ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

Tuesday, September 24, 2002

8:30 a.m.

Kennedy Ballroom

Holiday Inn

8777 Georgia Avenue

Silver Spring, Maryland

PARTICIPANTS

Donna Przepiorka, M.D., Ph.D., Chair

Karen M. Templeton-Somers, Ph.D., Executive Secretary

Members

Douglas W. Blayney, M.D.

Otis W. Brawley, M.D.

John T. Carpenter, Jr., M.D.

Bruce D. Cheson, M.D.

Stephen L. George, Ph.D.

David P. Kelsen, M.D.

Silvana Martino, D.O.

Jody L. Pelusi, F.M.P., Ph.D.,

Consumer Representative

Gregory H. Reaman, M.D.

Bruce G. Redman, D.O.

Sarah A. Taylor, M.D.

Consultants (voting)

Thomas R. Fleming, Ph.D.

Claudette G. Varricchio, DSN, RN, FAAN

Patient Representative

Thomas G. Simon

Industry Representative

George H. Ohye

Call to Order and Opening Remarks 5

Conflict of Interest Statement 7

Introduction of the Committee 10

Open Public Hearing 12

Carl Dixon, Kidney Cancer Association 14

Rick and Jane Lesser

Redondo Beach, California 18

Abby Myers, NORD 20

Carolyn Aldige, Cancer Research Foundation

of America 24

Susan Nelson, Paris, California 29

Anita Johnston, East Norwich, New York 32

Gloria Caruso, Tampa, Florida 35

Robin Prachel, National Patient Advocate

Foundation 39

Melissa Mahoney, Virginia Beach, Virginia 43

Janine Hutchison, Las Cruces, New Mexico 47

Adrienne Riddle, San Bernardino,

California 51

Blanche Taylor and Laura Turpak

Sparta, New Jersey 53

Charles Reilly, Tarrytown, New York 57

Erica Hertz, The Wellness Community 60

Sponsor Presentation

IRESSA (ZD1839) Monotherapy for NSCLC

Introduction and Rationale for

Clinical Development:

George Blackledge, M.D., Ph.D. MB 63

F.R.C.P.

Recurrent Non-Small-Cell Lung Cancer:

Frances A. Shepherd, M.D., F.R.C.P. 77

IRESSA (ZD1839) Efficacy:

Ronald B. Natale, M.D. 83

IRESSA Safety Profile:

Alan B. Sandler, M.D., F.A.C.P. 107

C O N T E N T S(Continued)

FDA Presentation

Introduction and Regulatory Background:

Grant Williams, M.D. 117

Review of the Clinical Trials:

Martin Cohen, M.D. 126

Statistical Analysis:

Rajeshwari Sridhara, Ph.D. 139

Questions from the Committee 152

Committee Discussion and Vote 210

P R O C E E D I N G S

DR. PRZEPIORKA: I would call the meeting to order. Dr. Pazdur has some opening remarks.

DR. PAZDUR: We would like to bid fond farewell to people that have been on the committee for several years and we really appreciate their service over these years. They have provided insights into drug development both on the committee and also individually in consultation on various applications throughout the years.

These members that are leaving the committee include Kathy Albain from Loyola University, Stacy Nerenstone, our former Chairman of this ODAC Committee, and George Sledge from the University of Indiana.

On behalf of the division and office and also on behalf of the FDA, we really appreciate their efforts in providing us this consultation.

With these members leaving, we have three new members. I would like to introduce them. They include Gregory Reaman who is Executive Director for the Center of Cancer and Blood Disorders at the Children's National Medical Center here in Washington, D.C. We really thank Dr. Reaman for his efforts not only on this committee but as a liaison to our Pediatric Oncology Advisory Committee which is a subcommittee of this committee which will be holding its next meeting in October. So we really appreciate his efforts to provide a pediatric insight into these diseases.

The next new member is Bruce Cheson who is Professor of Hematology Oncology and Chairman of Hematology at Georgetown University here in Washington, D.C. Bruce was formerly head, for many years, of the Medicine Section at the NCI, Division of Cancer Diagnosis and Treatment, Cancer Therapy Evaluation.

We, as government employees here in the Division, really thank Bruce for his many years of government service. On a personal note, I would like to also thank him for the guidance that he has given us throughout the years on specific consultations regarding hematological applications.

Our next new member is Silvana Martino who is at the John Wayne Cancer Center and is the Chairman of the SWOD Breast Committee. Likewise, Silvana has helped us in many applications and we appreciate her help.

With Stacy Nerenstone's departure, we have a new Chairman. This is Donna Przepiorka, Head of Malignant Hematology and Transplant at the University of Tennessee in Memphis Tennessee. Donna, we look forward to your leadership and we really thank you for taking this opportunity to work with us.

Thank you.

DR. PRZEPIORKA: Thank you, Dr. Pazdur. Again, welcome to the new members of the committee. We will start the meeting this morning. We have a rather long agenda that we are going to try to get through in a reasonable period of time. I will turn the microphone over to Dr. Somers to read the conflict-of-interest statement.

DR. TEMPLETON-SOMERS: I have a couple of announcements first. Welcome to everyone. We are glad to see that there is so much interest in ODAC and apologize up front for the crowded conditions. We do have a large overflow room available down the hall with a t.v. feed so you can watch from there if you get tired of standing in the back.

We also do have to honor the fire code so, if the hotel management tells you that you must leave because you are blocking the fire aisle, please honor that request.

We are also asking for a little more air conditioning because, with this many people, it will get warm. So I apologize up front. The temperature usually is a little variable.

The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting. Based on the submitted agenda and information provided by the participants, the agency has determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.

I accordance with 18 U.S.C, Section 208(b)(3) and Section 505(n)(4) of the FD&C Act, Dr. David Kelsen has been granted waivers for his ownership of stock in a competitor valued between $5,001 to $25,000.

Dr. Silvana Martino has been granted a waiver under 18 U.S.C. 208(b)(3) for her membership on two data-monitoring boards for a competitor and her review of a manuscript for a competitor. These activities are unrelated to the competing products. Dr. Martino receives less than $10,000 for serving on the data-monitoring boards and from $5,001 to $10,000 for the manuscript review.

Dr. Sarah Taylor has been granted a waiver under 18 U.S.C. 208(b)(3) because her employer is participating in National-Cancer-Institute-sponsored studies and an expanded access program involving the sponsor's product. The sponsor provides the drug only for the expanded-access program.

Dr. Thomas Fleming has been granted a waiver under 18 U.S.C. 208(b)(3) because he serves on three data-safety monitoring boards for a competitor on products unrelated to the competing products. He receives from $10,001 to $50,000 a year.

Dr. Douglas Blayney has been granted waivers under 18 U.S.C. 208(b)(3) and Section 505(n)(4) of the FD&C Act for his ownership of stock in two competitors. The first stock is valued from $5,001 to $25,000 and the second from $25,001 to $50,000.

A copy of these 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.

In addition, we would like to note that Dr. Stephen George is permitted to participate in today's discussions but he is excluded from voting.

Lastly, we would also like to note for the record that George Ohye is participating in this meeting as an industry representative acting on behalf of regulated industry. As such, he has not been screened for any conflicts of interest.

In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have 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 product they may wish to comment upon.

Thank you.

DR. PRZEPIORKA: Thank you.

I would like to turn next to the introduction of each member of the committee. What we will do is we will ask each member to introduce themselves starting with Mr. Ohye.

MR. OHYE: Good morning, everyone. I am George Ohye, the Industry Representative nominee.

DR. GEORGE: Stephen George, Duke University, Biostatistics, Member of the Committee.

DR. MARTINO: Silvana Martino from the John Wayne Cancer Institute. I am a medical oncologist.

DR. BLAYNEY: Doug Blayney, a medical oncologist, Wilshire Oncology Medical Group, Pasadena, California.

DR. VARRICCHIO: Claudette Varricchio from the National Institute of Nursing Research.

DR. BRAWLEY: Otis Brawley, medical oncologist, Emory University.

DR. PELUSI: Jody Pelusi, oncology nurse practitioner, Northern Arizona Hematology Oncology Associates. I sit as the consumer rep.

DR. REAMAN: Gregory Reaman, pediatric oncologist from the Children's Hospital and the George Washington University.

DR. PRZEPIORKA: Donna Przepiorka, malignant hematology and transplantation, University of Tennessee, Chairman of the Committee.

DR. TEMPLETON-SOMERS: Karen Templeton-Somers, Executive Secretary to the Committee, FDA.

DR. FLEMING: Thomas Fleming, Department of Biostatistics, University of Washington.

DR. REDMAN: Bruce Redman, medical oncologist, University of Michigan Comprehensive Cancer Center.

DR. KELSEN: David Kelsen, medical oncology, Sloan Kettering, New York.

DR. CARPENTER: John Carpenter, medical oncologist, University of Alabama at Birmingham.

DR. CHESON: Bruce Cheson, hematology-oncology, Georgetown University, Lombardi Cancer Center, Washington, D.C.

DR. TAYLOR: Sarah Taylor, University of Kansas Medical Center, medical oncology.

DR. SIMON: Tom Simon, Atlanta Georgia, patient representative.

DR. COHEN: Martin Cohen, Food and Drug Administration, medical reviewer.

DR. WILLIAMS: Grant Williams, Deputy Director, Division of Oncology Drug Products.

DR. PAZDUR: Richard Pazdur, Director, Oncology Drug Products.

DR. TEMPLE: Bob Temple, Director of Office of Drug Evaluation I in which Oncology lives.

DR. PRZEPIORKA: Thank you all.

We will move next to our open public hearing. I want to start with a statement from Dr. Somers.

DR. TEMPLETON-SOMERS: We have had a lot of interest in this open public hearing and we may be differing a little bit from the list that has been put out as a handout. So please be patient with us and we will try and follow it as much as possible. But open public hearing speakers, if you come up and it is not your name, make sure that you state it loudly for the record if you are a little bit out of order because there are a few rearrangements in there.

In addition, there have been many people submitting letters and e-mails to the committee. Everything that was received by last Wednesday was sent to the committee last Wednesday. In addition, the committee has copies of materials that were received through Sunday.

Copies of these have been provided to the committee in those ways and are also available for public viewing. There are two large binders out at the information desk. They will also be posted on the FDA website after the meeting and are considered part of the permanent meeting record.

Thank you.

DR. PRZEPIORKA: Thank you.

If we could have the first speaker to the podium, Mr. Carl Dixon from the Kidney Cancer Association.

MR. DIXON: Good morning. The May, 2002 Oncology Times carried an article entitled, What is it Like to Be ODAC Chairman. It reported some very troubling comments in my mind from former ODAC Chairs and members about the open public hearing and the contribution of patient advocates.

The article stated that, "Most of the Chairmen said that patient presentations were a federally mandated nuisance to be endured before real business got under way." An additional quote from an ODAC Chair summarized the sentiment as, "It is not as though we have no idea cancer is a terrible disease."

The FDA's advisory committee process is the only forum in which the people of this country have an opportunity to listen and participate in drug review. The scientific and regulatory details of oncology drug review are very daunting. Occasionally, even committee members can be confounded by the dizzying array of data and the convolution of comments on it.

Except for the information the drug companies are willing to disclose about their drugs, which is often favorably biased, the information on new drugs is simply not available to the average American. So what can the taxpayers, the public, fit into this complex drug-review process.

As someone who has attended and spoken at these meetings, I know that most often all the data the ODAC members receive is not available to the public before the advisory committee meeting. This leaves the citizen interested in speaking about a new drug in an untenable position. We are able to comment only from anecdotal experience, not from the scientific relevant information.

Well, perhaps what we have to say is not, indeed, scientifically relevant. The committee does have a choice about how they handle advocacy comments. The ODAC members can choose to understand that the deck is stacked against the public and pay close attention to the speakers and, perhaps, ask them questions which would inform the committee about an insight or experience of a "non-physician," otherwise known as "of the public" or a patient advocate.

