to

leave people off it.

So, the question is how do you get there.

Well, you can do an add-on study, as Rick said in

his opening remarks, that is easy. Those are

superiority studies and easy to interpret. But

exactly how to do these persuasively, especially

when there is only one or a small number of

studies, is one of the biggest current problems in

drug development. It is very thorny, you don\'t

want to make a mistake.

You don\'t want to overdo it, but you don\'t

want to approve something that doesn\'t work either.

220

So, good luck.

DR. BRAWLEY: Ms. Ross, did you have

another question?

MS. ROSS: No.

DR. BRAWLEY: Anybody else? Okay.

Given the potential confounding effects of

crossover and problems in estimating the control

effect, is there a convincing effect on survival to

warrant regular approval?

Let\'s start with Dr. Cheson.

DR. CHESON: No.

DR. PERRY: Yes.

DR. HUSSAIN: No.

DR. BRAWLEY: No.

DR. MORTIMER: Yes.

DR. RODRIGUEZ: No.

DR. DOROSHOW: Yes.

DR. BUKOWSKI: No.

DR. LEVINE: No.

DR. GEORGE: No.

DR. D\'AGOSTINO: No.

MS. HAYLOCK: Yes.

221

DR. GRILLO-LOPEZ: If I were to vote, I

would say yes.

MS. ROSS: Yes.

DR. BRAWLEY: The vote is 8 no, 5 yes.

Are there any other issues for the

committee from the Food and Drug Administration?

DR. PAZDUR: No, just on the part of the

FDA, we would like to thank you for your

deliberations and also Eli Lilly for their

participation during the NDA review process. We

found it was a very good process and a very

communicative process.

We brought this application here because

there were problems. We expect these problems to

be with other applications, and I think it needed

the light of day to really expose the problems of

the control effect and obviously crossover and

non-inferiority trials for others to consider

before they embark on this venture.

Thank you.

DR. BRAWLEY: With that, I would like to

thank Eli Lilly and thank the Food and Drug

222

Administration, and we are adjourned.

\[Whereupon, at 1:11 p.m., the meeting

adjourned.\]