ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ONCOLOGIC DRUGS ADVISORY COMMITTEE**
>
> **72nd Meeting**
>
> 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
>
> [C O N T E N T S]{.underline}
>
> 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
>
> **NDA 21-399, IRESSA (gefitinib)**
>
> **AstraZeneca Pharmaceuticals LP**
>
> 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]{.underline}(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]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Opening Remarks**
>
> 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.
>
> **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.
>
> **Introduction of the Committee**
>
> 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.
>
> **Open Public Hearing**
>
> 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.

**IRESSA (ZD1839) Monotherapy for NSCLC**

> **Introduction and Rationale for Clinical Development**
>
> 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?
>
> **The Need for Third-Line Therapy**
>
> **in Non-Small Cell Lung Cancer**
>
> 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.
>
> **Clinical Efficacy**
>
> 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.
>
> \[Slide\]
>
> Twenty-two patients achieved a partial response. Thirteen of these had
> bulky disease with a sum surface area 10-60 cm2. Five responding
> patients had less than 10 cm2 of measurable tumor at baseline. Four
> patients had non-measurable disease. Almost all of these patients had
> multiple metastatic sites. In the third-line setting a distinction
> between high versus low tumor burden is neither an accepted standard
> nor is it useful. Objective responses occurred rapidly, with 16
> partial responses occurring by week 4 and later confirmed.
>
> 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.
>
> \[Slide\]
>
> There were a total of 39 responders in trial 16. One patient achieved
> a CR, 38 patients achieved a partial response. Disease was bulky in 26
> patients, with baseline tumor area totaling 100-85 cm2. One patient
> had a non-measurable disease response.
>
> 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.
>
> \[Slide\]
>
> Patient 166 was 1 of the 5 responding patients identified by the FDA
> reviewers as having non-bulky and, therefore, implying more easily
> responsive disease. This patient was almost bedridden at the start of
> treatment. This patient achieved an objective response in 6.1 cm2 of
> liver metastatic disease, as well as a significant regression of
> non-measurable disease in other sites such as lymph nodes. Although
> this patient suffered pneumonia that blunted her initial symptom
> improvement in LCS score, an 11-12 point improvement was achieved and
> maintained for over 6 months of therapy. Most of the improvement
> occurred in breathing, cough and appetite. This patient was able to
> resume a 2-mile daily walk after being nearly bedridden.
>
> \[Slide\]
>
> 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.
>
> **Safety Profile**
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> **Summary**
>
> DR. BLACKLEDGE: Thank you, Dr. Sandler.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.
>
> \[Slide\]
>
> 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.

> \[Slide\]
>
> 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 confirmatory trial following
> subpart H approval.
>
> As Dr. Norton has said, we need new paradigms for the development of
> novel agents, and proposals for a confirmatory trial following the
> granting of accelerated approval of IRESSA would be appreciated.
>
> \[Slide\]
>
> Those are the questions that the FDA has raised. But there is a fifth
> question and that relates to the approvability of this application. We
> would like to ask you, on the basis of the data presented today and
> under subpart H, whether IRESSA is approvable for the treatment of
> patients third-line for non-small cell lung cancer. For patients and
> their families, their physicians and us, that is the critical
> question. Thank you.
>
> DR. PRZEPIORKA: Thank you very much, and we are going to hold the
> questions until after both presentations are completed. It is time now
> for a break. I would like to return at 11:20 on the dot to begin. So,
> please, return at 11:18 to get settled. Thank you.
>
> \[Brief recess\]
>
> DR. PRZEPIORKA: I would like to add to the record that Mr. Rick Lesser
> has informed us that he has no conflict of interest and AstraZeneca or
> any advocacy group did not pay for his trip here. That is just to add
> that to the record. Thank you.
>
> The next part of this meeting will be the FDA presentation of their
> review of IRESSA, and I would like to start with Dr. Grant Williams
> who will introduce the FDA review and the other reviewers involved.
>
> **FDA Review**
>
> **Introduction and Regulatory Background**
>
> DR. WILLIAMS: Good morning. Dr. Przepiorka, members of ODAC, ladies
> and gentlemen, I would like to introduce now the FDA presentation.
>
> \[Slide\]
>
> First I want to recognize the FDA review team headed by Amy Baird, our
> project manager. This slide lists the various primary and secondary
> FDA reviewers who evaluated this drug application. This includes
> pharmacists, chemists, medical oncologists, clinical pharmacologists,
> toxicologists and clinical site inspectors.
>
> Under the fast track regulations, FDA is conducting a rolling review
> of this ZD1839 application. Some parts of the application were
> submitted earlier than other parts. The last component of this
> application was received in August.
>
> \[Slide\]
>
> This slide presents the outline of our presentation. I will start with
> the regulatory background and an introduction of critical issues. Then
> Dr. Cohen will present the medical review, followed by Dr. Sridhara\'s
> statistical comments. Finally, I will briefly summarize the FDA
> findings and introduce questions for the committee, though they
> actually have been introduced and answered.
>
> \[Laughter\]
>
> \[Slide\]
>
> This slide summarizes the key FDA findings from review of this
> application. I will return to it briefly at the end of our
> presentation. In brief, AstraZeneca claims that ZD1839 provides
> symptom benefit in study 39, but FDA finds this claim unconvincing
> without a control arm.
>
> FDA and AstraZeneca agree there is a 10 percent response rate in 139
> patients with refractory non-small cell lung cancer, and there is no
> benefit of ZD1839 when added to chemotherapy in the first-line
> treatment of non-small cell lung cancer.
>
> The key question for ODAC is, in light of these data, is the 10
> percent response rate in refractory non-small cell lung cancer
> reasonably likely to predict clinical benefit? An affirmative answer
> to this question would be basically a recommendation to FDA to grant
> accelerated approval.
>
> \[Slide\]
>
> FDA must assure that marketed drugs are safe and effective for their
> proposed use. The efficacy requirement is from a 1962 law that
> requires substantial evidence of efficacy from adequate and
> well-controlled investigations. Efficacy endpoints must have clinical
> meaning. That is, they must measure clinical benefit.
>
> \[Slide\]
>
> As we begin the discussion of this drug and of the endpoints proposed
> to support its effectiveness, it is useful to reflect upon endpoints
> used by FDA to support cancer drug approval. It is often misstated in
> the media or in the oncology literature that FDA only approves cancer
> drugs based on survival. However, this is clearly not the case.
> Recently, the Division of Oncology Drug Products evaluated the basis
> of approval for drugs in our division since 1990. As shown on this
> slide, survival was the approval endpoint in the minority of
> applications. Excluding accelerated approval applications, 67 percent
> of approvals were not based on survival, and for all applications 73
> percent of all approvals were not based on survival.
>
> \[Slide\]
>
> This slide discusses tumor-related symptoms, one class of non-survival
> endpoints that FDA has used for approval of cancer drugs and also one
> relevant to the ZD1839 application. The FDA considers improvement in
> tumor-related symptoms to be clinical benefit, not just a surrogate.
> Therefore, studies adequately demonstrating improvement in tumor
> symptoms can support regular approval, not just accelerated approval.
>
> Tumor-related symptom observations were important in the approval of
> several oncology drug NDAs, including symptom improvement in patients
> with obstruction from lung or esophageal cancer; patients with
> cutaneous or subcutaneous tumors; and patients with painful bone
> metastases.
>
> \[Slide\]
>
> This application also included a description of symptom changes in
> patients with cancer. However, there are fundamental problems, in our
> view, with AstraZeneca\'s symptom benefit claims. Without a concurrent
> control arm we cannot know whether these symptom results might not be
> entirely from placebo effect; from a patient\'s hope that a company is
> getting a promising investigational cancer drug. As Dr. Cohen will
> discuss, some symptom improvements could be attributed to concomitant
> medications given to palliate these symptoms.
>
> Finally, AstraZeneca notes a correlation between symptom benefit and
> tumor response. However, a correlation between symptom improvement and
> tumor response might be expected regardless of whether the tumor
> response caused the symptom benefit. For instance, there could be
> patient bias. One might expect responders would feel better after
> being informed of their tumor status. Certainly, assessment bias would
> be expected. For instance, patients going off study early because of
> tumor progression might go off too early to be documented as a 28-day
> symptom responder. This would force an association between early tumor
> progression and lack of symptomatic response.
>
> Lastly, an association between tumor response and symptom change could
> be caused by shared baseline prognostic factors between tumor
> responders and symptom responders. This would be an association rather
> than a cause and effect relationship.
>
> In the final analysis it is unclear that the changes observed on the
> LCS symptom scale represent significant clinical benefit and that the
> changes observed can be confidently attributed to ZD1839 treatment. In
> order to substantiate these claims we believe a randomized study
> comparing ZD1839 to a non-ZD1839 treatment would be required.
>
> \[Slide\]
>
> Let\'s return to regulatory issues. We are considering this
> application under the 1992 accelerated approval regulations. This
> slide lists the major issues. These regulations are for diseases that
> are serious or life-threatening where the new drug appears to provide
> benefit over available therapy.
>
> The key point for our consideration is that accelerated approval can
> be granted on the basis of a surrogate endpoint that is reasonably
> likely to predict clinical benefit. After accelerated approval, the
> applicant is required to perform a post marketing study to demonstrate
> that treatment with a drug is, indeed, associated with clinical
> benefit. If the post marketing study fails to demonstrate clinical
> benefit, or if the applicant does not show due diligence in conducting
> the required study, the regulations describe a process for rapidly
> removing this drug from the market.
>
> \[Slide\]
>
> This is a list of ten drugs approved by our oncology division using
> tumor response under the accelerated approval regulations. The last
> addition to this group, oxaliplatin, was approved for refractory colon
> cancer just last month with data from a randomized study showing
> increase in the surrogate endpoints of response rate and time to
> progression compared to a control arm.
>
> \[Slide\]
>
> I want to emphasize an important point about accelerated approval, one
> you may have heard from our office director, Dr. Temple. The quality
> and amount of evidence required is no different for accelerated
> approval than for regular approval. We still expect substantial
> evidence from well-controlled clinical trials. We cannot accept
> borderline evidence. The difference is that the evidence may focus on
> a surrogate endpoint rather than a clinical benefit endpoint.
>
> \[Slide\]
>
> Here are the important points from accelerated approval regulations.
> In the following slides I want to discuss two of these in depth.
>
> \[Slide\]
>
> Because accelerated approval must show a benefit over available
> therapy, use of a single arm design for a clinical trial limits the
> treatment indications where accelerated approval may be used. It would
> be difficult to show superiority to other therapy in a single arm
> trial. So, practically speaking, accelerated approval can be used in a
> single arm trial only when there is no available therapy.
>
> Returning to the ZD1839 studies, because approved therapies exist for
> both first-line and second-line treatment of non-small cell lung
> cancer, our accelerated approval considerations are limited to
> third-line treatment of non-small cell lung cancer. Hence, only the
> 139 patients in study 39 are directly relevant to our accelerated
> approval deliberations.
>
> \[Slide\]
>
> The next accelerated approval point I want to emphasize is that the
> surrogate endpoint must be reasonably likely to predict clinical
> benefit. Obviously, this is a judgment based on scientific knowledge
> and on experience, and we must consider all available evidence.
>
> Whether a 10 percent response rate in lung cancer is reasonably likely
> to predict clinical benefit is a good point for discussion. Clearly,
> similar response rates in some tumors have correctly predicted
> subsequent clinical benefit, for instance, the 12 percent response
> rate of irinotecan in refractory colon cancer. However, we also have
> an unprecedented additional consideration.