It is dangerous when Americans' comments on the activities of their government are viewed as a "federally mandated nuisance." It might make the average American wonder if the rulers aren't just a little bit too far removed from the ruled.

Thank you.

DR. PRZEPIORKA: Thank you, Mr. Dixon. I just want to say, speaking for the committee, that we recognize that the recommendations that we make as a committee to the FDA affect not only the FDA, the industry and the medical community, but also all of the patients and their families. So we welcome all the input from the patients as well as their families and other individuals at this meeting so that we can have as much information as possible in order to make informed recommendations for the FDA.

Having said that, it is with pleasure that I will announce the next speaker to go on and get additional input from Rick and Jane Lesser from Redondo Beach, California.

DR. PAZDUR: Donna, if I could just mention, to follow up on Carl's comments, some of the things that we have done in the Division to really bring the Patient Advocacy Program into drug regulation. We have an ongoing Patient Advocacy Program where the advocates are actually consultants to the FDA and sit in in our Phase II, end of Phase II, meetings, our Phase III meetings with the sponsors.

We have an organized monthly telecom session where we go over regulatory matters with the advocacy community that are members of this group. That has been arranged by OSHI, both of these programs, Office of Special Health Issues.

In addition to this, we have been very active at sending not only myself but other members of the Division to various advocate meetings throughout the year. So I believe that these were very unfortunate comments. Obviously, they do not reflect those that are in the division where we are taking, really, efforts to basically be more inclusive of the advisory community and patients in general.

Thank you.

DR. PRZEPIORKA: Thank you. We apologize to the Lessers for the brief delay, but we appreciate Dr. Pazdur's comments.

MR. LESSER: No problem. We will try not to be a nuisance. My name is Rick Lesser. This is my wife, Jan. We are kind of unique because we are a happy lung-cancer story. In February, 2000, Jan presented at UCLA with Stage 4 non-small-cell lung cancer. She had a brain tumor the size of a golf ball. She had two lung tumors. She had two liver tumors.

She went through the usual protocol of the carbon-based, or the platinum-based. That didn't work. I learned about oncology words when they say the results are mixed. It means it didn't work. She had a second one. She had Gemzar. That didn't work. She had radiation then after they had taken out the brain tumor.

She then has laser surgery to get rid of the lung tumor. She went to a third cancer drug. At Thanksgiving, she spent the day in bed and I was trying to figure out how to raise three small kids.

The next day, she started with the IRESSA program with Dr. Natale at Cedars. We had been at UCLA where they didn't have it. The gal there sent us to him. Within a week, she felt better. Within a month, her tumors were half. Within two months, they were and now are gone.

This is the outside of Jan. You are going to see the inside of Jan later. But she is healthy. She is happy. We swim. We dive. We are spending our retirement rather dramatically. We have been diving all over the world, scuba dive. She runs. She works out three times a week. And she takes care of the kids.

We live our family like we did before this ever came along. If IRESSA works for other people like it did for us, it is the best thing that has ever happened.

Jan, say something. She is not big on public speaking, but just being here is enough. Tell them how you felt and what you are doing.

MRS. LESSER: Exactly what Rick said. I just--thank you very much, IRESSA.

MR. LESSER: Does the committee have any questions for her? We have got to kind of squeeze it out of her because, like I said, what do you say when you feel great and you feel normal? That's essentially how you are.

MRS. LESSER: Again, and my hair is coming back.

MR. LESSER: Thank you very much. Again, thanks to the IRESSA people.

DR. PRZEPIORKA: Thank you very much. Next is Abbie Myers from NORD.

MS. MYERS: NORD is the National Organization for Rare Disorders. Lung cancer is not rare. We are the consumer organization that worked for the Orphan Drug Act and we monitor its implementation. The reason that we are involved with this drug is that we operate mediation-assistance programs for people who have no health insurance, mostly for orphan drugs and we somehow became expert in early access programs because most of the time, manufacturers don't make enough of an experimental drug to give to large numbers of people.

Very often, with hopeless diseases, like lung cancer, there is a tremendous public demand. So AstraZeneca asked us to run or administer the early-access program for this drug. It became a very, very large program. There are more than 12,000 people in this program which is so unusual because AstraZeneca has been very generous with the drug.

Most manufacturers will give us a small amount of drug and we have an infinite number of people who want access to it. With this, we were enrolling 300 to 500 people per week through a randomized computerized program so that there is no chance of bias and that all people stood an equal chance of their name being drawn.

The most unusual thing is that companies don't like to start an early-access program while they are enrolling people for clinical trials. AstraZeneca wanted to enroll people for clinical trials and, at the same time, allow people who didn't qualify for the clinical trials to get this drug.

So it has been an extraordinary program. We have heard some extraordinary things and we have brought with us today a number of patients who just felt that the advisory committee concept gives them a very unique opportunity to speak to their government. These people truly want to speak to their government.

In reference to what Mr. Dixon said before, the advisory committee process is extremely important to the American public. I have served on the Biological Response Modifiers Committee and I understand some of the feeling behind it. But, as people come up to speak to you, it is their once-in-a-lifetime opportunity, other than voting every year, to talk to you and tell about their personal experiences.

So I hope that you will listen to these people today because their stories are really quite miraculous. I can't make any judgment about the scientific viability of IRESSA but we have heard stories about some people doing very, very well and some people who didn't do so well. You are the ones who are going to measure all the scientific facts.

But to people who were on their death bed and are now alive, a lot of them with no tumor at all, it has been an extraordinary experience for us as well as for them.

Thank you.

DR. PRZEPIORKA: Thank you, Ms. Myers.

DR. TEMPLE: Can I ask a question?

DR. PRZEPIORKA: Yes.

DR. TEMPLE: I want to break tradition here. Abby, did you say that in the early stages of the access program, people were randomized to treatment or not because there wasn't enough drug?

MS. MYERS: They called one centralized telephone number and they were screened at that number to see if they were appropriate for the clinical trial. If they were not appropriate for the clinical trial, they were sent to the early-access, the expanded-access, program.

DR. TEMPLE: But there was enough drug for everybody who met those criteria to be in the program?

MS. MYERS: Yes. Not only in the United States but even outside of the United States. It is extraordinary how AstraZeneca has supplied enough drug to meet the public demand. Yes.

DR. TEMPLE: I was tempted to ask because you mentioned the attempt to reduce potential bias. And I thought maybe--

MS. MYERS: No. The bias in the expanded-access is everybody's name goes into the computer. If we have enough drug to give to 100 people that week, the computer picks the 100 names and everybody else's name stays in the computer. The next week, when there is another selection, their name is in there so they have another chance of their name being pulled out.

But human beings don't pull the names. If the CEO of AstraZeneca got lung cancer, he would not be able to get access to the drug unless the computer pulled his name.

DR. PRZEPIORKA: Carolyn Aldige from the Cancer Research Foundation of America.

MS. ALDIGE: Good morning. My name is Carolyn Aldige and I am President and Founder of the Cancer Research Foundation of America which is a National Organization based here in Washington dedicated to the prevention of cancer.

Since 1985, CRFA has supported cancer research, education and public-awareness programs in excess of $57 million. The organization has funded more than 600 peer-reviewed research projects in more than 200 different institutions. Some of this research has resulted in the identification of new molecular targets and the development of promising agents for preventing cancer, among other types of research.

We are proud of our record of achievement, yet always mindful of the great unmet medical needs of people living with cancer throughout America. We at CRFA are also mindful that we, or any other nonprofit organization, cannot tackle the challenges of cancer research and drug development alone. That is an understatement.

We applaud the creativity of government agencies and the pharmaceutical industry and encourage their still stronger commitment to partnering with one another and with advocacy organizations for the benefit of cancer patients and their families and we are proud to work with them.

In that regard, I would like to disclose that CRFA has received unrestricted educational grants from AstraZeneca as we have from other leading pharmaceutical companies and companies that are part of other industries. No part of this company's support has funded IRESSA-specific activities, however, and I appear here today because I think it is important. AstraZeneca is not paying any expenses incurred in connection with this meeting.

Every day, our work in lung cancer makes it all too clear that patients living with the disease have too few effective therapeutic options. Too often, they are blamed for their disease and told to go home, get their affairs in order and await the end of their lives. I am familiar, personally, with more than one patient who has been given this type of advice but entered a clinical trial for IRESSA and is doing well months and even years after being given a limited life expectancy.

IRESSA is, therefore, an especially welcome development representing an important new treatment option that provides hope for those who have seldom known it. As you know, lung cancer kills more than 150,000 people each year in the United States. With statistics of this magnitude, even an 11 percent response rate will be helpful. We, therefore, urge that your committee give careful consideration to the needs of advanced lung-cancer patients.

It is especially gratifying to see that the first in a new class of cancer compounds has been submitted for your review. New ways of attacking cancer will mean new ways of looking at clinical benefit, new ways of reviewing drugs and new ways of balancing risk-benefit when looking at treatment options.

With the advantage of selectivity, we have the ability to free cancer patients from so many of the devastating side effects of traditional chemotherapy. Studies have consistently shown that patients fear the nausea and vomiting and alopecia associated with chemotherapy, in addition to the more life-threatening side effects such as neutropenia or tachycardia.

For patients with advanced non-small-cell lung cancer, preserving an optimal quality of life has been found to be a very high priority. IRESSA and related compounds address patients' needs and should be made available to them.

I was with a woman on Friday who, two and a half years after she starting taking IRESSA, alluded to the fact that she has had three more years to celebrate anniversaries with her husband. She was able to see her first grandchild graduate from high school and her last grandchild in her first grade. She said those milestones--"This drug has given me the ability to live life and achieve those milestones in my life," with very few side effects which, I think, is really extremely important.

I wish to comment AstraZeneca for conducting innovative research on quality of life with the cooperation of one of the foremost experts in this field, Dr. David Cella using validated instruments such as the FACT-L Questionnaire. The company has made an important contribution to the design and execution of clinical trials. We urge the committee and its staff to consider quality-of-life data and symptom improvement as integral parts of new drug applications representing, as they do, an important priority for patients living with advanced non-small-cell lung cancer and other diseases.

These are exciting times in clinical oncology marked by the development of so many new and promising treatment options. We at CRFA believe that they required a new perspective in their regulatory review and that quality of life and other data should be an important part of any decision-making process.

As cancer treatment changes, so must the approval process. Like all other responsible cancer patient groups, we look forward to working with you to insure the system remains agile and responsive to patients who desperately need new drugs.

Thank you.

DR. PRZEPIORKA: Thank you very much.

Next, we will hear from Susan Nelson from Paris, California.

MS. NELSON: Good morning. I would like to begin by thanking the Food and Drug Administration Advisory Committee for simply allowing me to speak. As well, I would like to give a special thank you to the National Organization of Rare Disorders, NORD, for helping me with my travel expenses in order to make this experience possible.

My name is Susan Nelson. I am a non-smoker and I have lived thirteen years with a lung cancer titled bronchoalveolar carcinoma. At the age of thirty-six, I was an athlete and a health-conscious person and it was absolutely devastating to receive the news that I had this type of disease. At that point, in '89, I went through surgery and upper right lobectomy. However, in five years, in 1994, the cancer returned metasticizing to both lungs.

Travelling throughout the United States and visiting world-renowned medical facilities for possible treatment then became my new life as the cancer continued to grow. Due to the nature, though, of my disease, commonly prescribed cancer treatments were not options for me. The only hope actually offered to me was in Los Angeles where I was recommended to be a recipient for a donor heart and set of lungs with the understanding, though, that the surgery was very invasive and that the life expectancy was minimal.

By the Year 2000, it was clearly apparent that I was losing my battle with the onset of physical disabilities and increased lung-cancer symptoms. Although I never gave up hope, each doctor's appointment ended with the disappointing news until one year ago, August 2001, when I became eligible for the IRESSA expanded-access program.

