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

                                                                  2

 

                               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.

                                                                  3

 

                             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

                                                                  4

 

                       C O N T E N T S (Continued)

 

                                                           Page No.

 

       Open Public Hearing                                      112

 

       Questions from the Committee                             114

 

       ODAC Discussion                                          195

                                                                  5

 

                          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.

                                                                  6

 

                 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

                                                                  7

 

       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

                                                                  8

 

       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

                                                                  9

 

       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

                                                                 10

 

       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.

                                                                 11

 

                 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.

                                                                 12

 

                 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

                                                                 13

 

       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

                                                                 14

 

       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

                                                                 15

 

       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

                                                                 16

 

       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

                                                                 17

 

       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."

                                                                 18

 

                 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

                                                                 19

 

       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,

                                                                 20

 

       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

                                                                 21

 

       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

                                                                 22

 

       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.

                                                                 23

 

                 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,

                                                                 24

 

       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

                                                                 25

 

       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,

                                                                 26

 

       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.

                                                                 27

 

                 [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

                                                                 28

 

       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

                                                                 29

 

       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

                                                                 31

 

       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

                                                                 81

 

       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

                                                                 82

 

       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