>
> \[Slide\]
>
> We have results from 2 large randomized studies of excellent design
> that show no benefit of ZD1839 added to chemotherapy and first-line
> treatment of non-small cell lung cancer. Ironically, had ZD1839
> already received accelerated approval, these studies would have served
> as the Phase IV post marketing commitment to verify its clinical
> benefit. Now that these results have become available prior to a
> regulatory decision we must weigh the significance of these negative
> findings on the accelerated approval process.
>
> That concludes my opening comments and Dr. Cohen will now present
> details of the medical review.
>
> **Medical Review**
>
> DR. COHEN: Thank you, Dr. Williams.
>
> \[Slide\]
>
> Madam Chairman, members of ODAC, ladies and gentlemen, I will present
> the FDA medical review.
>
> \[Slide\]
>
> As you have heard this morning, at the present time the FDA has
> approved three cisplatin containing doublets, as well as single agent
> vinorelbine for the initial first-line treatment of newly diagnosed
> non-small cell lung cancer patients with Stage 3B or 4 disease.
>
> In addition, docetaxel has been approved as a second-line treatment
> that is to be used after failure of first-line treatment. As you have
> further heard, there is no treatment that has been approved to date
> for patients who have progressed or who have been intolerant of their
> first-line and second-line treatments. This is an unmet medical need.
> Third-line treatment is what is targeted in the current application.
>
> One fact that must be kept in mind when evaluating third-line
> non-small cell lung cancer studies is that the study group is highly
> selected. Unfortunately, most advanced stage non-small cell lung
> cancer patients do not live long enough or do not have a good enough
> performance status to participate in these studies.
>
> \[Slide\]
>
> The sponsor has submitted data from several clinical trials. Trial 39
> is a third-line treatment trial for advanced non-small cell lung
> cancer patients. It was submitted for the purposes of obtaining
> accelerated approval for the treatment of advanced non-small cell lung
> cancer patients for whom there is no available therapy. As was
> indicated by Dr. Williams, accelerated approval is generally based on
> a surrogate endpoint that is reasonably likely to predict clinical
> benefit. The most commonly used surrogate endpoint is objective
> responder rate. The second submitted trial, trial 16 is primarily a
> second-line trial and, thus, serves to provide additional ZD1839
> efficacy and safety information.
>
> Summary data for 2 first-line trials, which are called INTACT 1 and 2,
> was also submitted and, as was mentioned previously, these trials were
> to be the basis for full approval of ZD1839. In my presentation this
> morning I will present the FDA analysis of trials 39 and 16. Dr.
> Sridhara, who follows me, will discuss the results and implications of
> the INTACT trials.
>
> \[Slide\]
>
> The 2 submitted trials, trial 39 and trial 16, had identical design
> and randomized patients to ZD1839 administered in a dose of 250 mg per
> day versus ZD1839 500 mg per day. The deficiency of the above design
> is that all patients received ZD1839. There was no non-ZD1839
> comparator treatment regimen. Because the efficacy results were
> comparable for the 2 ZD1839 doses, we are essentially left with what
> turns out to be a noon-randomized, non-blinded, single-arm ZD1839
> study.
>
> \[Slide\]
>
> Trial 39 coprimary efficacy endpoints were objective response rate and
> disease-related symptom improvement. As you have heard earlier, the
> instrument used for the latter evaluation was the Lung Cancer Subscale
> of the FACT-L questionnaire. It was recognized during sponsor-FDA
> discussions that the absence of a comparator treatment regimen would
> make symptom improvement data difficult to evaluate. The sponsor\'s
> task was to demonstrate that symptom findings are credible in a
> single-arm study.
>
> \[Slide\]
>
> Trial 39 patient characteristics are summarized on this slide. As
> indicated, the intent-to-treat population included 216 patients.
> Eighty percent of patients were ambulatory with mild or no symptoms as
> judged by the healthcare professional doing the performance status
> assessment. The predominant histology was adenocarcinoma, and 66
> percent of patients had this histology and an additional 7 percent of
> patients had mixed squamous cell and adenocarcinoma. It should be
> noted that adenocarcinomas generally have the slowest doubling time of
> all lung cancer histologies, and this is reflected in the long
> interval between date of initial diagnosis of lung cancer and date of
> trial 39 randomization. The median time was 20 months.
>
> At the time of diagnosis 50 percent of study patients had Stage 4 or
> metastatic disease, and at the time of study entry 89 percent of
> patients had metastatic disease. Since the median survival of newly
> diagnosed lung cancer patients with metastatic disease is in the range
> of 6 to 9 months this, again, suggests that the study population was
> enriched with slow growing, less aggressive tumors.
>
> \[Slide\]
>
> As stated previously, trial 39 was designed for patients with no
> available therapy, that is, a third-line treatment group. Study
> eligibility criteria, therefore, required that the patients be
> refractory or intolerant to 2 prior chemotherapy regimens. These
> regimens must have included a platinum drug and docetaxel administered
> either concurrently or sequentially.
>
> As indicated on this slide, only 139 of the 216 total study patients
> met the eligibility criteria. This is the patient group for whom there
> is no available therapy and for whom the accelerated approval
> regulations apply. The 58 patients who were refractory or intolerant
> to docetaxel but not cisplatin, the 11 who were refractory or
> intolerant to a platinum drug but not docetaxel and the 8 who were
> refractory or intolerant to neither drug provide supporting safety and
> efficacy information.
>
> \[Slide\]
>
> Turning now to trial 39 efficacy results, there were a total of 22
> study patients with an objective tumor response, 12 who received
> ZD1839 250 mg per day and 10 who received 500 mg per day. The
> characteristics of these patients are summarized on this slide.
>
> As indicated, responders were enriched for females and patients with
> adenocarcinoma. The study population included 43 percent females while
> 82 of responders were female. Sixty-six percent of the population had
> adenocarcinoma, whereas 80 percent of responders had that histology.
> While 59 percent of responding patients had metastatic disease at the
> time of diagnosis, their duration of illness was often prolonged.
> Thus, while 3 responders were less than 12 months from diagnosis to
> randomization, 12 were 13-24 months and 7 were more than 25 months
> from diagnosis. Approximately two-thirds of responding patients had
> received 3 to 5 prior chemotherapy regimens.
>
> \[Slide\]
>
> As described on a previous slide, only 139 of 216 trial 39 patients
> were refractory to both a platinum drug and to docetaxel and, thus,
> had an unmet medical need. The objective response rate for this
> population was 10.1 percent. The response rate among the 77 patients
> who were not doubly refractory or intolerant was 10.4 percent. This
> observation is somewhat surprising since one generally expects higher
> response rates in less refractory patients. We will come back to this
> point again when trial 16 results are discussed.
>
> \[Slide\]
>
> The coprimary endpoint of study 39 was disease-related symptom
> improvement. FDA had numerous problems in assessing symptom
> improvement. First, since all patients received ZD1839 and since
> ZD1839 250 mg per day and 500 mg per day had comparable efficacy, all
> patients were essentially receiving the same treatment. Since there
> was no comparator regimen, both patients and caregivers were unblinded
> as to the treatment.
>
> Second, patients who had an objective tumor response were informed
> that their cancer had significantly decreased in size. Providing that
> information introduces a potential bias that can help explain the
> correlation between response and symptom improvement.
>
> Finally, there was no prospective plan for managing concomitant
> medication. I will go into that in more detail on the next slide.
>
> \[Slide\]
>
> Classes of concomitant medication that were received by study patients
> during their time on study are listed on this slide. Most study
> patients were on multiple concomitant medications. It is clear that
> each of the drug classes listed on this slide can have a profound
> effect on lung cancer symptoms that were evaluated, including
> shortness of breath, cough, chest tightness and ease of breathing.
> Information on the doses and schedules of administration of
> concomitant medication was not collected, making it impossible to
> determine whether ZD1839 or concomitant medications were responsible
> for the observed symptom improvement.
>
> \[Slide\]
>
> Turning now to trial 16, as you remember, trial 16 is only a
> supporting trial. Eligibility for this study required that patients be
> refractory to 1 or a maximum of 2 chemotherapy regimens, and that they
> had to receive prior platinum treatment. This study population does
> not have an unmet medical need. Trial 16 simply provides additional
> ZD1839 safety and efficacy information.
>
> Two hundred and nine patients comprised the intent-to-treat study
> population. As shown, 87 percent of the patients were asymptomatic or
> mildly symptomatic, that is, performance status 0 to 1. About
> two-thirds of patients had adenocarcinoma. The median and mean
> interval from diagnosis to trial 16 randomization was 12 and 16 months
> respectively, and 79 percent of patients had Stage 4 disease.
> Approximately half of all study patients were Caucasian, primarily
> from Europe but also from other centers worldwide, and half were
> Japanese.
>
> \[Slide\]
>
> This slide summarizes prior chemotherapy treatment of trial 16
> patients. As indicated on the slide, all patients had received a
> platinum drug. However, only 35 percent of patients had progressed on
> prior chemotherapy; 65 percent of patients had not progressed on prior
> chemotherapy.
>
> \[Slide\]
>
> The objective response rate, which was the primary efficacy endpoint
> of trial 16, is shown here. As indicated, there was 1 complete
> response and 38 partial responses among the 209 study patients, for an
> overall response rate of 19 percent.
>
> \[Slide\]
>
> Characteristics of responding patients are summarized on this slide.
> Twelve percent of male and 34 percent of female study patients had an
> objective response. Caucasian patients had an 11 percent response
> rate, while Japanese patients had a 27 percent response rate. The
> reason for this difference is not known. The 11 percent response rate
> in Caucasians is disturbing because, as stated previously, less
> refractory patients are expected to have higher response rates than
> more refractory patients. As we will see in the next slide, most
> Caucasian patients had not progressed on prior chemotherapy.
> Consequently, a higher response rate than was seen in trial 39 was
> expected.
>
> \[Slide\]
>
> This slide reviews the relationship between response rate and prior
> chemotherapy progression. Looking at Caucasian patients, there were 9
> responders from 62 patients who had never progressed on chemotherapy.
> This is an analogous population to what might have been treated in a
> first-line setting, and is a patient group most likely to respond to
> chemotherapy. The response rate of 15 percent is somewhat
> disappointing for Caucasian patients who had progressed on either
> first- or second-line treatment the response rate was 5 percent. For
> Japanese patients the response rates were 28 percent and 27 percent
> for patients who had not progressed or who had progressed on
> first-line treatment and, obviously, they are comparable.
>
> \[Slide\]
>
> I had planned to devote one slide to safety information but that has
> been adequately summarized by Dr. Sandler earlier today and I will
> only say that the FDA safety analysis confirms that ZD1839 is well
> tolerated, especially in the 250 mg per day dose.
>
> \[Slide\]
>
> To summarize efficacy data, the response rate was the primary efficacy
> endpoint for both trials. In trial 39 the response rate for doubly
> refractory or intolerant patients to a platinum drug and to docetaxel,
> the accelerated approval population was 10.1 percent. The 95 percent
> confidence interval was 5.6 percent and 16.3 percent. Trial 39
> patients less than doubly refractory had a 10.4 percent response rate.
> In trial 16 Caucasian patients who were refractory to most single
> chemotherapy regimens had a 10.8 percent response rate. Japanese
> patients had a 27.5 percent response rate.
>
> This response rate data from the pivotal clinical trial and from
> Caucasian patients in the supporting clinical trial does not fit the
> classic oncology model of less refractory patients having higher
> response rates than more refractory patients. There is no clear
> explanation for this finding. As previously mentioned, there is also
> no clear explanation for response rate differences for Caucasian and
> for Japanese patients.