Certainly, at that time, even today, I knew that we were on the cutting edge of some absolutely remarkable medical discoveries but I never ever imagined that a pill such as this would be available within my lifetime nor would I have the opportunity to experience this first-hand.

In my case, IRESSA began eliminating cancer symptoms in precisely seven days. In just five weeks, my CAT scans showed a significant decrease in my tumors. It has continued to improve my health to this day. Tumor shrinkage is now up to 90 percent in some of the masses and I am completely symptom free with a normal breathing capacity.

Here I stand, before all of you, forty-nine years old and stronger and more active than I have been in years. My story is no more compelling than any other cancer patient's story. Today you are going to all be hearing heart-felt testimonials when it comes to those who have actually been in the trenches.

However, our stories are a little bit different than many of those who have experienced cancer because we have had an astonishing turn of events, thanks to IRESSA. As a committee, all of you have the difficult task of trying to see things from the perspective of the most important clients, those fellow human beings who have been fighting for their lives as well as those who may be in the future.

I speak for many by asking that you approve IRESSA as simply another choice, another choice, for the cancer patient. Please join us as pioneers in moving forward. Give others the gift that we have received, which is the gift of comfort and time.

Thank you.

DR. PRZEPIORKA: Thank you, Ms. Nelson.

Next is Anita Johnston from Each Norwich, New York.

MS. JOHNSTON: Good morning to all of you. I appreciate the opportunity of coming here to speak before you and I hope that what I say can make a difference.

My name is Anita Johnston and I have lung cancer. I have had it for about twelve years. When I was first diagnosed, I had surgery. I had a bilateral lung resection through a sternotomy. I chose this mode of surgery because I had lesions in both lungs and didn't wish to go through two different surgeries within two months.

My right upper lobe was removed and a wedge section taken from my left lung. I was told that I had two synchronous primary tumors, that the one in the left lung was not a metastasis from the right lung. My cancer seemed to disappear for a while, and several years later I was diagnosed with yet another primary. It was, like, pretty unbelievable. This time, it was in my left lung and in the lymph nodes in my mediastinum.

I was treated with what was then, and what may still be, the first-line of chemotherapy. It is carbo and Taxol. It made me very sick. I was nauseated and vomiting. I had a lot of lower-bowel problems. I had reflux. Of course, I lost all my hair. I was just overwhelmed with fatigue and I experienced terrible neuropathy in my hands and feet which I still have, and, most unkind, the loss of some of my cognitive powers.

I figured, you know, I was getting old and nothing good was getting left anymore but my mind. My God; I was so proud of my mind. This was also leaving.

I live alone and I had to get to and from my six-hour infusions all by myself. I had to change my own sheets when I soiled them. Happily, my cancer receded and I was cancer-free for another two years. When the same lesion in my left lung returned, along with metastases in my adrenals and in my liver, this time I treated with gemcibine and vinoralbine. The side effects of these were equally unpleasant; the same fatigue that I had experienced from the Taxol carbo returned and the residual neuropathy just was exacerbated.

I didn't lose my hair although it became very sparse. Actually, the first time, if you have never experienced it, it just came out in one sad little puddle in the shower. The second time, it was kind of molting. I looked like my cat in the spring. It was just a little hair and a little there and it was just not beautiful.

By this time, I became very sophisticated about lung cancer and I am now the regional representative of ALCASE which is the Alliance for Lung Cancer Advocacy Support and Education. I have been associated with them for six years and I speak with hundreds of people all over the United States and in Europe. I use the phone and e-mail. I belong to several support groups. My experience with traditional chemo can be multiplied by the suffering of almost all the people that I serve.

Since I have exhausted the traditional methods of chemo, the next time it came around I asked my doctor for IRESSA. It was that or go home and get in touch with your lawyer and make out your will. That was two years ago. IRESSA is a piece of cake. You pop a pill every morning with your vitamins. The side effects are minimal. I have not had diarrhea that I was told to expect. I do experience pox-like eruptions occasionally.

My nails are soft and my hair is straw-like but it is still on my head. My cancer is not discernable on a CAT or PET scan but, best of all, my life is not on hold while I take this extra pill in the morning. I am not concerned that I am alone while my children, who live in other states, are not frantic that I will crash the car coming home from an infusion high on steroids.

I almost forgot, speaking of steroids. I don't look like a blown-up balloon anymore either.

IRESSA is easy on your body. It appears to work as a single agent for people who had previous chemotherapy. I hope that IRESSA will become just another drug in the panoply of drugs that are used in the treatment of lung cancer.

Thank you.

DR. PRZEPIORKA: Thank you.

Next, Gloria Caruso from Tampa, Florida.

MS. CARUSO: Good morning. My name is Gloria Caruso. I am a sixty-three-year-old female, life-long non-smoker, who was diagnosed with non-small-cell lung cancer when a 1.5 centimeter nodule was removed in an upper right-lung lobectomy in December of '98. This was found during a routine chest X-ray that was taken along with my annual physical mammogram.

It was a small spot that was detected and the follow-up tests led to the surgery. Two lymph nodes were also removed during the surgery and one of them had microscopic traces resulting in my chemotherapy treatment of Taxol and carboplatin.

My chemotherapy consisted of four infusions, twenty-one days apart, from February through April of '99. It is almost impossible to describe your life under this type of chemo to someone who has not experienced it. You get extreme fatigue, nausea, pain in your joints, loss of appetite. The hair loss is to be expected, but the overwhelming malaise that drains you of any energy was just unbelievable. I could not work and I was in bed most of the time.

I looked and felt very sick. The only thing that kept me going was my normal high optimism, my family and friends and my faith in God. Follow up CAT scans were scheduled after my chemotherapy every six months and, by the end of '99, the cancer was back in the lymph nodes and the superior and anterior mediastinum.

Due to my lack of other symptoms and otherwise general good health, I decided to take a watchful "wait and see" course of action. In July of 2000, I had a PET scan which showed the nodule involvement had progressed to the supraclavicular areas on either side of my neck as well as the mediastinum. This news led to my search for clinical trials that might offer something better than the surgery and chemotherapy I had already endured.

My research on-line into clinical trials was frustrating at first because I discovered that my previous conventional treatments, in fact, disqualified me from most clinical trials. I was so fortunate to come across the new expanded-access program for IRESSA which was then starting in that Fall of 2000 and did not exclude me due to my previous treatment.

When I consulted with Dr. John Ruckdeschel at Moffit Cancer in Tampa concerning this program, he agreed to try to get their facility approved as one of the trial sites. After a few months of paperwork to set up the program, I was selected and began the once-daily dosage of 250 milligrams of IRESSA monotherapy.

My results at the first three-month CAT scan were better than my doctor or I had ever dreamed was possible. The tumors, in just those 90 days, were 90 percent gone and subsequent checkups over the last nineteen months have continued to show dramatic shrinkage of my tumors. They cannot locate them in my body anymore.

I know this is not a cure but my quality of life for these last nineteen months with IRESSA has been light-years away from my previous treatment. The fact that my tumors were gone as well is unbelievable but my quality of life--I work. I enjoy my family. In my case, the side effects were minimal, consisted primarily of skin acne and skin dryness and itching which are relieved with topical medications.

I can now describe myself as I truly am, a wife, a mother, grandmother, world traveler, a friend and co-worker--I am still working full-time--and grateful participant in the expanded-access program for IRESSA. I enthusiastically endorse the approval of this new drug and hope many more patients suffering with non-small-cell lung cancer can benefit in this same manner.

I want to thank this committee for the opportunity to participate in this hearing.

Thank you.

DR. PRZEPIORKA: Thank you.

Next we will hear from Robin Prachel from the National Patient Advocate Foundation.

MS. PRACHEL: Please bear with me. I am a little bit nervous and I am not feeling well. Actually, I am going through chemotherapy right now.

I am standing before you today to state some statistical facts you may already been familiar with. This year, 154,900 Americans will die from lung cancer. That is more than breast, prostate and colorectal cancers combined. While I may not be one of the statistical numbers this year, I may be one of the numbers next year or the year after.

Lung cancer accounts for 28 percent of all cancer deaths. I'm in the process of buying my burial plot because there is a 90 percent chance statistically speaking that I will die within the next three to four years.

It is estimated that there are 169,400 new cases of lung cancer this year. That is hard for me say, so I apologize if I get a little emotional, but when I sat down to write my speech, when you see all these numbers in black and white and you see the statistical numbers, and you see your own number, and you see your mother sitting in the audience, it is very hard. But, as I was saying, it is estimated that there are 169,400 new cases of lung cancer this year. That is a lot. I just never thought I would be one of them.

Smoking is directly responsible for 80 percent of all lung-cancer cases. I have never smoked.

Smoking is, by far, the most important risk factor in the development of lung cancer, as I just stated. Not all people get lung cancer from smoking. My cancer is a byproduct from my work in construction. I supervised construction on the outer banks of North Carolina. I built a new hospital, an aquarium and a couple other commercial buildings. Unfortunately, while working in construction, I was exposed to asbestos and dust-related particles and they have now settled in the bottom of my lungs and are now mass-producing tumors.

Only 15 percent of people are diagnosed in an early localized stage. Cancer treatment has come so far. In November, 2000, when I was first diagnosed, I was one of the lucky ones. I was Stage 1. Mine was confined to the lower left lobe of my left lung. With the type of cancer I have, BAC, two years ago, the aggressive protocol for treatment was to remove the malignant tumor and/or section the lung with no chemotherapy to follow.

Now, the preferred choice of treatment has changed. Lung cancer is having significant results with chemotherapy first then followed up with surgery as was reported in May's American Society of Clinical Oncology (ASCO) conference in Orlando, Florida.

This past summer, while most people were taking family vacations, I had another lung resection. I had brain surgery and started chemotherapy, and a lot more. Would my outcome have been different if the drug IRESSA had been available when originally diagnosed two years ago? Now I am at Stage 4 with only a 10 percent survival rate projected for the next three to four years.

Two years ago, even six months ago, I was a healthy, active single mom who never smoked. I coached soccer. I taught Sunday school. I have volunteered with the Civil Air Patrol and much more. Now I am sick. I feel sick. I am scared to say, I feel like I am dying, and it is not from the cancer at the present moment. It is from the chemotherapy that kills your good cells and your bad cells.

You go through many emotional stages when you find out you have cancer. They are hard to understand unless you have been there. To be honest, the last three weeks, I have been battling this feeling over and over again; is this really helping me? Would I have eventually gotten sick if I didn't decide to fight this disease head-on.

Cancer is not all scientific facts. Yes; you need to fight to disease, but you hear, again and again, it is the patient's overall emotional state that helps win the battle. In my case, as I stated before, chemotherapy was not given with the original diagnosis due to the detrimental side effects it would pose to my lungs.

IRESSA, without the side effects, may have been more readily given and certainly would have helped my physical and emotional well-being by keeping the healthy cells doing what they are supposed to be doing. Chemotherapy, with all its side effects is tough, both physically and emotionally. It is tough to stay positive when you look in the mirror, or when you look at your child scared face, it is a constant reminder that your cells are being killed, hopefully, for the greater good.

Common sense tells you you have to fight this. But sometimes it is hard. When I first started dealing with the cancer recurrence, I kept telling myself I wanted to live to see my grandchildren. Now, I just want to see my sons graduate from high school. It is a scary feeling. It is probably normal to feel this way, but it is very real to me and to my family.

I may not be telling you anything you may not have already heard before, but I hope you take this into consideration, you think of the person, a person like me, or you, with your families, when you make your decision today.

Thank you.

DR. PRZEPIORKA: Thank you, Ms. Prachel.

Next is Melissa Mahoney from Virginia Beach, Virginia. I would like to remind the speakers, or ask the speakers, to disclose any financial assistance including travel that they have received from any pharmaceutical companies or advocacy groups.

MS. MAHONEY: Good morning. Thank you for the opportunity to speak to you today about my experience with the experimental drug IRESSA. When I registered with this meeting, I was asked if I would be using a visual aid. It didn't take me very long to realize that the very best visual aid I could use is me.

The very fact that I am standing up here today is nothing short of a miracle. In February of this year, I was at the end of the line. I had received the best standard care available; surgery, radiation, various and numerous chemotherapy regimens, two separate phase I clinical trials at a large teaching hospital.

My condition continued to worsen. Disease progression compounded by the physical toll of the treatments was very hard. My performance status was poor. I was on daily pain medication and I was so short of breath I could barely walk up a flight of stairs. The simple act of taking a shower wiped me out for hours.

On February 16, I began taking IRESSA. Within days, and I mean days, I felt significantly better. By the end of March, I was power-walking on the beach in Fort Lauderdale as I was vacationing with my family.

Let me read you my oncologist's report from my June CT. "The patient is recovering and responding very well to IRESSA. She actually is having a dramatic response to the drug with an improvement in performance status. Her CT scan is quite amazing. There has been a 90 percent-plus reduction in hundreds of pulmonary nodules. There is no new disease present. She feels very well and continues on treatment."

The actual radiologist's notes say, "There has been almost complete resolution of numerous small pulmonary nodules in both lungs seen in the previous study with very few tiny faint nodules remaining in the left lower lobe either representing a remarkable response to chemotherapy," the radiologist did not know that I was on IRESSA, "or complete resolution of opportunistic infection."

The doctors' reports put in clinical terms the evidence you see before you. I urge you to approve this drug. Also, I hope you recommend additional trials with IRESSA as a single first-line agent. On chemotherapy, I was sick and fatigued. It was painful and time-consuming. I experienced numerous unpleasant side effects and the emotional toll of losing one's hair is very hard to explain to someone who has not experienced it.

With chemotherapy, it was months before it could be determined if this treatment was working or, in my case, not working. IRESSA is a blessing. When this drug works, it works fast and it works well. One little pill a day. I had had the side effects of skin rash and diarrhea but they are manageable and well worth the benefit. With IRESSA, I am not merely living. I am thriving.

It has not just given me more time. It has given me my life back. In August, my physician apologized to me. He said that if he had had any idea IRESSA would work so well, I could have been spared much suffering. But that decision was not in his hands. He could not have prescribed it to me and I had to fail several chemotherapy regimens before I could receive through the expanded-access program.

Members of the advisory committee, the decision is in your hands. I am alive today thanks to the grace and mercy of the Lord in providing me with this wonderful drug. I would ask that you would remember this visual aid and approve IRESSA.

Thank you.

DR. PRZEPIORKA: Thank you, Ms. Mahoney.

Next is Janine Hutchison from Las Cruces, New Mexico.

MS. HUTCHISON: Good morning. My name is Janine Hutchison and I am from Las Cruces, New Mexico. I am 59 years old and non-smoker. Sounds familiar. I was diagnosed on November 3, 2000 with non-small-cell carcinoma in the fourth stage at Memorial Medical Center in Las Cruces, New Mexico. I had pleural effusion of the right lung and a thoracentesis was done at that time. Fluid was sent to Mayo Clinic and confirmed the presence of adenocarcinoma.

A CT of my chest showed a lobulated soft-tissue mass in the anterosuperior mediastinum and right peritracheal region. A bone scan was also done and showed osteoblastic activity in the prenemial right femur. An MRI of the femur showed metastatic disease.

I went to MD Anderson in Houston, Texas for a second opinion. I was only offered chemotherapy and given a year to live. I was also told my passing would not be too hard. This was hard to take. I decided to go home and fight as I felt there must be some other newer treatment somewhere available.

I was hospitalized again in December, 2000 at Memorial Medical Center in Las Cruces. This time it was to have a pleurodesis which was to drain my right lung on a machine for a week and then try to seal it with talc. We hoped it would work. It did. A portacath was also inserted at that time.

Chemo was started at the end of December, 2000. I had six cycles of cisplatin and Gemzar ending in April of 2001. I improved somewhat. My CEA had been normalized from 5.9 to 0.6. A CT scan at that time showed stable disease with pleural thickening along the right lateral chest wall with blunting of the right costaphrenic angle. There was also persistent right peritracheal density that was still persistent disease.

After chemo, my doctor said that there was nothing more that he could do. I remember telling him that there must be something out there. On my next visit, he asked me how I would feel if I was given an experimental drug. I said, "I'm there. Make an appointment."

My oncologist then referred me to Dr. Jesus Gomez in El Paso, Texas who was at the El Paso Cancer Treatment Center as a possible candidate for IRESSA in the IRESSA expanded-access program. I was examined by Dr. Gomez and he thought I would make a good candidate.

The paperwork was submitted and I was accepted by the program and started on IRESSA June 25, 2001. Each month, I showed an improvement and, by December of 2001, the only signs I had were a small pleural effusion with calcified pleural density. My last CT scan, taken on June 28, 2002 was fantastic. There was even further resolution of air-space opacities in the right lower lobe and in the right hemithorax with calcified pleural density unchanged which was from the pleurodesis.

No lung mass, no nodule, no lymphadenopathy, no effusion. I have also had a bone scan done September 28, 2001 and it also showed that my problem in my pronemial right femur had shrunk.

I can remember back when I was first diagnosed that I found it even hard to walk down the hall in the house and had to have someone to help me dress. I would be out of breath and coughing. It was the darkest time of my life.

I can now walk briskly, run, drive, drive my car and work in my garden and play with the grandchildren that I love. Life once again has meaning. I thank God every day that he gave such wonderful brains to the people that are responsible for this drug. I am very fortunate, especially when I think of the people that have passed on in a lot of agony with not a glimmer of hope.

At this time, I would like to ask you to take this drug under serious consideration as I feel that it could help so many people. These are people in the advanced stages of cancer of the lung, non-small-cell carcinoma, as, up to this point, there has only been chemotherapy, radiation and surgery.

These options may bring a person a couple more months of life or a somewhat longer life, but the majority of these people feel that, in the long run, there is no option but to die. The side effects of chemo and radiation are numerous--example, myself. With chemotherapy, I have a loss of hearing, arthritis in my joints, and the nerves in my feet are dead. I have no feeling. And, of course, I lost my hair while on the treatment.

On the other hand, with IRESSA, all I have are pimples. It makes me feel like a teenager again. IRESSA is commercially available in Japan. Japan has had the foresight to be on the cutting edge of the new technology while we here, in the United States, seem to be dragging our feet which means that every day someone is dying that we could have helped.

Please give patients with non-small-cell lung cancer back hope and a renewed quality of life. They have nothing to lose.

Thank you.

DR. PRZEPIORKA: We appreciate your comments, Ms. Hutchison.

Next is Adrienne Riddle from San Bernardino, California.

MS. RIDDLE: Good morning and thank you today for this opportunity to speak with you. When I first learned of this meeting a week ago, my mother and I, we felt it was essential that I come and tell you about my story.

We have come here independently of any sponsorships. Even my doctor, Dr. Natale, didn't even know I was coming and was surprised to find out I was here. My name is Adrienne Riddle. I am from San Bernardino, California and I was born in 1982.

I graduated from San Bernardino High School in 2000 and went to San Jose State on a water polo scholarship. I finished out my Freshman year, having played the whole season to come home and become very, very sick. When I came home, I was diagnosed with a tangerine-sized tumor in my right lung and had a complete pneumonectomy on 6-7-2001.

After an MRI and a CAT scan, it showed nine to ten tumors in my brain. It was throughout my lymph nodes and there were nodules in my left lung. I was classified as a Stage 4 non-small-cell adenocarcinoma.

I have never been around second-hand smoke. I have never picked up a cigarette. I was just this healthy incredible athlete. After six months of exhausting chemotherapy, I finally had to stop. I couldn't take it any more. At this time, my tumors appeared to be regressing. I then found about IRESSA from Dr. Natale. He suggested that we try to IRESSA expanded-access program. I felt that this trial study showed hope in the midst of very, very few options.

In January, 2000, I started IRESSA. Since that time, all the remaining brain lesions and nodules in my left lung have ceased to appear. Approval of this drug is very important to me. It has given me a chance to turn 20. I am no longer a teen-ager anymore. It has given me a chance to return to college, to just live life, grow.

I urge you to approve this drug because, if someone like me can get lung cancer at age 18, then the future will bring more. IRESSA has helped me fight through this an I feel it was truly the missing links along with chemotherapy and my surgery. It was a group effort among the options that I decided to take. It has given me a second chance.

Thank you very much for this time. I know you will make the right decision.

DR. PRZEPIORKA: Thank you, Ms. Riddle.

Next, we will hear from Blanche Taylor from Sparta, New Jersey. Following her, we will be going out of order just a bit and we will hear from Laura Turpak.

MS. TAYLOR: My name is Blanche Taylor. This is so hard because this drug has given me back my life. I was diagnosed in December and given a very short life expectancy. I have cancer in both lungs, no metastases outside of the lungs. I had a second opinion from Sloan Kettering and they agreed.

I was directed eventually by Dr. Fazal Bari, my oncologist, to try IRESSA. I was grateful because the chemotherapy regimen I was on did not affect my cancer. My cat scan showed continued growth every time.

The very first day I took IRESSA, stopped coughing. I would cough every day, every fifteen, twenty minutes to clear my lungs and my chest, my bronchi. At night, I never slept through the night. I would wake up every hour to clear my chest and my bronchi. I would become very fragile, weak.

With the IRESSA, the very first day it changed. I am strong and healthy. I am back to work. I do everything myself. I do all my housework. I have twelve grandchildren that I would like to see grow up. Their ages are two to twenty-one. I have a husband who loves me and needs me and two daughters. I am just very, very grateful to IRESSA for providing this pill for me.

Please consider it for others. They need a chance to live. I would also like to thank NORD for providing me the means to get here. This is my helper, my daughter. NORD notified me the opportunity to speak, I knew I had--when I got that letter a week ago, I knew I had to come. As you see, I am not a speaker--and AstraZeneca for their incredible for and for their dedication to helping cancer patients.

Thank you very much.

MS. TURPAK: My name is Laura Turpak and I am the daughter of my mother. I didn't even know I was going to have the opportunity to speak so I will make it very short. My father died of lung cancer that metasticized to the brain. After many chances of getting diagnosed, it took them over a year and a half to figure out what he had. And we had one week. I found out and a week later he had passed away.

Had I had the opportunity of IRESSA, I would have certainly done everything in my power to get the medication to him. Now I am faced with my mother's illness and I cannot thank AstraZeneca for being so incredibly supportive, cooperative--Sloan-Kettering as well--for giving me the direction to help my mother. And, of course, my mom's oncologist, Dr. Bari.

But I have to say, if I may, this is a science, obviously. You can get caught up in the figures. You can get caught up in the financial end of things. But the bottom line is that it is extending the quality and quantity of many people and I am really hoping--I am not a good public speaker either, but I am really hoping that, since this was our last resort, since my mother was diagnosed Stage 4 lung cancer that you will, as a no-brainer, approve this drug.

I am begging you, please, to approve this drug because, if it was you, any of you doctors, nurses, professionals--if you only had one last resort, and you knew it was helping others, I am sure you would want it available to yourself.

Thank you for letting me speak.

MS. TAYLOR: I just want to say one more thing. I didn't plan to say this but I want to realize the jolt you can have when your doctor tells you the results of all your tests and he tells you to get your affairs in order. Think about it.

DR. PRZEPIORKA: Thank you.

I would like to call to the podium Pat Meredith from San Diego, California, please.

If Ms. Meredith does come later, we will hear from her. But right now, we are going to move to Mr. Charles Reilly from Tarrytown, New York.