>
> \[Slide\]
>
> Similar to concerns about response rates in relationship to
> refractoriness to prior chemotherapy, there are also concerns about
> the responding patient population in trial 39. As is evident on this
> slide, the responding patient population does not reflect a typical
> non-small cell lung cancer patient with metastatic disease, rather,
> the responding patient population is enriched for slowly growing
> cancers of low biologic aggressiveness.
>
> Evidence of the slowly growing nature of these cancers is the fact
> that the median time from cancer diagnosis to randomization in trial
> 39 was almost 20 months. Further, the large majority of responders had
> adenocarcinoma, the slowest growing of all lung cancer histologies.
> The low biologic aggressiveness of these cancers is evidenced from the
> fact that despite the long interval from diagnosis to randomization
> and the prior therapy with several chemotherapy regimens, 16 of the 22
> responding patients still had a baseline performance status of 0 or 1,
> indicating no symptoms or only mild symptoms by this measure.
>
> \[Slide\]
>
> Similar to problems in interpreting response rate data, there are
> problems in interpreting symptom improvement data. Foremost, the study
> was not blinded since there was no comparator regimen. It is probably
> impossible to assess symptom relief in such a setting. Further,
> patients were receiving concomitant medications while on study that
> might have contributed to symptom relief. Unfortunately, drug dose and
> schedule information was not collected so that it was impossible to
> judge the relative benefit of ZD1839 to symptom improvement.
>
> Finally, the relationship between treatment response and symptom
> improvement is also difficult to evaluate. Telling a patient that his
> or her cancer is shrinking is likely to make the patient feel better.
> Also, this type of analysis has the same flaws as does any other
> comparison between responders and non-responders.
>
> This concludes my presentation and I would like to call on Dr.
> Sridhara.
>
> **Statistical Review**
>
> DR. SRIDHARA: Thank you, Dr. Cohen, and thank you to the committee and
> everybody here.
>
> \[Slide\]
>
> I am here to present some of the major statistical concerns with this
> application. The registration trial 39 conducted in a third-line
> setting of non-small cell lung cancer patients was designed as a
> single-arm trial to eliminate a response of less than 5 percent. That
> is, even though the trial was randomized between 250 mg of ZD1839 and
> 500 mg of ZD1839, the trial was not sized to compare between the 2
> arms and, in fact, was sized to independently evaluate efficacy in the
> 2 ZD1839 treatment arms.
>
> Secondly, the patient population was heterogenous, as previously
> presented by Dr. Cohen, in that both second-line and third-line
> patients were included in the trial. Also, the sponsor specified 2
> primary efficacy endpoints, namely, objective tumor response and
> symptom improvement rate. The agency had clearly communicated to the
> sponsor, in June and August of 2001, that the Lung Cancer Subscale, or
> LCS, data will only be considered as supportive to the validity of the
> response rate for accelerated approval. When the sponsor proposed once
> again to retain symptom improvement rate as a coprimary endpoint, the
> agency left to the sponsor the burden of demonstrating that the
> symptom findings are credible in a single-arm study. The most critical
> issue is that there was no comparative control arm in this study.
>
> \[Slide\]
>
> The results of the study with respect to tumor response have been
> extensively discussed by Dr. Cohen. Just to recap, there were 139
> patients in the 250 mg and 500 mg ZD1839 arms who were refractory to 2
> chemotherapy regimens, and 14 of the 139 had partial responses. The 95
> percent confidence interval for the response rate of 10.1 percent was
> between 5.6 and 16.3.
>
> \[Slide\]
>
> The total of LCS score was the specified score to be evaluated for
> efficacy regarding symptom improvement. The 7 items included in this
> subscale were shortness of breath, losing weight, clarity in thinking,
> cough, good appetite, tightness in chest and breathing is easy. These
> were measured on a scale of 0-4, as given here, with 0 being not at
> all and 4 being very much. Note that the highlighted 4 items, namely,
> shortness of breath, losing weight, cough and tightness in chest are
> in reverse order. However, in the computation of total LCS score these
> 4 scores were inverted so that 0 meant worst symptom and a score of 4
> meant no symptom on all items. Thus, a total LCS score of 28 would be
> asymptomatic and a score of 0 would be symptomatic.
>
> \[Slide\]
>
> The sponsor defined a patient as symptomatic at baseline if the total
> LCS score was less than or equal to 24. For example, at baseline if 4
> of the 7 items were scored as 4 and the others as 0, as highlighted in
> yellow here, then the total baseline score would be 24. All patients
> who had less than or equal to a total LCS score of 24 at baseline were
> considered by the sponsor as symptomatic patients.
>
> \[Slide\]
>
> Improvement was defined by the sponsor as an increase in the score by
> at least 2 from baseline score for a duration of 28 days. For example,
> if the score increased by a score of 1 in 2 items, as in this
> illustration, then the patient is recorded to have improved in
> symptoms. That is, in this illustration an increase from a baseline
> score of 24 to 26 is considered as improvement. Please note that there
> is a ceiling effect on the maximum score of 28 that a patient can
> have.
>
> I would like to add another comment here regarding the reference that
> was brought up by the sponsor regarding the publication where a
> 2-point change was considered to be meaningful. This was based on a
> retrospective analysis and this was a hypothesis generating
> publication, and this was based on looking at the difference in scores
> from baseline to 12 weeks, and not the way it is done here , and also
> in a combined group of patients receiving 3 different treatment
> regimens. Thus, it was not compared to any control arm.
>
> \[Slide\]
>
> As per the sponsor definition of symptom improvement explained in the
> previous slides, in the combined 250 mg and 500 mg ZD1839 treated
> arms, there were 45 patients who were scored as having improvement in
> the LCS symptoms among the 139 third-line or double refractory
> patients.
>
> \[Slide\]
>
> This is an example of the LCS profile of a patient from the start of
> the treatment to 24 weeks. This example illustrates the difficulty in
> interpreting the total LCS score without a comparative control arm.
> This patient had a baseline score of 24. As seen in this graph, this
> particular patient did not have scores recorded between the weeks 1
> and 4. At 4 weeks an increase of 4 points was recorded to 28, which is
> the ceiling effect. Then, between 5 and 9 weeks, an increase of 2
> points from baseline was recorded, that is, a score of 26 for a period
> of 4 weeks, qualifying this patient to have symptom improvement
> although in later weeks there were some variations in these scores
> and, in fact, in this case a worsening of symptoms.
>
> \[Slide\]
>
> This is the same example as presented in the previous slide, except
> that the profile of each of the LCS scale over the same period of time
> is presented here. The 7 horizontal lines in this graph represent each
> of the 7 items in the LCS scale. The first line corresponds to
> shortness of breath; second, losing weight; third, thinking is clear;
> fourth, coughing; fifth, appetite; sixth, tightness in chest; and
> seventh, breathing is easy.
>
> In the previous slide we saw that improvement was recorded between 5
> and 9 weeks, which is the time period between the green and the red
> vertical lines in this slide. The improvement observed is basically in
> 1 or 2 items by a point. This illustrates that a 2-point change on a
> scale of 28 is difficult to interpret without a comparative non-ZD1839
> arm because of minor changes of a point in 1 or 2 items.
>
> \[Slide\]
>
> This slide illustrates the percentage of patients who were evaluated
> for symptom improvement at each of the time points starting from
> baseline. As seen here, 25 percent were lost by week 1, and about 25
> percent remained at 16 weeks. The attrition may be due to progression
> of disease. However, again, without a comparative arm it is not
> possible to comment on this attrition rate.
>
> \[Slide\]
>
> To summarize the critical issues in the registration trial 39, they
> are that the efficacy with respect to objective tumor response with
> ZD1839 could be as low as 5.6 percent. Symptom improvement is
> uninterpretable without control data. Symptom improvement is possibly
> confounded by concomitant medication effect and patient
> characteristics.
>
> \[Slide\]
>
> Approximately 4 weeks back the sponsor shared with the agency results
> of 2 well-conducted, double-blinded, placebo-controlled randomized
> Phase III studies in first-line non-small cell lung cancer patients.
> These trials are also referred to as INTACT trials 1 and 2. The agency
> expected these studies to be the confirmatory studies of the Phase II
> study 39 under review here.
>
> Study 14 had 3 treatment arms, gemcitabine, cisplatin plus 250 mg of
> ZD1839, gemcitabine plus cisplatin plus 500 mg of ZD1839 and
> gemcitabine plus cisplatin plus placebo. A total of 1093 patients were
> treated in the study and overall survival was the primary endpoint of
> the study.
>
> \[Slide\]
>
> The results of the overall survival analysis of this study are as
> presented in this graph. The green line represents the chemo plus
> placebo arm. The blue line represents the chemo plus 250 mg ZD1839
> arm, and the red line represents the chemo plus 500 mg ZD1839 arm.
> Although the difference between the ZD1839 arms and placebo were not
> statistically significant, the observed difference favored the
> chemotherapy plus placebo treated arm. That is, the green line is
> above the blue and red lines. The comparisons presented here were the
> protocol specified comparisons. At the time of these analyses, 70
> percent of the events had occurred and the survival data was mature
> for analysis.
>
> \[Slide\]
>
> Progression-free survival and response rates were 2 of many secondary
> endpoints studied in this trial. This graph represents the analysis of
> comparing progression-free survival of the 2 ZD1839 arms versus
> placebo. Again, the green line represents the placebo arm. The blue
> line represents the 250 mg arm and the red line represents the 500 mg
> arm. There is no apparent difference between the ZD1839 and placebo
> treated arms in this study.
>
> \[Slide\]
>
> This table gives the response rates in each of the 3 treatment arms
> and an estimate of the 1-year survival rate. The response rates ranged
> from 45 percent in the placebo arm to 50 percent in the 250 mg arm.
> Estimates of the 1-year survival rate range from 42 percent in the 500
> mg arm and 45 percent in the placebo arm.
>
> \[Slide\]
>
> The second randomized study in first-line non-small cell lung cancer
> patients was study 17 which had 3 treatment arms, Taxol plus
> carboplatin plus 250 mg of ZD1839; Taxol plus carboplatin plus 500 mg
> of ZD1839; and Taxol plus carboplatin plus placebo. A total of 1037
> patients were treated in this study and overall survival was again the
> primary endpoint of this study.
>
> \[Slide\]
>
> The results of the overall survival analyses of study 17 are as
> presented in this graph. Again, the green line represents the chemo
> plus placebo arm. The blue line represents the chemo plus 250 mg arm
> and the red line represents the chemo plus 500 mg arm. No differences
> were observed between the ZD1839 arms and placebo treated arms. Again,
> these were the protocol specified comparisons.
>
> \[Slide\]
>
> This graph represents the analysis of comparing progression-free
> survival of the ZD1839 treated arms versus placebo in study 17. The
> green line, again, is the placebo line; blue is 250 and red is the 500
> mg arm. There is no observed difference between the ZD1839 treated arm
> and placebo treated arm.
>
> \[Slide\]
>
> This table gives the response rates in each of the 3 treatment arms
> and an estimate of 1-year survival rate in study 17. The response
> rates range from 34 percent in the placebo arm to 35 percent in the
> 250 mg arm. Estimates of 1-year survival rate range from 38 percent in
> the 250 mg ZD1839 arm and 42 percent in the placebo treated arm.
>
> \[Slide\]
>
> In conclusion, the results of the 2 well-conducted, double-blinded,
> placebo-controlled randomized studies in over 2000 patients are as
> follows. In both the studies there was no statistically significant
> difference between ZD1839 treated arms and placebo treated arm with
> respect to overall survival. There appears to be no difference between
> the ZD1839 treated arm and the placebo arm with respect to secondary
> endpoints including response rate and time to progression in both the
> studies.
>
> Now Dr. Williams will summarize the FDA presentations. Thank you.
>
> **Summary**
>
> DR. WILLIAMS: Thank you, Dr. Sridhara.