MR. REILLY: I, for some reason, received the notice of this meeting really late. It was Wednesday and I haven't had much time to really put this together. I thought I would have a lot less time and I boiled it down quite a bit.

I will give you what I have got. Good morning, ladies and gentlemen. My name is Charles H. Reilly. I own a home at 36 Hamilton Place in Tarrytown, New York. I am forty-six years old, been married for eleven years and have a four-year-old son. I am speaking to you today because IRESSA saved my life.

I have come here on my own, at my own expense. I am not being compensated in any way by AstraZeneca, nor have I ever met or spoken to anyone from AstraZeneca. If they wish to compensate me for this trip, I would be delighted.

But I really think the most important thing is that I have the opportunity and the privilege to speak here where the most can be made from what I have to say. Some of you today will have the chance to make a decision that could accomplish incredible good. IRESSA has made me one of the luckiest people alive.

In January of 2000, I was diagnosed with inoperable lung cancer. A pancose tumor in my right lung had spread to the base of my neck. I had a group of the best doctors at Sloan Kettering in New York City. I insisted that they tell me what they really thought would happen to me.

Without treatment, I had about seven months. Even with radiation and chemotherapy, I would live for about two-and-a-half years. I received the treatments but the cancer came back in the same places. Now the only option was chemotherapy by itself and two other types were tried to no avail. By now, I was in tremendously bad condition.

As with many patients receiving these treatments, I developed blood clot in my right arm which limits its use and a weakening of my heart resulted in me having a heart attack. This is now permanent, physical damage which is potentially life-threatening.

Looking at me now, it is hard to believe the devastation the treatments, themselves, caused. I had nothing left to lose so a friend convinced me to look into IRESSA. I was immediately accepted into the program and began taking IRESSA July 30, 2001. The next test I did showed all my cancer getting smaller. I have had two other MRIs after that showing the cancer smaller each time.

Without chemotherapy, I started feeling better within a few weeks. To the best of my knowledge, I have had no bad side effects whatsoever. I just keep getting better and better and there is no question that IRESSA is the only reason I am alive today.

The chances given to me of success with IRESSA were much better than they were with radiation and chemotherapy, both of which have done serious permanent damage to me. It is inconceivable to me to think IRESSA should not be given the same chance as any other treatment. Had I started with IRESSA, I could have avoided going through so much mental anguish and physical pain and avoided the possibility of another heart attack.

I am proof that IRESSA will save lives. The only next logical step is to approve IRESSA and to allow it to be used as a first-line of defense. Not only will IRESSA save lives, it may greatly increase the quality of the life saved.

DR. PRZEPIORKA: Thank you, Mr. Reilly.

Next is Erica Hertz from The Wellness Community.

MS. HERTZ: Hello. Thank you for the opportunity to speak today. I'm the last on the roster, so I appreciate that. My name is Erica Hertz. I am the Director of Patient Education and Outreach for The Wellness Community. We are a national nonprofit organization with twenty-five facilities serving cancer patients worldwide.

For the record, The Wellness Community receives unrestricted educational grants from AstraZeneca. However, no funding was received today for my compensation to be here.

By way of background, The Wellness Community provides emotional support, education and hope to people with cancer and their loved ones at no cost and our facilities provide support groups, educational seminars on treatment decisions, nutritional workshops, exercise, mind-body programs and more.

Our aim is to help people with cancer and their loved ones regain a sense of control over their lives and their disease and to help them feel less isolated, restore their hope, regardless of the stage of their disease. We have grown to serve an estimated 25,000 people just this year alone.

Since we do see a wide range of diagnoses and provide services directly to thousands of people at every stage of lung cancer, we have learned a great deal from the patients we serve. People with lung cancer often feel alone, afraid and without hope after they receive their diagnosis. They often don't know what their options are and they need to know that they have access to innovative approaches to treating their cancer.

As you know, we are in great need of improved treatment options, especially those that have limited toxic side effects, and provide alternatives for patients when prior therapies fail. It is critical that new treatments not only fight the cancer but also allow patients to experience a meaningful quality of life, whether that means continuing to work, travel or enjoy time with family and friends, as you have heard today, with an estimate of nearly 170,000 new lung-cancer diagnoses each year, this year alone, the availability for more treatment options is critical.

So I would ask today that you carefully consider the plight of the patients with lung cancer and endeavor to understand the range of both the medical and emotional issues that these patients face on a daily basis. I would ask that you seriously consider the need that patients with lung cancer have for new and broader range of treatment options with better outcomes for reduced side effects in the hope that there is more that can be done to fight the disease.

You have heard several important personal stories today and you have the power to bring hope to thousands of people who just need to know that they have more choices for the possibility of longer, better lives even after receiving a diagnosis of cancer.

Thank you.

MS. TEMPLETON-SOMERS: Again, I would like to remind everyone that the letters and e-mails received are available for your viewing at the information desk. The majority do speak positively of IRESSA but there are also some stories of negative and neutral experiences, and they will be part of the meeting record also.

Thank you, speakers.

DR. PRZEPIORKA: This actually ends the open public hearing. If there are no more speakers, we appreciate the comments that were provided to us and we will now move on to the sponsor presentation.

I would like to call to the podium Dr. Blackledge from AstraZeneca and ask that he introduce the topic as well as the speakers. The format will be presentation over one hour by AstraZeneca. I would ask that the committee members hold their questions to completion of the presentation and after the FDA presentation.

Thank you.

DR. BLACKLEDGE: Good morning, Dr. Przepiorka, ladies and gentlemen.

[Slide.]

I am representing the sponsor, AstraZeneca, for today's presentation to the FDA Oncology Drugs Advisory Committee. My name is George Blackledge. I am clinical vice president of oncology for AstraZeneca and I have worked with IRESSA from when it was first administered to humans.

[Slide]

The agenda for our presentation is shown here. I will begin by providing an introduction and review the scientific rationale and clinical development program for IRESSA. Dr. Frances Shepherd will discuss the impact of refractory non-small cell lung cancer and the clinical unmet need. Dr. Ronald Natale will review the clinical efficacy from our pivotal trial program and supportive study. Dr. Alan Sandler will review the safety profile of IRESSA and, finally, I will summarize our presentation.

[Slide]

We also have a number of other experts available for questions and answers. Dr. Jose Baselga, who has participated in clinical trials with IRESSA, has also conducted some of the preclinical studies. Dr. David Cella developed the quality of life tool that we have used in assessing the patients' clinical symptoms in these trials. Dr. Gary Donaldson is a statistical expert on quality of life and psychometric analyses and he is also with us today. In addition, Drs. Mark Kris and Thomas Lynch, who are internationally acknowledged lung cancer experts and who have participated in IRESSA clinical trials, are also with us.

[Slide]

We also have a number of experts from AstraZeneca who are available to answer questions if required.

[Slide]

We need to acknowledge that third-line non-small cell lung cancer has a high unmet clinical need. There are literally tens of thousands of patients who develop this disease each year, and when the disease returns it is a disease of symptoms. These patients feel ill. As you have heard today, they are ill. It is an enormous unmet medical need. IRESSA has demonstrated unprecedented activity in this target population. In addition, we have demonstrated that symptom control correlates with response and IRESSA has an excellent safety profile.

[Slide]

That is why we are applying to the FDA for accelerated approval. Our data will demonstrate that IRESSA 250 mg once daily orally can be used in the third-line treatment of patients with locally advanced or metastatic non-small cell lung cancer.

[Slide]

Now let me share with you a little bit about the development of IRESSA. In 1990 our research colleagues began to look at molecular targeted agents, particularly in common solid tumors. We wanted to look at agents which had a new mechanism of action and, hopefully, would be active in new settings with better tolerability. We particularly focused on the epidermal growth factor receptor pathway which is known to be activated and over-expressed in many common solid tumors.

In 1994 ZD1839, known by the trade name IRESSA, was discovered. Following preclinical safety studies which showed excellent tolerability, we were able to start our initial studies in human volunteers.

[Slide]

Let's look at a little bit of the science behind IRESSA. This is the beginnings of the EGFR signal transduction pathway. We can see from this diagram of a cell that the epidermal growth factor receptor is a transmembrane receptor. Now, when a ligand binds, such as EGF or TGF-alpha, there is homodymerization and heterodymerization and this leads to autophosphorylation at the tyrosine kinase site on the internal domain of the receptor. This results in a downstream cascade of the MEK kinase pathway which leads to cellular proliferation and, through the AKT pathway, to the inhibition of apoptosis or programmed cell death.

[Slide]

We also know that stimulating these pathways is responsible for other factors such as the stimulation of angiogenesis and the potential for metastasis. If you can inhibit this pathway in some way, you may have an effect on proliferation, and by inhibiting tyrosine kinase on the internal domain of the receptor you get down-regulation of the entire pathways, inhibition of proliferation and other factors which influence the malignant process. IRESSA down-regulates these key pathways.

[Slide]

We know that IRESSA is selective for the epidermal growth factor receptor tyrosine kinase enzyme. There is 100-fold selectivity for this enzyme over other cellular kinases. We also know that IRESSA works in EGF-stimulated cells, and you can see that it inhibits EGF-stimulated cells, at the bottom of this slide, at nanomolar concentrations compared with serum-stimulated cells where there is only micromolar inhibition.

[Slide]

We have also seen activity for IRESSA in lung cancer cell lines. This is xenograft data, and here we have a lung cancer xenograft growing in an uncontrolled way. When you co-administer IRESSA to this xenograft for about 20 days you see inhibition of growth. When you stop IRESSA, the tumor starts to grow again. If you administer IRESSA for prolonged periods of time you can continue to see inhibition of cell growth.

[Slide]

With our clinical pharmacokinetic studies we demonstrated approximately 60 percent bioavailability and a half-life of 41 hours. This meant that we had an agent which could be given orally on a daily basis.

[Slide]

Let me now spend a little time taking you through the clinical development program for IRESSA. Our program has four key components. First is our Phase I clinical trials. Second, which is the subject of this submission, is the third-line monotherapy trials, trials 39 and 16. We also investigated IRESSA in first-line in combination chemotherapy, which I will be discussing today. Both of these two programs were separate fast track designations by the FDA and were developed in full consultation with the agency. In addition, as you have heard, in response to both patient and physician demand, we opened an expanded access program 2 years ago, which I will present to you as well.

[Slide]

Let's now review our Phase I clinical trials. We evaluated doses of IRESSA ranging from 50 mg to 1000 mg daily. From this large clinical trial program we demonstrated a safety profile which suggested that the most common toxicities were Grade 1-2 gastrointestinal and skin toxicity. The dose-limiting toxicity was reversible Grade 3 diarrhea at around 800 to 1000 mg daily.

What was really exciting about this Phase I program is that we saw striking symptom improvement and anti-tumor activity in non-small cell lung cancer. We had 10 objective responses in 100 patients with non-small cell lung cancer. That is a 10 percent response rate. Now we have 17 patients that have been on study for more than 6 months.

[Slide]

Here is a radiograph of one of the patients with non-small cell lung cancer demonstrating the extent of the disease. You can see disease in both lungs and the very significant clearing observed after only 14 days of treatment with IRESSA. These kinds of radiographs are things that we found exciting.

[Slide]

Now let me introduce you to the third-line monotherapy program which is the subject of this submission.

[Slide]

The reason we carried out this program was that we had seen activity in the Phase I trial and that there was no approved therapy for third-line non-small cell lung cancer patients. There was, therefore, a clear clinical need for a therapy that provides objective responses and symptom improvement in this highly symptomatic disease and, if at all possible bearing in mind the clinical condition of these patients, was also well tolerated.

[Slide]

The Phase II trials have demonstrated clinically meaningful responses. The response rate was 10 percent in trial 39, with an additional 30 percent stable disease. This was also associated with highly significant symptom improvement. We also have similar supportive data which you will hear in trial 16. In all of these trials we have a highly acceptable safety profile.