>
> \[Slide\]
>
> Again, I will summarize the FDA findings with this slide, which I
> promise to return to. I must admit that we are following the
> presentation principle of repeating our main point here. AstraZeneca
> claims that ZD1839 provides symptom improvement in study 39, but FDA
> finds this claim is unconvincing without a control arm.
>
> FDA and AstraZeneca agree there is a 10 percent response rate in 139
> patients with refractory non-small cell lung cancer, and that there is
> no benefit of ZD1839 when added to chemotherapy in the first-line
> treatment of non-small cell lung cancer.
>
> \[Slide\]
>
> The last question, which would be the central question for our
> deliberations will be summarized on this slide. Again, you have seen
> this before and you will get a chance to answer this after lunch for
> yourselves.
>
> Can symptom improvement claims in this application be adequately
> assessed without a control arm? Given a finding of no clinical benefit
> from ZD1839 in large randomized trials in the first-line treatment
> setting of non-small cell lung cancer, is the 10 percent response rate
> in refractory non-small cell lung cancer reasonably likely to predict
> clinical benefit of ZD1839 in the treatment of lung cancer?
>
> Lastly, two points for discussion, first, thousands of patients have
> received ZD1839 for treatment use under an expanded access program.
> Please discuss how FDA should approach expanded access with ZD1839.
>
> Lastly, regardless of whether the application is approved at this
> time, additional clinical trials may be planned for ZD1839 in lung
> cancer. Please discuss your recommendations for trial design.
>
> That concludes the FDA presentation. As I understand it, we get to eat
> lunch before asking and answering questions.
>
> DR. PRZEPIORKA: Thank you, Dr. Williams. Yes, indeed, this will
> complete the presentations and the morning session. We will adjourn at
> this time until 1:10 p.m. and start with questions for both the
> company and the FDA prior to discussion of the questions. Thank you.
>
> \[Whereupon, at 12:25 p.m., the proceedings were adjourned, to resume
> at 1:20 p.m.\]
>
> A F T E R N O O N S E S S I O N
>
> **Questions from the Committee**
>
> DR. PRZEPIORKA: I would like to start the afternoon session by
> clarifying some ground rules for our discussion, if I may. This
> morning we had a presentation by the sponsor and a presentation by the
> FDA. This afternoon we will open the second session with questions
> from the committee to the sponsor and to the FDA. For the purposes of
> making transcription a little bit simple, I would ask that the members
> of the committee try to address their questions to a specific
> individual according to the list of speakers we were given, and if
> that individual cannot answer the question and needs to defer, please
> indicate verbally to whom you are deferring the question so that the
> transcriptionist knows who will be speaking.
>
> I will try to keep questions from the committee to the FDA or to the
> sponsor rather than having additional presentations made. So, when you
> are asked the question, please limit your answer to the question that
> has been asked. I will actually start, while people are still taking
> their seats, by asking the first question to Dr. Blackledge, please.
>
> The most obvious question that I can come up with was observing that
> the demographics of the individuals during the open public hearing did
> not match the demographics of non-small cell lung cancer in the
> country, I was wondering if there was additional information on the
> breakdown of the subgroups of adenocarcinoma regarding response rates
> and bronchoalveolar carcinomas specifically.
>
> DR. BLACKLEDGE: Thank you, Madam Chairman. It is certainly true that
> we saw a majority of women respond in our trials, but it wasn\'t only
> women who responded. Both men and women responded.
>
> I think it is important to remember that the situation with non-small
> cell lung cancer has changed dramatically over the past few years.
> Adenocarcinoma is now the most common subgroup of non-small cell lung
> cancer. I would like to ask Dr. Frances Shepherd to comment on the
> incidences of adenocarcinoma and its effect, if I may.
>
> DR. SHEPHERD: That is entirely true. It is Dr. Shepherd speaking.
> There has been a marked demographic shift over the last ten or more
> years so that adenocarcinoma now represent anywhere from 50 percent to
> two-thirds of lung cancer in the Western world.
>
> First of all, I think there is a lot of danger in doing a lot of
> sub-sub-subgroup analyses in this relatively small data set, but since
> it is being done we might as well carry on in that vein and I think
> that we should look very favorably on the fact that we have an agent
> that targets what is now the most common form of lung cancer in North
> America. I don\'t think that this should be looked on as a negative
> aspect of the results of the trial but, rather, a positive aspect.
>
> DR. PRZEPIORKA: The answer to the question there then is the response
> rate specifically in bronchoalveolar carcinoma?
>
> DR. BLACKLEDGE: Well, in our trials we didn\'t specifically break out
> bronchoalveolar carcinoma from adenocarcinoma so it is within that
> group.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Bruce Cheson. I don\'t think it matters who I address it
> to, Dr. Sandler or yourself. Based on the requirements for the
> interval since prior therapy and based on the fact that a number of
> patients improved symptomatically, what was the median amount of time
> since prior therapy, and how can we be assured that the fact that a
> lot of these patients felt better wasn\'t because they were recovering
> from the toxicities of their prior therapy?
>
> DR. BLACKLEDGE: I would like Dr. Kay to answer this question, please,
> who was the physician for trial 39.
>
> DR. KAY: Andrea Kay, AstraZeneca, trial physician. It is true that
> about a quarter of the patients who enrolled into the trial had a
> duration of less than 30 days from their last chemo dose but 75
> percent did not; 75 percent were greater than 30 days.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: One of the things we heard a lot of discussion about
> was the true eligibility for this study. As these inclusion criteria
> are listed, it seems possible that the sponsor may have interpreted
> these differently than the FDA did. As I read these, it says 2
> previous chemotherapy regimens must have included a platinum and
> docetaxel; that they must have progressed on therapy. But the FDA
> seems to have interpreted this to mean progressed on first-line or
> second-line therapy, and the sponsor seems to have interpreted this to
> mean progressed on some therapy and have had the first two. What I am
> interested in knowing is how was eligibility really decided during the
> course of the study?
>
> DR. BLACKLEDGE: Well, the precise words of the eligibility criteria
> were agreed between ourselves and the FDA. Now, the people who really
> had to deal with the eligibility criteria were the investigators and I
> would like to ask Dr. Natale to comment further on that because he,
> and other lung cancer investigators that we have here, had to
> interpret those data.
>
> DR. NATALE: Thank you. Dr. Ron Natale. Let\'s think for a moment about
> what I view as a very rigid definition by the FDA regarding patient
> eligibility and what it really means. It came as a surprise to all of
> us. Their definition, first of all, is that patients had to have
> progressed on a first-line platinum regimen. Those are the patients
> who don\'t respond to the treatment or have a short-lived response and
> progress during their 3 or 4 cycles of chemotherapy. Those patients
> rarely live long enough to receive a third-line treatment, number one,
> and, number two, there has never really been any proof that
> rechallenging those patients with platinum, patients who have
> responded then progressed 30, 60, 90 days later\--there is no evidence
> that they are platinum sensitive because the FDA has said patients who
> don\'t progress during treatment are, therefore, platinum sensitive.
> Yet, there is no data in the literature to support that. In fact, all
> physicians who care for cancer patients know that once you have used a
> platinum regimen up front it does not work subsequently.
>
> Point number two is that they then applied that definition to the
> second-line treatment which, in most cases, was second-line docetaxel.
> In second-line docetaxel if a patient progresses during the first,
> second or third cycle of treatment they rarely live long enough to go
> on to receive a third-line treatment. Remember, the goal of the study
> was to look at the efficacy of this agent in the third-line setting.
>
> So, again, they have given us a rather strange, very restrictive
> definition that does not apply. If we look at patients who received
> docetaxel in second-line trials, the ones that were reviewed by the
> FDA about two years ago, in Dr. Shepherd\'s trial, and we have Dr.
> Shepherd here fortunately to support this, there was only one
> responder in patients who were platinum refractory. This is
> second-line docetaxel. I think this again reflects the fact that this
> very restricted patient population does not respond to subsequent
> treatment. Some of them did respond to subsequent treatment with
> IRESSA. In fact, the response rate was 10.4 percent according to the
> FDA\'s calculation.
>
> In Dr. Facella\'s study we can\'t really tease out that information
> specifically but we do know that in Dr. Facella\'s study 25 percent of
> the patients had performance status of 2. None of them responded to
> second-line docetaxel.
>
> Finally, regardless of how many subsets you try to claim in this
> 200-and-something patient population, the response rate is always 10
> percent. So, these strained definitions of refractory, resistant and
> sensitive don\'t apply to a novel biologic agent.
>
> DR. CARPENTER: But what I am asking is this, as I read these inclusion
> criteria, it does not specifically state that they have to progress on
> first- or second-line therapy; it says failed therapy because of
> disease progression. What I am asking you is how were these things
> interpreted as the trial went on.
>
> DR. NATALE: Investigators who entered patients into the study, and we
> have several of the major accruers here including myself, we know that
> patients who had received a prior platinum regimen and then progressed
> at some time during or after the treatment, and then got a second-line
> therapy and progressed during or after the treatment were eligible for
> the study.
>
> DR. CARPENTER: Thank you.
>
> DR. PRZEPIORKA: Dr. Kelsen?
>
> DR. KELSEN: I have a question for Dr. Cohen. Can I talk to the FDA as
> well? So, the first question is for Dr. Cohen and then I think I have
> a question for the sponsor.
>
> You expressed concern about the fact that the response rate didn\'t
> seem to drop in patients who received more prior therapy or less prior
> therapy. I think this might follow-up on a comment we just heard. But
> this agent has a different mechanism of action so I, personally,
> didn\'t find that quite so troubling. I wonder if it isn\'t like
> hormonal therapy in women with breast tumors who may have had multiple
> prior chemotherapeutic regimens or only one or two prior
> chemotherapeutic regimens and still will have the same response rate.
>
> DR. COHEN: Well, I am not sure that you are correct in your response
> rates to hormonal therapy. It is my impression from the literature
> that the response rate to tamoxifen in the first-line setting is
> considerably higher than it is further down the road, approximately
> double.
>
> DR. KELSEN: So, your concern is that even though it is a novel\--
>
> DR. COHEN: And we reviewed glevac which is also a novel
> chemotherapeutic agent, molecularly targeted, and the response rate in
> the chronic phase of disease was significantly higher than it was in
> the accelerated phase or the blast crisis phase of disease. So, there
> you have a model where stage of disease appears to be important.
>
> DR. KELSEN: If I can follow-up, in summary then although it has a
> different mechanism of action, you are still expressing concerns as to
> the lack of an observed higher response rate in the less heavily
> pretreated patients?
>
> DR. COHEN: That is correct.
>
> DR. KELSEN: So, I have a second brief question for the sponsor.
> Looking at the first-line study, which I know you felt is not germane
> to this application but it certainly is an interesting although
> disappointing observation, I think we were all hoping to see a
> different outcome, what is your hypothesis as to why there was no
> benefit in either response rate, which was seen in this third-line
> therapy, or in survival in the first-line study? And what implications
> do you think that has for using this agent in combination with a
> cytotoxic drug?
>
> DR. BLACKLEDGE: I think there are a number of hypotheses and I will
> ask one of my colleagues to discuss that in a minute. I think the
> results of this trial, the INTACT program and, indeed, the results of
> other trials which have emerged recently have enormous implications
> for the use of these kinds of agents with cytotoxic chemotherapy. For
> whatever the reason is, and I don\'t think we fully understand it
> yet\--we certainly don\'t fully understand it yet, we are going to
> have to find new treatment paradigms, as Dr. Norton implied. But I
> know that Dr. Natale has some hypotheses, if you would like to go
> ahead.