[Slide]

Let me now touch briefly on the first-line combination therapy program, which is not included in this submission but since we recently obtained the results we reported these to the FDA.

[Slide]

Our rationale for initiating the combination therapy trials was that we had an agent with a novel mechanism of action and we had seen objective responses in Phase I trials. Therefore, we felt that this was the next logical step after the third-line therapy trials with the goal of improving outcomes in non-small cell lung cancer.

The trial design included previously untreated patients with advanced, unresectable non-small cell lung cancer. The patients were all treated with standard combination chemotherapy and randomized to one of two doses of IRESSA or placebo. The primary objective of these 2000-patient trials was to determine if IRESSA could increase survival in this setting.

[Slide]

The results from both well-controlled trials were representative of typical first-line populations. Each trial had well-balanced baseline patient characteristics. The results, in short, were that there were no differences in overall survival rates across treatment arms in both trials, and we did not achieve our primary endpoint. In addition, if we look at the secondary endpoints, response rate and time to disease progression, again we showed no additional benefit for IRESSA when added to 2-drug chemotherapy. A positive outcome of these trials were the safety results. We did not identify any additional safety issues in this randomized, placebo-controlled setting.

[Slide]

We believe that these first-line results, although disappointing, are not germane to the results demonstrated in third-line non-small cell lung cancer. First-line therapy represents a different treatment setting, combination with chemotherapy rather than monotherapy. The lack of a survival benefit in first-line therapy does not negate the anti-tumor responses and symptom improvement that we will report in the third-line trials.

[Slide]

We have tried to think about why we should have got this result when there was so clearly activity in our Phase I studies and Phase II third-line studies. Numerous colleagues have examined these results in an attempt to understand the data.

We have had discussions with Dr. Larry Norton, who is the immediate past president of the American Society of Clinical Oncology, and here are some of his comments: With Genentech's anti-VEFG announcement recently, SWOGs evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy and the IRESSA results, I think we're seeing a pattern emerge that is really, paradoxically, quite hopeful. We've said that these new therapies are dramatically unlike chemotherapy but we've tried to develop them as if they were. Now we know they're not, and IRESSA has to be used following different paradigms.

[Slide]

That is exactly what we want to do. You will see the third-line monotherapy data today. We have taken note of the first-line data and here you can see some of the trials that are either ongoing or planned. We will have trials across the whole continuum of non-small cell lung cancer, but initially they will focus on monotherapy.

[Slide]

Finally, let me summarize the expanded access program. The rationale behind establishing the expanded access program was based on the evidence of unprecedented clinical effects we saw in the Phase I trial. These preliminary results were presented at various scientific meetings, such as ASCO, which resulted in significant patient and physician demand for access to the compound. Therefore, we developed this program in close collaboration with the FDA, the National Organization for Rare Disorders, patient advocates and medical ethicists. The population for the expanded access program was patients with advanced non-small cell lung cancer and no other treatment options.

[Slide]

The program has confirmed a very high unmet need in refractory non-small cell lung cancer. More than 18,000 patients worldwide have enrolled into this program. We administer the drug as a 3-month supply and, therefore, we can measure the rate of resupply. We know that currently there are more than 40 percent of patients continuing IRESSA beyond 6 months in this program. These data suggest a sustained clinical benefit.

As you take into consideration all the evidence from all the patients treated, it is important to consider the patients that we have heard from today and the many thousands of other patients treated in expanded access. We must look at the whole body of data.

[Slide]

Our clinical development program for IRESSA that we will present today will focus on third-line monotherapy which has been designated fast track by the FDA.

[Slide]

As we go through our presentation, you will need to bear in mind the four questions that you have been asked to address by the FDA.

[Slide]

We will demonstrate to you the relevance of our symptom improvement data. We do not agree that symptom improvement cannot be adequately evaluated in this Phase II setting, and we will show you the data to support this.

[Slide]

We will demonstrate to you that the response rate of 10 percent in trial 39 is a robust endpoint predicting clinical benefit. The disappointing results from the first-line program do not impinge upon the validity of this endpoint.

[Slide]

We will discuss with you the expanded access program and implications of different decisions.

[Slide]

And, we will welcome potential study designs to provide a confirmatory trial following accelerated approval for IRESSA in third-line non-small cell lung cancer.

[Slide]

IRESSA addresses a high unmet medical need in a large patient population. We will demonstrate a consistent response rate that correlates with symptom benefit with a drug that is well tolerated and easily administered.

Now I would like to introduce Dr. Frances Shepherd who will describe the unmet clinical need in refractory non-small cell lung cancer. Dr. Shepherd?

DR. SHEPHERD: Thank you, Madam Chairman, members of the ODAC committee and guests for the opportunity to present to you today. I am Frances Shepherd, a medical oncologist from the Princess Margaret Hospital, in Toronto.

[Slide]

In 2002, the American Cancer Society estimates that 170,000 Americans will be diagnosed with lung cancer. This represents 13 percent of all cancers diagnosed in the U.S. Non-small cell lung cancer accounts for 80 percent of these malignancies. Regardless of the stage at diagnosis, the majority of patients with lung cancer are candidates at some time for systemic therapy. Approximately 50,000 persons undergo surgery, however, nearly half of these relapse with distant metastatic disease. Another 70,000 have locally advanced disease. Sadly, among this group 80 percent or more will suffer disease recurrence and may require chemotherapy. However, the majority of initial cases present with advanced metastatic disease and are primarily treated with systemic therapy. In total, therefore, more than 110,000 new patients are eligible for systemic therapy each year in the United States.

[Slide]

The only proven systemic treatment for non-small cell lung cancer is chemotherapy. Decades of research have demonstrated that in the first-line setting chemotherapy modestly improves survival and lessens the symptoms of non-small cell lung cancer. Platinum-based regimens remain the standard of care for first-line treatment, although recommendation to date has demonstrated an uncertain benefit in patients with performance status 2. Unfortunately, as you have heard so eloquently from our patients this morning, the benefits of chemotherapy are often offset by its toxicities such as febrile neutropenia, anemia, neuropathy and hair loss and, in particular, overwhelming fatigue.

[Slide]

Docetaxel is the only therapeutic agent that is approved for second-line treatment of non-small cell lung cancer. The response rate to docetaxel is low, at only 6 to 7 percent. But despite this low level of activity, clinical benefit has been demonstrated in trials. However, as docetaxel is a chemotherapeutic agent, all the issues of toxicity that apply in the first-line setting are also applicable here.

[Slide]

Despite the growing number of patients in need of third-line therapy, little research has been focused on this group, and no studies have identified patient populations who have the potential to benefit most from further therapy. Specifically for non-small cell lung cancer, there is no standard definition for disease refractoriness in either the second-line or the third-line setting. In fact, the issue has not yet been considered relevant in this disease where response rates are often measured only in single digits.

In general, most physicians feel that patients treated previously with cisplatin or carboplatin combinations, as well as second-line docetaxel are unlikely to benefit from further additional courses of these same agents. Thus, most oncologists currently turn to other commercially available chemotherapy agents, either alone or in combination in a third-line setting, despite the lack of proof that they are either effective or safe.

[Slide]

Massarelli et al. presented data for the use of chemotherapy in the third-line and fourth-line setting at the 2002 meeting of the American Society of Clinical Oncology. Only 1 of 143 patients in their series experienced a radiographic response to treatment. Furthermore, the median survival of their cohort was only 4.5 months and the 1-year survival from the start of third-line therapy was only 5 percent.

[Slide]

Surveys have shown that the vast majority of patients with advanced non-small cell lung cancer receiving any line of therapy, and particularly third-line therapy, suffer from disease-related symptoms. Pulmonary symptoms are the most common, including shortness of breath, cough and chest tightness. Poor appetite, fatigue and weight loss also occur.

[Slide]

Thus, it is absolutely critical that studies of new treatment strategies in the third-line setting address not only the classical endpoint of tumor response but also the important endpoints of clinical benefit and tolerability. In fact, these latter factors may be more important to patients than response and survival.

[Slide]

In a survey recently done in patients with advanced non-small cell lung cancer who had received platinum therapy, the majority of patients clearly voiced the desire for symptomatic relief. In fact, despite the known side effects and modest benefit of chemotherapy, they would choose to have further chemotherapy if symptoms could be substantially reduced even in the absence of a survival benefit of 3 months.

[Slide]

As we develop agents for use in the third-line therapy of non-small cell lung cancer, we must select treatment goals specific for this patient group. To be useful, an intervention must improve disease-related symptoms and symptom improvements also must be shown to allow the patient to maintain or resume their normal life style. Moreover, the treatment itself must not add any burden to the patient.

An oral treatment might be expected to best meet the needs of this patient population. Oral drugs can provide a holiday from more difficult and potentially more toxic intravenous medications. Because these drugs can be administered anywhere, oral treatments help the patients spend more time at home or even at work. In addition, some patients feel that an oral treatment provides them with an enhanced feeling of control over their disease.

[Slide]

In conclusion, in the United States today there is an increasing number of patients with non-small cell lung cancer who are in need of third-line therapy. Most of the persons seeking third-line therapy suffer from life style limiting disease-related symptoms. There are no approved agents for us in the third-line setting. Therefore, third-line therapy for non-small cell lung cancer represents an unmet medical need of major medical importance.

Thank you. I will now invite Dr. Ronald Natale to present the clinical efficacy for the two second and third-line trials of IRESSA in non-small cell lung cancer.

DR. NATALE: Good morning. Madam Chairman, committee members, thank you for giving me the opportunity to help you make a recommendation to the FDA that will be in the best interests of a large number of patients who suffer a terrible and usually fatal disease.

[Slide]

I am Dr. Ron Natale. I am a medical oncologist and a clinical investigator from the Cedar Sinai Comprehensive Cancer Center in Los Angeles. I have had a primary interest in clinical investigations of lung cancer for 25 years and I have been heavily involved in the IRESSA development program for over 2 years. I was the major accruer in trial 39 and I have enrolled over 125 patients in the expanded access program. Therefore, I have had extensive clinical trial and bedside experience with IRESSA as monotherapy.

[Slide]

My presentation will consist of four parts. The first part, which is the major focus of our presentation today, is the pivotal trial data for trial 39. This trial was conducted entirely in the United States. The second part will consist of key efficacy findings from the supportive trial 16, a trial conducted entirely outside the United States in patients with less advanced and less heavily pretreated disease. The third part will drill down on the important inter-relationships between objective response, patient assessment of symptom improvement and physician assessment of performance status. This analysis provides physicians and patients with the information necessary to arrive at the optimal and appropriate therapeutic decisions. Finally, I will give our conclusions.

[Slide]

The primary goal of all physicians caring for non-small cell lung cancer patients in the third-line setting, with limited survival, is to provide palliation of the debilitating symptoms. Cytotoxic chemotherapy can sometimes be offered but only to the few better performance status patients who are willing to accept more chemotherapy. Unfortunately, objective response and true palliation are rare; toxicity is certain.

As presented by Dr. Shepherd, there is no effective treatment for patients following second-line therapy. In these patients disease progression is inevitable. The best these patients can hope for is that disease-related symptoms will stabilize for a brief time with optimal supportive care. Sustained improvement is rare; more likely, symptoms will worsen. The need for a novel biologically based oral agent with intrinsic anti-tumor activity and minimal toxicity would satisfy this large unmet need. IRESSA would satisfy this unmet clinical need if the Phase I findings--objective responses and physician observation of an apparently rapid and durable palliation--could be confirmed in a subsequent trial.

[Slide]

Therefore, in discussions with the FDA trial 39 was developed with the following aims: To determine for each dose the objective response rate and symptom improvement rate using prospectively defined criteria. Patients served as their own controls. For both endpoints we had hypothesized that a response rate greater than 5 percent would be clinically significant in the setting where no effective therapy exists. Lastly, as will be discussed by Dr. Alan Sandler, we sought to determine the safety profile of IRESSA. Patients were randomized in a double-blind manner to either 250 mg or 500 mg daily oral doses.

[Slide]

The rationale for dose selection was as follows: Although a response was observed at the 150 mg dose level in Phase I trials, 250 mg was chosen because it was considered to be the minimally effective dose that would ensure adequate drug exposure in a patient population. And, 500 mg was chosen because it was considered the highest dose that is well tolerated on a chronic daily basis by most patients. Remember that dose-limiting toxicity occurred at doses of 800 mg to 1000 mg in the Phase I trial, thus, a 500 mg dose level ensured a wide safety margin. The randomized trial design allowed for an assessment of the optimal dose based on efficacy and safety.

[Slide]

This slide details inclusion criteria as worded in the protocol with respect to prior therapy. These criteria were both specific and relevant to a third-line patient population and defined the unmet clinical need.

First, patients must have received prior therapy with at least 2 chemotherapy regimens that had to have included platinum and docetaxel given concurrently or in separate regimens. Secondly, prior regimens must have failed the patient because of disease progression on third-line or unacceptable toxicity.

Patients who entered the trial due to disease progression on therapy had to have documentation that their most recent dose of chemotherapy had been within 90 days prior to progression. Again, this is defining a very heavily pretreated patient population who have exhausted all therapy options using standard available chemotherapies.

[Slide]

Patient eligibility issues have been raised by the FDA. Ninety-six percent of patients recruited to this trial satisfied the inclusion criteria as worded and defined. The investigators in this study interpreted the eligibility criteria in a way that did not require patients to have disease progression on treatment with platinum and docetaxel given separately or concurrently.

Furthermore, we believe the distinction between refractory, resistant and sensitive is not relevant to third-line non-small cell lung cancer and is without precedence. The limited data available, as presented by Dr. Shepherd and the universal bedside or clinical experience indicates that patients rarely respond to any third-line therapy, regardless of the interval or response to the second-line treatment. Thus, there was no available therapy for all of the patients entered into this clinical trial.

[Slide]

Objective responses by the treating investigators used the SWOG modification of the UICCC/WHO criteria. These criteria are standard and well-established, and allow response assessment in patients with both measurable and non-measurable disease. Response categories, including CR, PR and stable disease, required confirmation by a second assessment at 28 days or later. Tumor responses were assessed on days 28, 56 and every 2 months afterwards. All tumor responses were independently verified by the FDA.

[Slide]

In this trial symptom improvement was a coprimary endpoint and response criteria were prospectively defined. For this assessment we used the Lung Cancer Subscale, or LCS of the FACT-L. This is a validated, sensitive and reliable instrument and it has been validated in multiple languages. This simple tool asks patients to score 7 symptoms, 4 pulmonary and 3 related to advanced cancer on a scale of 0 to 4, with 0 representing the worst possible symptoms and 4 representing no symptoms. The scores of each of the 7 items is totaled so that a score of 28 represents a patient who is completely asymptomatic. Total scores decreasing towards zero represent worsening symptoms. As in the case of radiographic assessments of response, patients completed pretreatment baseline LCS questionnaires and served as their own controls.

[Slide]

A minimum improvement of 2 points or more in total LCS score for a minimum of 4 weeks was the response criteria established and stringently applied in this study. It was based on a large validation study of the LCS in a 573-patient Eastern Cooperative Oncology Group trial in which changes in LCS scores were anchored to and found to have statistically significant association with clinically important outcomes such as objective response, time to tumor progression, survival and changes in performance status and body weight.

[Slide]

Symptom improvement criteria were applied stringently. LCS assessments failing to confirm a 2-point or greater improvement for a minimum of 4 weeks without a worsening of 2 points or more from baseline were considered symptom improvement failures. This stringency was based on the belief that symptom improvement of greater than 4 weeks in a patient with an expected median survival of 6 months would be clinically meaningful, and would serve to reduce the influence of a placebo effect in which improvements are usually very short-lived.

In trials 39 and 16 LCS was assessed weekly following the start of treatment. Therefore, patient assessment in changes of their lung cancer-related symptoms preceded radiographic assessment and eliminated the potential bias of knowledge of objective disease response or progression. If high compliance could be achieved the weekly assessments would provide a very large database that would minimize the impact of an occasional missing data point.

[Slide]

Now for the results of trial 39, again focusing on the key primary endpoints.

[Slide]

The patient population in this trial had a median age of approximately 61. There were slightly more males than females. Notably, approximately 20 percent of patients had a performance status of 2. These patients are known to tolerate chemotherapy poorly and to rarely respond even in the first-line setting. As is typical of non-small cell lung cancer trials in the United States and other developed countries, about two-thirds of patients had adenocarcinoma histology. Approximately 90 percent had metastatic disease, with two-thirds of patients having 2 or more metastatic sites. The median time from diagnosis to entry was approximately 20 months, 24 in the 250 mg group and 17 in the 500 mg group. This is to be expected in third-line clinical trials, reflecting the interval between the initial diagnosis and first-line platinum treatment, the 10-month median survival to first-line therapy, the interval needed for the second-, third- and fourth-line treatments given to the patients entered in this trial.

[Slide]

This slide summarizes prior treatment history and 214/216 patients had received 2 or more prior regimens, including platinum and docetaxel. As specified by the protocol, 80 percent of patients had progressive disease during or within 90 days of their most recent therapy. About 17 percent of patients entered the trial because of unacceptable toxicity with their most recent therapy.

[Slide]

As you will see, this is a highly symptomatic patient population. This bar graph shows the range of baseline scores for the 7-item LCS, with 28 representing patients who are asymptomatic for all 7 items and progressively lower scores representing progressively more severe symptoms. Baseline scores were obtained from all patients entered into this trial. All but one patient satisfied the eligibility criteria of a baseline score of 24 or lower. The median score in this group was 16. Compare this to the baseline median score of 19 in the ECOG LCS validation study in chemotherapy naive patients with newly diagnosed advanced or metastatic non-small cell lung cancer. This confirms the natural history of non-small cell lung cancer in which symptoms progressively worsen over time through successive failed chemotherapies and reflects the highly symptomatic patient population entered into this trial.

[Slide]

This slide graphically presents the radiographic response data. Ten percent of patients achieved a confirmed and FDA-verified objective response. There were no statistically significant differences in the 250 mg and 500 mg dose levels, with patients in the combined groups and in the 250 mg level meeting the prespecified statistical criteria of greater than a 5 percent response rate. Although the 95 percent confidence interval around the response at the 500 mg dose level does not quite clear the 5 percent mark, there is considerable overlap in the two error bars.

It is important to note that the response rates are identical for intent-to-treat populations, as well as for the 139 selected patients by the FDA. The lack of a difference in response rate speaks to the activity of IRESSA regardless of prior chemotherapy history.

[Slide]

Objective responses had a median duration of 7.4 months at the 250 mg dose level and 5.8 months at the 500 mg dose level. Responses occurred regardless of the number of prior regimens, performance status and age and were documented in both men and women. The lack of relationship to the number of prior regimens and performance status is a remarkable observation that distinguishes this biologic agent from cytotoxics which rarely produce objective responses in patients with more than 2 prior regimens or with performance status 2.

[Slide]

This slide graphically presents the symptom improvement rate. Forty percent of patients reported a 2 point or greater improvement in disease-related symptoms sustained for a minimum of 28 days. There was no statistically significant difference in the symptom improvement rate between the two randomized dose level arms of the trial.

Please note that the lower 95 percent confidence interval was greater than 5 percent in both dose levels. It should be emphasized that the average weekly compliance rate of LCS data collection was 84 percent. This remarkably high compliance rate is unprecedented in quality of life and symptom assessment endpoints in cancer clinical trials, and speaks to the rigor with which this study was conducted.

[Slide]

This slide graphically presents the average or mean change in LCS score from baseline by week in all patients. A 2.6 overall change in mean LCS score was rapid, sustained and durable. There were no differences in the 2 dose levels in the study and for simplicity the data are combined in this graph. As I will show you shortly, the mean change among the 40 percent of patients meeting or surpassing the minimum criteria for symptom improvement was 4.6.

[Slide]

Overall, 84 patients, 40 percent, can be classified as symptom improvers. In this group the mean change was 4.5, with the greatest score improvement occurring in the 4 pulmonary items of the LCS, shortness of breath, cough, ease of breathing and chest tightness.

The improvement occurred rapidly, meeting or surpassing the 2 point or greater criterion within the first 4 weeks, in other words, prior to the first radiographic assessment.

Symptom improvement was durable, lasting at least 3 months in 75 percent of patients; at least 6 months in 65 percent; and with the median duration not reached by the time of data cut-off in this analysis.

The quality of symptom improvement produced by IRESSA is reflected in its lack of relation to the number of prior regimens or patient performance status, age or gender. Forty percent of the symptom improvers reported a 1 point or greater improvement in 6 or 7 of the individual items in the LCS. As many of you know, advanced lung cancer patients present a number of management problems in that they frequently require changes in supportive medications such as bronchodilators, cough suppressants, antibiotics, pain medications, etc., raising the possibility that this symptom improvement was due to concomitant medications rather than IRESSA, however, please note that the percentage of patients requiring any new supportive medications was significantly lower, 32 percent in the symptom improvement group compared to the group without symptom improvement in which new medications were prescribed in 46 percent.

[Slide]

In summary, IRESSA produced a confirmed and verified objective response rate of 10 percent in heavily pretreated patients with non-small cell lung cancer. Forty percent of patients achieved a significant improvement in specific disease-related symptoms. The radiographic responses in symptom improvement occurred rapidly, were durable and similar for both dose levels.

[Slide]

Trial 16 was conducted entirely outside the United States--Europe, Australia and Japan, and offers a unique and valuable opportunity to examine IRESSA's objective response and symptom improvement rates in lung cancer patients with a different cultural and ethnic background.

[Slide]

Trial 16 used the same basic design and methods, prospective, randomized, double-blind, timing of assessments, etc., as used in trial 39. Patients served as their own controls. However, there were significant differences in patient eligibility criteria. They were less heavily pretreated, requiring a maximum rather than a minimum of 2 prior regimens which had to have included platinum. Although many patients had received prior treatment with docetaxel, it was not required. Disease progression during or within 90 days of study entry was not required. There was no minimum severity of symptoms required for patient entry.

[Slide]

The results are as follows.

[Slide]

This slide summarizes patient characteristics. Similar to trial 39, the median age in this trial was 61 and about two-thirds of patients had adenocarcinoma. Compared to trial 39, there was a slightly greater preponderance of males; a slightly lower proportion of patients with performance status 2 and metastatic disease; approximately 13 percent of patients had PS 2. The median time from diagnosis to trial entry was 14-19 months, shorter than in trial 39, as expected in a predominantly second-line study. About two-thirds of patients had symptom scores of 24 or lower at baseline and were, therefore, eligible for assessment of changes in disease-related symptoms. All patients received prior platinum therapy. Slightly less than half had received a second-line treatment.

[Slide]

The overall objective response rate was 19 percent, with no significant difference between the 2 randomized dose levels.

[Slide]

Responses occurred rapidly, with first evidence of partial response subsequently confirmed occurring with the first radiographic assessment at week 4. Responses were durable, with the median duration not reached at the time of data block, with 90 percent ongoing with 4 to 8 months of follow-up. Responses were independent of the number of prior regimens, performance status and age and were observed in both men and women.

[Slide]

One hundred and forty, a subset of the 210 patients in trial 16, were evaluable for symptom improvement. The compliance rate was 64 percent, good but slightly lower than in trial 39. The results, however, are nearly identical, with 39 percent of patients achieving the minimum criteria for symptom improvement overall. There was no significant difference between the 2 randomized treatment arms.