>
> DR. NATALE: Thank you, Dr. Kelsen. It is an important question. I
> think there are two possible explanations or hypotheses. The first
> answer is that, unfortunately, in all of the clinical trials that have
> compared three drugs to two drugs, three agents to two agents in
> non-small cell lung cancer we have never been able to prove that the
> addition of a third agent impacted on any of the therapeutic outcome
> endpoints at all. So, I think if one takes the view that this is an
> agent that has a chemotherapy-like action and we just happen to know
> what the target is, then I think the answer is that three drugs are
> not better than two drugs, yes, once again in non-small cell lung
> cancer.
>
> I think we are also interested in this aspect because we all thought
> that the biological agents would be different, whether it was IRESSA,
> Avastin, SU54416 and even tamoxifen. Now we are beginning to generate
> the hypothesis, and you asked for one, that perhaps there is an
> adverse interaction between cytostatic biological agents and
> cycle-dependent cytotoxic agents so that they tend to perhaps cancel
> each other out when used in combination.
>
> I think one of the best pieces of evidence partially supporting that
> hypothesis are the results of the South West Oncology Group trial,
> presented at ASCA this past year, in which patients with breast cancer
> who were treated with chemotherapy plus tamoxifen had an inferior
> survival compared to patients who received chemotherapy followed by
> tamoxifen.
>
> DR. KELSEN: Thank you.
>
> DR. PRZEPIORKA: Dr. Pelusi?
>
> DR. PELUSI: My question is geared to either Dr. Blackledge or Dr.
> Cella. In terms of quality of life, which I know that we are all very
> much interested in, a question arises in terms of the other things
> that could influence quality of life, especially anemia. In this
> patient population with their previous treatment that is of great
> concern. Would we not have, or do you not have the data that would
> show us what was going on with hemoglobins that might affect fatigue,
> cognitive function or shortness of breath to go along with your
> quality of life data?
>
> DR. BLACKLEDGE: I will ask Dr. Cella to comment on the quality of life
> story generally. I wonder if Dr. Kay could actually comment
> specifically on the anemia.
>
> DR. PELUSI: And while Dr. Kay is coming up, if I could ask in terms of
> the epo if we know if they were started on that after their previous
> chemotherapy or if they were placed on it during?
>
> DR. KAY: Andrea Kay, trial 30 physician, AstraZeneca. We did not
> collect anemia specifically to look at it with regard to quality of
> life. We collected anemia in the safety data and, indeed, a very small
> proportion would be less than 5 percent. So, it is not one of the
> common AEs. Likewise, the need for blood transfusions was rare and the
> use erythropoietin was incredibly rare, again in less than 5 percent
> of the patients. So, we did not feel that that would strongly
> influence the outcomes in our questionnaire.
>
> DR. BLACKLEDGE: Perhaps Dr. Cella could comment more on the actual
> questionnaire itself.
>
> DR. CELLA: I am David Cella, from Northwestern University and a
> developer of the FACT instrument that was used in the trial.
>
> Thank you for your question. I will try to somewhat restrict my
> response. There is a lot I would like to say about the FACT but I will
> reserve that for the curiosity of the committee, if you are curious.
> As you know, the use of erythropoietin is not approved for people who
> are not getting chemotherapy so its use would be off-label. We heard
> it was very rare. So, that seems unlikely to be a major player in the
> story.
>
> In addition, we know from erythropoietin trials that selectively there
> is an improvement in fatigue relative to other symptoms and concerns,
> and we didn\'t see that here in this trial. The improvement in fatigue
> seemed comparable to the improvement in the other lung cancer-related
> symptoms. So, I don\'t think it is a major candidate for concern.
>
> DR. PRZEPIORKA: Thank you. Dr. Blayney?
>
> DR. BLAYNEY: Thank you. I have three questions directed toward the
> sponsor. First, Ron Natale implied in his presentation that the use of
> adjuvant medications decreased during time on trial. Dr. Cohen said
> that that information wasn\'t collected.
>
> Secondly, I am having trouble sorting out that this is really, truly a
> different study population, that the responders are different than the
> typical lung cancer patients whom we see, and perhaps some of that
> could be clarified. It seems to me there is confusion between the
> interval of the diagnosis and going on study and relapse and going on
> study. You have about two years of diagnosis that go on study, so if
> there is a number of patients who were metastatic when they went on
> study, if you could give us that number.
>
> Finally, in the safety data, how are we going to use this in patients
> who may have metastatic disease and compromised liver function and
> renal function?
>
> DR. BLACKLEDGE: Let me deal with your last question first and then I
> will ask Dr. Kay and, if necessary, Dr. Ochs, study physicians, to
> comment on your other points.
>
> We have looked at mild to moderate renal impairment and there is no
> evidence of any problems there. We have obviously not looked at it in
> severe liver impairment, but in the patients who have been treated in
> the trial program and in the expanded access program, patients with
> mild to moderate hepatic impairment have no evidence of any
> unfavorable interactions with IRESSA. I will hand it over to Dr. Ochs
> to talk about the symptoms.
>
> DR. OCHS: Dr. Ochs, AstraZeneca. With respect to the concomitant
> medications, the data that was previously presented to you was a
> comparison of the frequency of additional symptomatic care agents that
> were added to the patients comparing the symptomatic versus the
> non-symptomatic patients.
>
> At one time we had provided the FDA with data concerning those
> patients who had had a marked increase in a single symptom such that
> they had a 2-point out of a 4-point possible change in their scales.
> When you look at the concomitant medications looking at those, of
> those 31 patients that were identified, in my medical judgment
> reviewing the onset of the medication, the type of the medication, the
> duration of the symptom improvement, there were, at best, 5 patients
> for whom I could say that there was even a potential for some benefit
> for the supportive care medication.
>
> DR. BLAYNEY: Thank you. To the issue of duration of disease before
> going on study, it seems like if somebody had an operation, was
> disease-free for a long time and then relapsed quickly, got 2
> therapies and went on study, that patient is quite different than
> somebody who had 20 months of chemotherapy, 10 months of a platinum
> regimen and 10 months of docetaxel regimen and then went on your
> study. Those are quite different populations and I can\'t tell who
> your responders are. Could you help me?
>
> DR. BLACKLEDGE: I will ask Dr. Ochs to comment on that.
>
> DR. OCHS: Twenty-five percent of the patients who were enrolled in
> this trial had Stage 1 to 3A disease at the time of their original
> diagnosis. One of the things we did look at, and compared it
> predominantly by histology\--because a statement has been made that
> adenocarcinomas are slower growing which is difficult to understand
> since adenocarcinoma and squamous-cell have exactly the same prognosis
> in the advanced-disease setting\--in fact, what happened was that the
> adenocarcinoma patients did have the longest interval between the time
> of diagnosis to when they came on the IRESSA study but it largely
> accounted for the interval between when they had their diagnosis of
> lower-stage disease until they developed advanced disease.
>
> When you compare the interval of time on therapy with the first
> therapy, the second therapy and the third therapy, there really is no
> difference. I might point out that the second patient that Dr. Natale
> showed, the patient who had 6 cm of disease with other metastatic
> sites with unmeasurable disease, that PS 2 patient was the longest
> patient on this study who is 50 months from diagnosis to the time she
> came on study, and that patient obviously had a significant symptom
> improvement and improvement in performance status. Again if you
> compare the numbers, they are fairly similar.

DR. PRZEPIORKA: Dr. Fleming?

> DR. FLEMING: I have a question for Dr. Cohen and Dr. Sridhara to make
> sure I am interpreting the data correctly. We have had a lot of
> discussion about whether response rates are independent of the number
> of prior regimens where you had progression. I am using as a source of
> my information the FDA document, page 66, Table 27. In that document
> it is indicated that in the 16 trial, of the 39 responses that
> occurred, 29 occurred in the cohort where there had been no
> progression on chemotherapy.
>
> What is important is to have the denominators. So, using the table on
> page 63, it appears that in the cohort where there was no progression
> on chemotherapy there were 20 responders in 136 for a response rate of
> 21.3 percent. In those that progressed only on first-line and only on
> second-line response rates respectively were 6/38 for 16 percent and
> 3/18 for 17 percent.
>
> But the group of particular interest, those people that progressed on
> both first- and second-line chemotherapy, there were 17 of those
> patients of which only 1 responded for a 5 percent response rate. This
> is including the Japanese cohort that has a higher response rate. Am I
> interpreting these numbers correctly?
>
> DR. COHEN: Yes, I think so. I have the same table that you are
> referring to and I think you are right.
>
> DR. FLEMING: So, in essence, it says that the most relevant people
> from the 16 trial are the 17 people who progressed on both first- and
> second-line. There are 17 even if you include the Japanese cohort;
> only 1 responded. You have only a 5.6 percent response rate. So, this
> study would seem to say the response rate is very unimpressive in this
> third-line cohort if you focus on the 17 most relevant people from
> study 16.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: Just a clarification because of the implication of the
> quality of life. When was the first time point in the Phase II trial
> for response evaluation? Was it at 4 weeks or 8 weeks?
>
> DR. BLACKLEDGE: It was at 4 weeks, and the radiographic evaluation was
> carried out after the patients had filled in the quality of life form
> on that day. So, the patients did not know whether they had responded
> or not when they filled in that quality of life form.
>
> DR. PRZEPIORKA: Dr. Varricchio?
>
> DR. VARRICCHIO: For the statisticians involved in this, I am curious
> to know, the sponsor said there was 80 percent compliance with this
> trial, but they didn\'t state how compliance was defined. But, then,
> when we had the FDA presentation it looked like 25 percent persisted
> to the end of the trial. I am curious about the attrition and how were
> the missing data points handled in the statistical analysis,
> especially for the symptom management part.
>
> DR. BLACKLEDGE: Perhaps I can make this clear. Of the possible forms
> that could have been filled in, 85 percent were. Now, as it was made
> plain earlier, once a patient had progressed, once they had achieved
> the endpoint of the trial, they no longer filled their forms in and,
> therefore, the numbers naturally fell at the same rate as we saw
> patients failing therapy. So, we saw the median duration of response
> which actually correlates very tightly to the number of forms being
> filled in at any one time.
>
> DR. VARRICCHIO: I am still concerned about what you considered the
> endpoint then? Where was the comparison point? Because if you are
> persisting to those 25 percent that made it to the end, those are
> probably the best patients. The ones who fell out sooner because of
> recurrence, what happened to their data?
>
> DR. BLACKLEDGE: I would like Dr. Cella to comment on this. He devised
> the score and helped to set us up.
>
> DR. CELLA: David Cella, from Northwestern. If I could just clarify why
> there is the disparity that you pointed out, Dr. Sridhara presented a
> slide that showed the proportion of patients who from the point of
> entry continued to produce data. She mentioned it but it wasn\'t
> particularly highlighted. That excluded from the numerator but
> included in the denominator anybody who didn\'t complete the form
> because they were off study. The purpose of this trial was to evaluate
> the symptom response to being on IRESSA. So, by protocol design that
> was worked out between the company and the FDA, patients, when they
> progressed, were taken off study, which included not performing any
> more quality of life evaluations. So, the 84 percent number, the
> compliance number, is the proportion of people who had expected\--the
> way it is typically done in the field, the proportion of expected
> evaluations that were, in fact, received. So, 84 percent of the
> expected evaluations by protocol were received. That is not the 25
> percent. That is overall across the duration of the study.
>
> I asked for a very conservative sensitivity analysis to be done,
> imputing for all those 16 percent of missing data elements a zero
> score, meaning the worst possible score in the LCS which virtually no
> patient ever provides; it rarely happens. We computed that and the
> benefit remains among the responding patients. You continue to have an
> average improvement of over 2 points in the responding patients.
>
> DR. VARRICCHIO: Before you leave, just to clarify that in the field
> what is frequently done is to follow patients for at least 30 days
> after discontinuing medication, and I just wanted to clarify that
> these patients did not have anything further done after discontinuing
> medication so there was no follow-up for 30 days?
>
> DR. CELLO: There was no follow-up for 30 days. There isn\'t a standard
> approach to this. The protocol called for final assessment at
> discontinuation of drug.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: You raised a very key point. Essentially what we are
> hearing is that the analyses that are being presented to us are what
> is the symptom relief conditionally given that you haven\'t
> progressed, which really isn\'t a fully interpretable result. It
> doesn\'t really maintain an intention-to-treat type of analysis. Those
> people who tend to do more poorly are systematically pulled out. So,
> as Dr. Sridhara has pointed out, there is very significant
> \"missingness\" here. You have 25 percent missing. You have 50
> percent, I think you said, missing by 8 weeks. Part of that missing is
> due to progression so we get a result that is conditional. Given that
> you haven\'t had a downhill course in progression, what are your
> symptom results? And, that is a very biased analysis for the entire
> cohort.
>
> Secondly, what we just heard was imputing on the 16 percent. That
> wasn\'t imputing on those that progressed; that was imputing on those
> that hadn\'t progressed but had missing information. This is a very
> significant amount of \"missingness\" and it is not unrelated to the
> number of factors that the FDA had raised that raise serious concerns
> about interpreting the symptom data.
>
> DR. PRZEPIORKA: Dr. Brawley?
>
> DR. BRAWLEY: A couple of questions. The symptom improvement LCS score
> that the FDA presented, they had a summary score there and some of the
> sums don\'t quite make sense to me. Is it possible that we could just
> go through it for a second? For example, you could have a summary
> score from the 7 things and 4 was very much. This is page 2 from the
> FDA presentation. If you said I have been coughing, you scored that at
> zero for not at all, which to me would be a very positive thing. But
> if you said\--help me figure this out. It seems like you would score
> zero for some very positive things and 4 for some very negative
> things.
>
> DR. SRIDHARA: Can I answer that? I think I mentioned that, you know,
> of those 7 items, 4 of them as you read them, yes, you are right, zero
> means that there are no symptoms and 4 means that they had the
> symptom. But for those 4 items, they were inverted when computing the
> total LCS score. So, for all 7 of them zero meant no symptoms.
>
> DR. PRZEPIORKA: Dr. Brawley, do you have any other questions?
>
> DR. BRAWLEY: Just one more. Of the 40 percent who had an improvement
> of 1 or greater in 6 to 7 items, I am wondering how many were in that
> group that was in the 25 percent who got treated on this drug within
> 30 days of finishing treatment on another drug.
>
> DR. BLACKLEDGE: I don\'t believe we carried out that precise analysis.
>
> DR. BRAWLEY: What I am getting is that in screening we have this
> principle of bias, which is actually what Dr. Fleming and Dr.
> Varricchio have been talking about and simply stated it is that people
> who do well tend to do very well. I am concerned that there may be a
> selection bias in responders for people who have\--I hate to use the
> word subset\--lung cancer that tend to do very well even without
> treatment.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: I have a question about the INTACT studies, even though
> you didn\'t present a lot of information on them. It has to do with
> whether you have any information from them whatsoever about quality of
> life or symptom improvement.
>
> DR. BLACKLEDGE: We have only received these data very recently and we
> have analyzed the objective endpoints. We have not yet analyzed fully
> the other endpoints.
>
> DR. GEORGE: But you are planning on this? I wasn\'t familiar with
> these studies until I saw these disappointing results with the primary
> endpoints, but you do have a plan for analysis?
>
> DR. BLACKLEDGE: We do plan to explore these studies fully, firstly, to
> see if we can understand why we got the results we have.
>
> DR. GEORGE: I raise it just because that is potentially a benefit that
> we haven\'t heard anything about. We don\'t know one way or the other
> but it is just because it is too early? Is that it?
>
> DR. BLACKLEDGE: Yes.
>
> DR. PRZEPIORKA: Dr. Taylor?
>
> DR. TAYLOR: I actually have three questions. Back to his on the INTACT
> trial, was the IRESSA given always concomitantly with the chemotherapy
> or was chemo given and then dropped and then IRESSA given?
>
> DR. BLACKLEDGE: It was given concomitantly and continued for as long
> as the patients were showing benefit.
>
> DR. TAYLOR: But both were continued indefinitely?
>
> DR. BLACKLEDGE: No, the chemotherapy was limited to a maximum of 6
> courses.
>
> DR. TAYLOR: Secondly on the quality of life, you talked about the
> anemia; it did not get worse. Do we know did the hemoglobin get better
> because they were no longer taking chemotherapy, and would that be a
> reason they felt better?
>
> DR. BLACKLEDGE: We saw no major changes in any of the hematological
> parameters in trial 39.
>
> DR. TAYLOR: The third one, I was struck by the number of non-smokers
> who presented this morning. Do we have any data on responses in
> smokers versus non-smokers?
>
> DR. BLACKLEDGE: Could I ask Dr. Kay to comment on that?
>
> DR. KAY: Andrea Kay, AstraZeneca, trial 39 physician. Overall, 41
> percent of the patients enrolled in the trial were smokers in the past
> or currently. We did not distinguish between the two of them. Indeed,
> the response rate remains the same; the tumor response rate and the
> symptom response rate remains the same whether they were non-smokers
> or classified as smokers.
>
> DR. BRAWLEY: I have a quick follow-up. Is there any work ongoing to
> try to define the subset of individuals with cancer who would respond
> to this drug? Quite honestly, when you just say non-small cell lung
> cancer or even adenocarcinoma you are probably talking about several
> different diseases that you are treating.
>
> DR. BLACKLEDGE: Yes, I think that you probably are. I think you need
> to remember that from the findings of trial 39 it is about 40 percent
> of the patients who get some benefit. That is, clearly, a very clear
> 10 percent who get a response and symptom-related response. We are
> looking at trying to identify whether or not there is a specific
> subset of patients who will respond. I don\'t believe that we can do
> it histologically at the moment. We are looking at EGFR expression. I
> personally believe it is going to be something more subtle than that.
> For example, we are carrying out gene array studies in some of our
> ongoing trials to try to identify patients more or less likely to
> respond. But I think the important thing from the patient\'s point of
> view is that 40 percent of them are going to gain some benefit from
> IRESSA.
>
> DR. PRZEPIORKA: Dr. Martino?
>
> DR. MARTINO: Thank you. I have several questions, namely things that I
> need to understand here. Can someone tell me what the actual time to
> response was in measurable patients? In other words, I know that you
> looked at 28 days and then you looked again I believe a month later.
> When did most responses demonstrate themselves?
>
> DR. BLACKLEDGE: Eighty-five percent of the responses had occurred at
> the one-month radiographic assessment.
>
> DR. MARTINO: The next question I have relates to when I look at this
> data the impression that I get is that this is not a drug that works
> often. In fact, most of the time, overwhelmingly, it does not work.
> There are a couple of subsets that you have alluded to that would
> imply that perhaps it is a better drug in some, and those subsets, as
> I see them, are women and the Japanese. Now, I have yet to hear a
> reasonable or intelligent explanation as to why that should be the
> case, and there may be one. But if there is, I would very much like to
> hear it because if I were a Western male with this disease I am not
> sure that for a response rate of less than 5 percent I would
> volunteer. So, I am trying to figure out what is there about either
> being Japanese or being female that may be different and, therefore,
> meaningful so that I don\'t sort of group all of them within this
> fairly low response rate.
>
> DR. BLACKLEDGE: Well, we obviously looked very carefully at the
> striking Japanese results. A response rate of 27 percent is clearly
> higher than we have seen consistently across the rest of our trial
> program. We can actually explain much of the difference in terms of
> the baseline characteristics of the patients who were entered in
> Japan. There were more women. They had better performance status and
> there were more patients with adenocarcinoma. All of these factors
> contributed, we believe, to this favorable response rate.
>
> If we put those into a multivariate analysis, the actual difference
> between the Japanese and the rest of the world actually loses
> statistical significance. There is still a trend which we cannot
> explain, but it loses statistical significance when you take into
> account known favorable baseline prognostic factors.
>
> DR. MARTINO: Can you deal with the issue of the female gender?
>
> DR. BLACKLEDGE: I can\'t, other than to say that women are very lucky
> in this situation.
>
> DR. MARTINO: Well, maybe so but it does not speak well for the men.
> One additional issue that I need to understand relates to this quality
> of life measure. It is a lovely scale in the sense that it is simple
> and there are questions that one can answer, but I am trying to figure
> out in my own mind what does it actually mean clinically when a
> 2-point difference is noted and now someone gets excited over that? I
> need one of the clinicians to help me understand how much improvement
> in practicality does this mean. I ask this question with full respect
> to all of those predominantly women, but gentlemen too, who also got
> up this morning and showed us that in their own minds there appeared
> to be some dramatic difference. I am grateful for their experience but
> I am not sure that 2 points means very much. I need someone to help me
> understand how properly to interpret that.
>
> DR. BLACKLEDGE: We will do that. I think it is important to stress
> that the majority of the patients who gained benefit had a much
> greater than 2-point increase. I mean, the responders had a greater
> than 4-point increase, really quite a dramatic response.
>
> I think it is also important to remember that as part of accelerated
> approval we want this score to be robust enough to be linked to
> response, but not to prove definitively that symptom control is there.
> If that was the case, then I think we should be looking at full
> approval. So, we need to have enough confidence, and we will show you
> some of the sensitivity analyses, that there is a probable predictive
> linkage here.
>
> DR. MARTINO: And maybe even at 4 points someone needs to help me
> understand how much does that really mean because I am thinking this
> is on a scale of 28, and 4 out of 28, gee, that doesn\'t sound
> terribly exciting to me. So, someone help me there.
>
> DR. CELLO: It is my pleasure. Can I start with the ECOG slides first?
>
> Let me try to explain to you from my perspective, I am a
> psychometrician; I developed the questionnaire and I can speak to
> that. I also am a clinician. I work with cancer patients and I will
> also try to speak to that. But if I fall short I am sure Dr. Natale
> will chime in. I am David Cello, from Northwestern University.
>
> First, let me just provide some background about how the 2-point
> change was developed. It goes back to the original development of the
> questionnaire in which we asked 15 patients and 5 experts what kinds
> of questions we should be asking. Then we went on to test that with 30
> more patients and then again with 90 patients, separate from the
> previous 45. In each of those testings we would say are you sure we
> are asking the right questions and we would refine those questions.
> So, we are quite confident, from a thorough preliminary set of
> exercises, that we have the right mix of questions in the
> questionnaire.
>
> Then, in order to be efficient and not have 30 or more endpoints,
> because there are more than 30 questions in the questionnaire, we have
> to decide how to aggregate those questions, and we need to do it
> intelligently in a way that can be justified empirically.
>
> So, the Lung Cancer Subscale which was selected, those seven questions
> as the primary endpoint in this trial, we had studied over the
> previous ten years and determined, first in the initial validation
> paper in [Lung Cancer]{.underline}, in 1995, that two to three points
> was about the magnitude of difference that we saw between patients
> with performance status 0 versus performance status 1 versus
> performance status 2. We then went on to confirm that\--rather than,
> as Dr. Sridhara had mentioned to hypothesis generate, we confirmed
> that in trial 5592, and I will show you that in a moment.