[Slide]

In summary, trial 16 achieved an overall objective response rate of 19 percent and an overall symptom improvement rate of 39 percent. These results are highly corroborative in support of trial 39 results.

In a clinical trial lacking a comparison control group it is important to examine whether there is an association between the 2 validated and independently assessed primary endpoints--tumor response and symptom improvement.

[Slide]

This slide demonstrates the strong association of tumor response with symptom improvement. Twenty-one of 22, 96 percent of the patients achieving radiographic partial responses enjoyed significant symptom improvement. Some patients in the radiographic stabilization category achieved tumor regressions, slightly less than the stringent criteria required for partial response, or stabilization of prior progress of disease. This probably accounts for the lower but important symptom improvement enjoyed by some of these patients. A few patients with disease progression satisfied the minimum criteria for symptom improvement.

[Slide]

Let me remind you of the 2.6 mean change in LCS score from baseline by week in all patients. This curve is a composite of the 3 radiographic categories of partial response, stable disease and disease progression, and is broken down in the following slide.

[Slide]

You should note that there is a logical rank order in the magnitude of change of these 3 categories with the partial responders in yellow, stable disease in red, progressive disease patients in green.

[Slide]

Let us focus especially on the partial responders. Please again note the rapidity of improvement, the magnitude of improvement with the mean change of 4.8 and with the lower 95 percent confidence limit of 3.1 being well above the minimum criteria of a 2-point improvement. Please also note the consistency or stability of improvement week to week to week and the duration. The strength of this result virtually eliminates the possibility of a placebo effect.

[Slide]

Several patient examples served to illustrate some of these important points. Patient 37, at the time of trial entry, was a 46-year old woman with Stage 4 non-small cell lung cancer, brain metastasis, progression of disease on platinum and docetaxel, failure to respond to gemcitabine and vinorelbine. At baseline she has a 6 by 5 cm right lower lobe lung mass and 1 or 2 large hepatic metastases are depicted. Within 1 month there was a substantial regression in cancer. The cancer was minimally visible 12 months later.

[Slide]

This represents her symptom improvement. Symptom improvement occurred rapidly, prior to the radiographic assessment, and correlated throughout with continued response of treatment. There was a temporary decrease in performance score, symptom improvement at a time when this patient developed symptoms of radiation necrosis, she underwent a craniotomy for removal of that tissue and, after recovering from surgery, resumed IRESSA and promptly resumed a near normal symptom improvement state. Most of her improved symptoms were in cough, appetite and chest tightness. Her score went from 11 to near normal. She regained her life. As she and her husband said so eloquently, now, 2 years later, she is normal.

[Slide]

[Slide]

We found that improvement in physician assessment of performance status was also strongly associated with tumor response. The importance of this association is based on the fact that performance status is 1 of the strongest independent predictors of a favorable outcome in patients with non-small cell lung cancer. Eleven of 22 responders had an improvement in performance status. Nine of the remaining 11 maintained their initial performance status of 0 or 1; there was little room for improvement. Sixteen percent of patients with stable disease had an improvement in performance status. Improvement in performance status was rare among patients with progressive disease.

[Slide]

In summary, data show that IRESSA produces a significant rate of objective response and symptom improvement from which we believe patients derived significant clinical benefit. Significant symptom improvement was rapid and durable.

[Slide]

The overall efficacy conclusions are as follows: IRESSA produces a 10 percent objective response rate as third-line therapy in non-small cell lung cancer. Although modest, unlike other Phase II trials, this radiographic response rate was confirmed, verified by FDA reviewers, and durable. In fact, it is the highest response rate ever observed in this far advanced disease setting. A few of these responses have been dramatic with imminently terminal patients surviving, and surviving well for a year or more.

IRESSA produces a 40 percent symptom improvement rate in highly symptomatic patients with advanced non-small cell lung cancer. The strong association of this outcome with radiographic response and its rapidity, magnitude, week to week stability and durability indicates a placebo effect to be very unlikely. The decreased use of other supportive medications in the symptom improvers compared to the symptom non-improvers rules out an effect of concomitant medications.

These efficacy findings have been corroborated by a second large clinical trial conducted entirely outside the United States. It is clear that the effects of IRESSA cut across geographic and cultural boundaries. We believe that the totality of the data satisfy a rigorous definition of clinical benefit in the radiographic responding patients. The efficacy of IRESSA was comparable at both the 250 mg and the 500 mg dose levels.

The only remaining question relates to the safety of this agent. The data and discussion will be presented by Dr. Alan Sandler, a major co-investigator in this trial. Thank you.

DR. SANDLER: Thank you, Dr. Natale.

[Slide]

I am Alan Sandler. I am an associate professor of medicine at Vanderbilt University, and it is my privilege today to provide you a summary of the safety profile of IRESSA.

As you will see, IRESSA with its selective, targeted mechanism of action has a safety profile that is exceptionally favorable and distinct from that of traditional chemotherapy.

[Slide]

The safety data for IRESSA is based predominantly on the database submitted to the NDA, comprised of data from trials 39 and 16, as well as from 6 additional Phase I trials. The favorable profile is further reinforced by the extensive patient experience in over 18,000 patients in the expanded access program, as well as from investigator initiated trials in other tumor types. I will be presenting the safety data from trial 39. The safety is further corroborated by the data in trial 16 and the additional supportive safety information.

[Slide]

This slide summarizes the most frequent adverse events, occurring in 15 percent or more of the 216 patients exposed to IRESSA in trial 39, regardless of causality. The most frequently occurring adverse events were diarrhea and skin rash. Skin rash was also commonly reported as acne, dry skin or pruritus.

Other commonly reported events were related to the gastrointestinal track or were reported as asthenia, dyspnea or cough, symptoms commonly associated with advanced non-small cell lung cancer. Notably absent from this list are hematologic toxicity, neurologic toxicity and alopecia, commonly observed with chemotherapy.

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This slide shows the drug-related skin adverse events by both dose and grade. All of these events were Grade 1 and 2 for the 250 mg dose. The majority of events for the 500 mg dose were also Grade 1 and 2. However, the overall frequency and number of Grade 3 events were clearly higher in the 500 mg dose. Note, however, there were no Grade 4 skin events in either group and, again, no Grade 3 events in the 250 mg group.

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A similar pattern of frequency and severity was also seen with respect to the gastrointestinal toxicities. Reversible diarrhea was the most commonly reported event. Nausea, anorexia and vomiting were much less frequently reported and, again, there were few Grade 3 toxicities and no Grade 4 toxicities in either group.

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This slide shows the other Grade 3 and Grade 4 drug-related adverse events that were reported in trial 39. Any of these events might be seen in this advanced cancer population and there are no patterns to suggest an association with IRESSA therapy.

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Further evidence of IRESSA's safety is shown by the low frequency of drug-related withdrawals and deaths. Only 1 percent or 1 patient in the 250 mg group had a drug-related withdrawal compared to 4 percent or 4 patients in the 500 mg group. Most deaths on study were due to disease progression. The several deaths resulting from adverse events were largely due to pulmonary events such as pneumonia or other co-morbid conditions. The only drug-related adverse experience leading to death was observed in a patient receiving the 500 mg dose. This was a 70-year old gentleman who had received prior chest radiotherapy, pulmonary fibrosis and had hemoptysis prior to entering on study. Additionally, he had a large left upper lobe cavitating mass with mediastinal adenopathy. He continued to suffer with hemoptysis and expired 2 weeks into therapy.

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In addition, few patients required dose interruptions or dose reductions. Only 15 percent of the patients taking the 250 mg dose had dose interruptions. Only 1 percent had a dose reduction. These were uniformly mostly associated with rash or diarrhea and the dose interruptions generally lasted two to three days, after which patients were then able to resume IRESSA at the same dose.

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With respect to subgroup analyses, demographic subgroup analyses demonstrated no specific safety concerns in special populations characterized by gender, ethnic origin, age, body mass index, performance status or renal impairment. These findings were also confirmed by a similar analysis in trial 16, as was the overall safety profile.

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In summary, IRESSA was found to be well tolerated. The safety profile was characterized by predictable, low grade and manageable skin and gastrointestinal events. The adverse experiences were reversible, noncumulative, and IRESSA was especially well tolerated when compared to cytotoxic chemotherapy. There are no special population safety concerns. The data consistently demonstrates that the 250 mg dose provides a more favorable safety profile than the 500 mg dose.

I would now like to reintroduce Dr. George Blackledge who will provide a summary of today's presentation.

DR. BLACKLEDGE: Thank you, Dr. Sandler.

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I will now summarize the data that we presented today which has established the safety, anti-tumor activity and clinical symptom benefit in third-line non-small cell lung cancer patients. In addition, I will place the data in context with the questions raised by the FDA.

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The first point I want to stress as a clinician is that the goal for third-line for patients with non-small cell lung cancer is treating a disease of symptoms. There is an incredibly high unmet medical need, with thousands of patients each year falling into this clinical situation. These patients are usually highly symptomatic and there is no available or proven therapy.

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I think what we have done with IRESSA is to suggest that it fulfills this unmet medical need in this setting. We demonstrated to you that we have achieved a 10 percent response rate which is predictive of clinical benefit in third-line non-small cell lung cancer.

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It is worthwhile reminding you how we define clinical benefit. The FDA guidance indicates that clinical benefit can be demonstrated either by prolongation of life, or better life, or an established surrogate for either or these.

In our submission for IRESSA, we have demonstrated that the clinical benefit endpoint is a better life. Responding patients exhibit meaningful radiographic response, which occurs rapidly in bulky disease and in numerous metastatic sites and is durable. These objective responses are linked to improvement in lung cancer symptoms and, as such, confer a better life.

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It is worth saying a little bit more about the lung cancer symptoms. We conducted a thorough and informative investigation assessing symptom data in an advanced cancer patient population. The trials had a rigorous design and implementation with high compliance and minimal missing data. This is especially significant considering that the patients completed the forms on a weekly basis.

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What we demonstrated in trial 39 was a highly significant correlation between the objective response and symptom improvement. We demonstrated measurable improvement across the whole population, something that is really quite unprecedented in this clinical setting.

In addition, we saw clinically important and personally important improvements to individual patients, observations that are unlikely to be a placebo effect.

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In fact, let's look again at this slide showing the three plots for response, stable disease and disease progression in terms of the Lung Cancer Subscale. At 4 weeks, prior to their being any radiographic assessment, patients who showed eventual radiographic response had already distinguished themselves from the other groups in terms of symptomatic benefits. It is hard to explain this as a placebo effect. Furthermore, the symptomatic benefits persist and we do not agree.

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Secondly, there is the question of the response rate. We do not believe that the combination of first-line results are applicable to the application of IRESSA in the treatment of third-line non-small cell lung cancer. We have reproducible data from our Phase I trials where we saw a response rate of 10 percent.

The rest of the world trial 16 demonstrated a response rate greater than 10 percent. In our pivotal trial 39 there was an unequivocal 10 percent response rate. The FDA has confirmed the objective responses. These objective responses are associated with and highly correlated with symptomatic improvement and, therefore, the 10 percent response rate is reasonably likely to predict clinical benefit.

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The FDA has raised issues about the expanded access program. We have given this careful consideration and whatever happens, AstraZeneca will continue to supply IRESSA to patients already enrolled in the program. We believe the best solution for patients appropriate for the expanded access program would be accelerated approval for IRESSA. However, we need to bear in mind that if the FDA considers that IRESSA cannot be approved based on the current data, then the ethical premise of continuing to accept patients into the program will need to be reevaluated with the FDA, and we will have to seriously consider our

position.

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Finally, AstraZeneca would welcome suggestions concerning potential study designs. We already have many trials ongoing, both in non-small cell lung cancer and other diseases, and ideas which have been preliminarily presented to the FDA for a