>
> ECOG study 5592, conducted in the mid-\'90s, was a 3-arm randomized
> trial of platinum etoposide versus standard dose Taxol with cisplatin
> versus high dose Taxol with cisplatin with growth factor rescue, all
> patients getting chemotherapy. We wanted to determine from that trial,
> with the original data from our early validation studies that had
> previously been published, could we support these differences that we
> were seeing between patients with, say, 0 performance status and 1
> performance status. We also wanted to see if we could divide patients
> into those that had more than 5 percent weight loss or less than 5
> percent weight loss which, as you know, is another important clinical
> indicator in lung cancer medicine.
>
> \[Slide\]
>
> So, what we did, we divided groups into patients according to their
> ECOG performance status to determine what is a clinically meaningful
> change for dividing up patient groups and then for classifying
> individual patients. We started by first using a separate trial, this
> ECOG 5592, and we wanted to determine what was clinically meaningful
> and we anchored to various clinical differences and changes.
>
> The differences, the two lower bullets, ECOG performance status and
> weight loss simply divided the patients at baseline into those who
> were 0 versus those that were 1. The difference between the 0\'s and
> the 1\'s was 2.5 points. We divided patients who had more than 5
> percent weight loss versus those that had less than 5 percent weight
> loss, again a difference between 2 and 3 points.
>
> \[Slide\]
>
> Then we went on to look at the change score in the LCS, the seven
> questions, based on this trial as to whether patients were
> responders\--these are data at 12 weeks; stable disease or progressive
> disease. Lo and behold, we see that same number, 2.5 points, which is
> the magnitude of improvement which, I might add, in trial 39 is twice
> that, the reason being, as was mentioned earlier, this is cytotoxic
> chemotherapy so even though there is some symptomatic benefit in
> responding patients, the side effects of the chemotherapy are driving
> down the score presumably. But we have that 2.5 point difference
> again.
>
> \[Slide\]
>
> So, we are settling in on these 2 points. Now we divided patients into
> those who progressed early versus those who progressed later and the
> later progressors at 12 weeks, forecasting the fact that they would do
> better over time, and they had 2-point improvements.
>
> We put all this together, along with some other distribution-based
> statistics looking at the standard deviation of the spread of scores
> in a population at baseline and in an unchanging population, and the
> standard error measurement, all of which settled by currently accepted
> criteria for clinical significance in the neighborhood of 2 to 3
> points.
>
> So, when I was asked by the sponsor what number I would use in a
> prospective analysis plan, which is what they wrote, I said either 2
> or 3 points. They selected 2. As you heard, had they selected 3 the
> results would be virtually identical because almost all of the
> improvements were beyond 2 points.
>
> I just want to make one other comment about that selection of 2
> because it is true that one can look at that list of 7 questions and
> 28 possible points and one would wonder in a given patient, as
> illustrated in the earlier presentation by Dr. Sridhara\--here is
> somebody whose score was up 2 point, does that really mean something?
> Well, I am quite confident that a group of people, as actually
> illustrated on page 61 in the FDA briefing document where they compare
> in this trial performance status 0 to 1 to 2 and, lo and behold, the
> median LCS difference is 2 points between each group. I am confident
> that in group comparisons 2 points is a very solid number for
> differentiating clinically meaningful groups.
>
> Then the question is can you reasonably classify people as changed if
> they move 2 points? You will make classification errors no matter
> where you set that number. My goal is to try to set that number at the
> bar where you minimize the number of classification errors. So, some
> people who posted a 2-point change will truly not have changed. Others
> who posted a 1-point change will truly have changed. That is inherent
> in classification in any diagnostic test when you look at sensitivity
> and specificity. So, we tried to maximize the sensitivity and
> specificity, if you will, and again that number is between 2 and 3
> points, and we have solid data to show that.
>
> \[Slide\]
>
> Now if I could show you from trial 39, if you wanted to set the bar
> higher and you wanted to move it all the way to 7 points, the
> conclusions of the trial where there is meaningful benefit in
> responding patients remains the case. The number would lower to
> somewhere in the 10-15 percent range. So, if your preference is to
> make what I consider to be more misclassification errors in the
> direction of assigning people as unchanged because they didn\'t change
> enough for your criterion, you would still have a 10-15 percent group
> of patients who are answering better than 1 full point on this 4-point
> scale, better or improved; they are saying they are getting better on
> every symptom to a meaningful degree in each and every one of the 7.
> So, this gives you an overview of what would be across the group
> improvement rate.
>
> \[Slide\]
>
> If you decided that you wanted to go to 4 points, which is what you
> had suggested, that would change the 39 percent LCS improvement rate
> down to 29 percent, still meaningful improvement if you changed the
> number to 4, requiring that it be repeated at 4 weeks without a
> significant drop.
>
> This looks at it by response criteria so that if your number was 4,
> over here, which is the number you asked about, you still would have
> more patients, CR\'s and PR\'s, showing symptom response compared to
> the stable disease patients and far more than the progressive disease
> patients.
>
> If I could make one other comment to Dr. Fleming\'s point because you
> raised a significant concern about the data overall, it is that I
> think that there is quite a bit of protection in the concern about
> missing data when you consider that this form of classification
> analysis, which is driven by current state of the measurement science
> as well as FDA direction\--this current approach to analysis of
> classifying patients as improved or not actually does count everyone
> in the denominator in that intent-to-treat sense because if you don\'t
> provide data, you are counted as a non-improver. So, these are
> proportions of the overall population and I think there is some
> protection there. Thank you.
>
> DR. PRZEPIORKA: Dr. Cello, before you leave, has this scale ever been
> used in a randomized trial of lung cancer where one arm was either
> placebo or best supportive care? If so, what happened to the scores in
> that arm?
>
> DR. CELLO: The answer is no. As you know, there are precious few
> trials in lung cancer, particularly in the U.S., where there is a
> placebo or best supportive care arm. So, the answer is no.
>
> DR. PRZEPIORKA: Dr. Reaman?
>
> DR. REAMAN: Just a question in the follow-up to the comments of Dr.
> Shepherd about this agent being particularly exciting in the
> histologic subtype of adenocarcinoma, are there any data to suggest
> differential expression of the EGF receptor in adenocarcinoma, and
> particularly in the patients entered on this trial?
>
> DR. BLACKLEDGE: I will ask Dr. Averbuch to comment on that.
>
> DR. AVERBUCH: Steve Averbuch, clinical research, AstraZeneca. As was
> mentioned earlier, EGFR is expressed across all the histological
> subtypes of non-small cell lung cancer. In fact, the over-expression
> is more frequent in squamous cell carcinoma, but it does still occur
> in adenocarcinoma as well.
>
> DR. REAMAN: But in the individual patients who responded was there any
> correlation with EGF receptor expression?
>
> DR. AVERBUCH: As agreed with the FDA and as of great interest to all
> of us, the analysis of EGFR was identified as an exploratory endpoint.
> Now, that has proven to be extremely difficult in the absence of
> validated standardized assays. So we are currently working with
> collaborators to get those assays standardized. We have collected
> samples, about 40 percent of patients, and we are currently trying to
> establish those assays so that that analysis can be done. So I think
> there will be an answer forthcoming.
>
> DR. REAMAN: Do you have any information on gender relationship with
> pharmacokinetics or pharmacodynamics of this agent?
>
> DR. BLACKLEDGE: We have looked carefully at that and there are no
> gender relationships.
>
> DR. PRZEPIORKA: Dr. Varricchio?
>
> DR. VARRICCHIO: I think we are all kind of going around the same
> question. It is impressive that when it works, it really works and
> when it doesn\'t, it doesn\'t, and trying to see if we can get our
> thinking around what is it about those people in which it worked that
> made them different from the ones where it didn\'t. I guess I am just
> kind of making a request that you mine your data to see if you can
> find some kind of profile that would predict in which patients this is
> likely to work if it goes forward. It seems it is an \"all or
> nothing\" almost.
>
> DR. BLACKLEDGE: I take your point about that. We believe it is more
> than an \"all or nothing\" because we have 40 percent of patients who
> have either partial response or stable disease, and 40 percent of
> patients who show these quite striking differences in their Lung
> Cancer Subscale. But there is a group of patients who are exquisitely
> sensitive, I agree. And, there is a further group of patients who gain
> some benefit, and about 50 percent of patients who really have no
> benefit. That is very similar to what we see with many other
> non-cytotoxic agents. Those are roughly the data you see with
> tamoxifen, 10-15 percent good response, stable disease in about 30
> percent and progression in the rest. It is actually what you see with
> glevac. If you look at GIST tumors which express C-KIT but do not have
> mutations, the response rate in those patients is 10 percent. A
> further 30 percent benefit and the rest do not benefit.
>
> Something is starting to come out with non-mutated receptors and these
> inhibitors of these receptors, and it looks as if it is something like
> that. No one yet knows why it is. We have over 100 collaborations with
> laboratories worldwide looking specifically at trying to identify
> these but at the present time I am afraid we can\'t give more guidance
> than a pathological subtype.
>
> DR. PRZEPIORKA: Dr. Kelsen?
>
> DR. KELSEN: Sort of following on that and Dr. Taylor\'s initial
> question about the INTACT trial, if I understand your answer
> correctly, in the first-line randomized study there was a period of
> time in which patients were getting this drug without receiving
> chemotherapy. That is, there was a maximum of 6 months of
> chemotherapy. Were responding or stable patients then continued
> indefinitely on IRESSA?
>
> DR. BLACKLEDGE: Well, they continued for as long as there was no
> evidence of progression.
>
> DR. KELSEN: Yes, I understand that. So, as long as they were having
> benefit they were continued. The placebo patients presumably received
> placebo indefinitely until they progressed?
>
> DR. BLACKLEDGE: That is correct.
>
> DR. KELSEN: Have you looked or do you plan to look at outcome from the
> moment that chemotherapy stopped, or do you have any data you could
> tell us today?
>
> DR. BLACKLEDGE: Well, I think you actually saw some data in the time
> to progression slide in one of the trials that was shown by the FDA
> this morning. If you actually look at that, the curves actually cross
> and both the 250 arm and the 500 arm start to separate from the
> placebo arm, which is suggestive but not proving a maintenance effect.
>
> DR. KELSEN: When I looked at the data for survival, they looked
> awfully tight.
>
> DR. BLACKLEDGE: Well, I agree.
>
> DR. KELSEN: Could you show us those slides again just to refresh my
> memory?
>
> \[Slide\]
>
> DR. BLACKLEDGE: There is a small amount of separation but I believe
> that if you are going to do a maintenance trial you should do a
> maintenance trial because you may well have developed resistance in
> combination with chemotherapy during that first 90 days or so. So, I
> think whilst these data might be suggestive that there might be some
> kind of effect there, I believe that you actually have to do a
> prospective trial to determine the value of IRESSA in that situation.
>
> DR. PRZEPIORKA: Mr. Simon?
>
> MR. SIMON: I direct mine to Dr. Cohen, FDA. You mentioned with regard
> to trial 39 that 66 percent of the patients had adenocarcinoma,
> slow-growing cancer. I believe the sponsor may have addressed parts of
> that but could you address why that is so significant with regard to
> that trial?
>
> DR. COHEN: Well, I think the major issue was time from initial
> diagnosis to time to randomization for IRESSA. The principle point
> that I wanted to make was that this was a selected population, that
> this was not the typical lung cancer population that most of us see
> who present with metastatic disease and die quickly.
>
> There is considerable overlap in doubling times between histologies.
> If one looks overall, adenocarcinoma tends to be the slowest, but
> there are exceptions and some adenocarcinomas are fast growing and
> some adenocarcinomas are aggressive. But in this particular study it
> appeared that the patient population selected was those with the
> slow-growing tumors that were less aggressive based on their
> maintenance of performance status.
>
> MR. SIMON: Did the results in those that did not have adenocarcinoma,
> did they differ from them?
>
> DR. COHEN: The numbers were very low. We are only talking about 22
> responders total and the majority of them were adenocarcinomas so that
> the numbers of other histologies were very small.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Just a couple of minor questions. First of all, in many
> diseases females do better than men. If you look at myeloma or other
> diseases, that is a fairly consistent observation amongst the number
> of tumors. What intrigues me a little more is the Japanese situation,
> which would lead to a suggestion to look at the pharmacogenomics,
> which hasn\'t been mentioned. Is there some difference in metabolism
> of the product whether it be women or whether it be a cultural thing?
>
> My question is I have been involved in designing questionnaires and
> questions and exams for a long time, and maybe you went over this but
> when you have questions that are backwards that may tend to confuse
> people and they put the wrong answer down. Was there some sort of
> protection? You know, when one is positive and is on the right and the
> other is negative and is on the right, is there some protection
> against the patient putting the wrong answer there because they
> thought everything\--like, I do that on all kinds of forms and I find
> I did the wrong thing and, you know, it gets you into problems when
> you are trying to get over the border?
>
> \[Laughter\]
>
> DR. CELLO: David Cello. You might not like my response, Dr. Cheson,
> because the reason we do that is that it actually is one of the
> principal teaching points of creating questionnaires, which is that
> the best way to keep people paying attention and not doing \"I\'m in a
> hurry doctor routine\" in running down a questionnaire is to mix
> things up a little bit so people actually have to read the questions.
> So, reversing the order, if you will, reversing the frame positive and
> negative, sticks people on task more. It doesn\'t allow somebody to
> say, \"oh, I get it, you are asking about a lot of negative things;
> I\'m doing fine so I\'m going to say a bunch of zeros,\" which is a
> problem that some instruments have. So, this is a protection against
> that. We can recheck that after we have the data through a measurement
> model using item response theory where we can determine whether any
> individual question misperform or whether people misperform on those
> questions. So, yes, there are protections.
>
> DR. CHESON: I am not concerned about the two ends of the spectrum. I
> am more concerned about the ones in the middle obviously. Obviously, I
> am not an expert in this field so I don\'t know how you measure
> whether there is variability or not, but do you really instruct them
> to be careful that some of these are backwards, or do you make sure
> they read them? It is just a minor point of concern.
>
> DR. CELLO: People are asked to read every question carefully. You
> can\'t guaranty that people won\'t do that. Like I say, this is a
> protection against the most common response bias that people show.
>
> DR. CHESON: Thank you.
>
> DR. PRZEPIORKA: Dr. Blayney?
>
> DR. BLAYNEY: You mentioned that the median time to response was 4
> weeks. Am I remembering that correctly?
>
> DR. BLACKLEDGE: Yes, nearly 80 percent of the patients had shown their
> initial x-ray response at 4 weeks.
>
> DR. BLAYNEY: So, what is the last responder?
>
> DR. BLACKLEDGE: The last responder that we saw was at 16 weeks.
>
> DR. BLAYNEY: Sixteen weeks?
>
> DR. BLACKLEDGE: Yes, but in the vast majority the response had
> occurred within the first 4 weeks.
>
> DR. BLAYNEY: So, if you wanted to put somebody on, 80 percent of the
> time they would declare themselves early as a responder.
>
> DR. BLACKLEDGE: Well, I think you heard today that certainly many
> people start to feel better within a matter of days. That may be the
> ultimate way of choosing which patients are going to benefit or not.
>
> DR. BLAYNEY: And which ones you are going to continue for a long time?
>
> DR. BLACKLEDGE: Sure.
>
> DR. PRZEPIORKA: Dr. Kelsen?
>
> DR. KELSEN: One of the questions we have been asked to comment on
> regards future study design whether accelerated approval is
> recommended or not. A number of potential designs are possible, almost
> all of which I would think would be randomized to the drug versus
> something, placebo and a variety of treatments. What is the sponsor\'s
> feeling on the willingness of patients to enter into such a
> confirmatory trial in which they will be receiving or not receiving
> this agent if it is available widely via accelerated approval, and
> then if it is available widely via the extended access program?
>
> DR. BLACKLEDGE: Well, the definition of clinical benefit that we are
> using is a better life, and it has been very clear from all the
> discussions that we have had this afternoon that symptom control seems
> to be a key aspect. We believe that we would be able to perform a
> trial looking at IRESSA versus best supportive care and looking at
> time to symptom worsening, and then crossing over to IRESSA. So this
> would not be a survival trial; this would be a confirmation of the
> benefits that are predicted in the trial which we have submitted for
> accelerated approval.
>
> The alternative to that would be to carry out a randomization versus a
> common chemotherapy agent, say gemcitabine, which has a low response
> rate and, again, provide the crossover at time of symptom worsening.
>
> Rather than my saying whether I think these are feasible, perhaps I
> could ask Dr. Mark Kris to comment on that and Dr. Lynch who would be
> potential investigators.
>
> DR. KRIS: Mark Kris, medical oncologist from Memorial Sloan-Kettering.
> I think the kind of trial designs that Dr. Blackledge just mentioned
> would be very doable here, and I think they would allow patients
> access to the drug; allow us to confirm the endpoints that we have;
> and I think that they easily could be done.
>
> DR. LYNCH: Tom Lynch, Mass. General. Just to echo Mark\'s feeling, I
> think one of the comments made earlier was about the rapidity of
> response to this agent makes it particularly appealing to look at in a
> crossover design, having treated hundreds of patients on expanded
> access and a number on trial 39, you know within 4 to 6 weeks whether
> there is benefit. So, ethically, morally to put a patient on a quick
> crossover, 4 to 6 week period before the crossover, I think is very
> doable versus not just best supportive care, but I think you actually
> have to do it versus placebo to be certain that what you are seeing is
> truly effect of the drug.
>
> DR. KRIS: Actually, we seldom tell the patient they respond; they tell
> us, just as we heard this morning.
>
> DR. PRZEPIORKA: Dr. Martino?
>
> DR. MARTINO: The more I think about this, the more it becomes apparent
> to me that the real key for me as to whether this is a good drug or
> not is really not response rate, because response rate is very
> difficult to measure, particularly when you are dealing with patients
> who have had several previous therapies. So, the fact that this
> response rate is fairly unimpressive I guess is the lot of our lives
> in many of our tumors right now. But to me the key really, again, has
> to do with this quality of life issue. I am not sure that I am ready
> to accept that what appears to be an impressive quality of life, which
> is not necessarily directed at measurable response because you have
> this group of patients who have stable disease who appear to get
> something out of this. If, in fact, that is correct then this is a
> worthwhile endeavor. If, on the other hand, there is some other
> explanation, then this is not a worthwhile endeavor. So, to me, what
> it really comes down to is to what degree can I accept this quality of
> life information.
>
> DR. PRZEPIORKA: Are there any other questions from the committee? Dr.
> Redman?
>
> DR. REDMAN: A clarification on the response again, most of the
> responses occurring at 4 weeks, is that PR or is that PR plus stable
> disease?
>
> DR. BLACKLEDGE: Those are the PRs that I was talking about.
>
> DR. REDMAN: At 4 weeks?
>
> DR. BLACKLEDGE: At 4 weeks the radiographs had shown 50 percent
> reduction.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: A brief follow-up to some earlier discussion, in the FDA
> briefing document, bottom of page 14, top of pate 15, discussing some
> of the methodologic problems with the assessment of symptom relief, a
> sentence at the top of page 15, \"there are also methodologic issues,
> including early progressors being censored.\" Could you clarify in
> your analyses essentially what that means, what you are reviewing?
>
> DR. SRIDHARA: We didn\'t really go into details of who progressed, but
> as I showed in that graph, by week 1 there was 25 percent who were not
> there. So, yes, those are the only ones who were available for
> assessment of quality of life.
>
> DR. FLEMING: So, in the analyses that you were able to validate that
> we are looking at for symptom relief, progressors were censored?
>
> DR. SRIDHARA: Yes, but the denominator was everybody.
>
> DR. PRZEPIORKA: Dr. Blayney?
>
> DR. BLAYNEY: This is a question that is sort off the topic of response
> but could you clarify the relationship between AstraZeneca, the
> sponsor of this product, and Cedar Sinai Comprehensive Cancer Center,
> the major accruing organization, just for the record?
>
> DR. BLACKLEDGE: I am happy to do so. Cedar Sinai Cancer Center is part
> of Salek Healthcare which employs a number of independent physicians.
> I don\'t know if Dr. Natale wants to comment further on that.
>
> DR. NATALE: Salek Healthcare is a subsidiary of AstraZeneca that is
> completely independently managed. The physicians, including myself,
> who work in the Cedar Sinai Comprehensive Cancer Center are private
> practicing physicians who entered patients onto this clinical trial.
> My salary does not come from AstraZeneca. They don\'t influence my
> salary or my bedside practice.
>
> DR. PRZEPIORKA: Dr. Varricchio?
>
> DR. VARRICCHIO: Just in terms of sort of where do we go from here and
> our comfort level with this data, the fact that there is no control
> group is one concern to knowing what is going on. But also we were
> told that the subjects were on quite a few concomitant medications
> that would address the symptoms in and of themselves. That data was
> not collected nor reported on the frequency of use and what was going
> on in terms of the people who were responding positively to a
> reduction in symptoms\--what was going on with the other medications
> they were taking. So, I think, you know, if there is a next step, it
> should be a controlled trial and keeping track of the concomitant
> medications as well.
>
> DR. PRZEPIORKA: Dr. Kelsen?
>
> DR. KELSEN: A very brief question, it is clear you have been thinking
> a lot about the next step, no matter what is decided today, as far as
> a confirmatory trial. I am struck by the comments about how rapidly
> patients could be accrued to such a trial and that you would not have
> a question about accruing the patients. So, how large would that trial
> be and how fast can you do that to obtain the information that would
> then answer the questions that have been raised today?
>
> DR. BLACKLEDGE: Well, we haven\'t absolutely established the size or
> the power of the trial. We have an efficient recruitment mechanism and
> we would obviously try to recruit it as rapidly as we could, but we
> don\'t have any actual specifics as yet because we haven\'t agreed on
> trial design.
>
> DR. PRZEPIORKA: If there are no further questions, we will go on to
> the next section where we will address the questions. The format will
> be to first discuss the questions before we take a vote. Before we
> start that part, I would like to again remind everyone here that we
> sit in advisement to Dr. Pazdur and Dr. Temple and I would like at
> this point to ask if either of you have any further instructions to
> the committee before we undertake the questions.
>
> DR. TEMPLE: Actually, I just have one question because it is important
> to us later. The view was expressed that it would be easy, even if the
> drug were available, to randomize people in third-line therapy to, I
> guess you would call it, early treatment versus slightly later
> treatment. Could somebody elaborate on that? Obviously, if the drug is
> not available you could probably do that trial, but people seem to
> think that would be no problem and I just wondered why everybody
> thought it wouldn\'t be a problem.
>
> DR. LYNCH: I think the biggest point is that the time frame you are
> looking at is a relatively short time frame, and this would be a study
> that is important to do to be able to distinguish the robustness of
> the quality of life data. Because of the importance of this study and
> because of the fact that you are only asking patients for a 4- to
> 6-week crossover, I think it is a study that actually is a doable
> study, particularly early on.
>
> DR. TEMPLE: Despite the feeling that we heard expressed here that the
> improvement in symptoms and all of those things is so very dramatic?
> This is an important question. One can only speculate obviously since
> you haven\'t done it yet, but you think people would be willing to
> enter such a trial even though the drug was commercially available?
>
> DR. LYNCH: I would think so.
>
> DR. FLEMING: On a related point though, this is probably raising a
> really key issue because what I am hearing there is a crossover that
> they propose would be occurring very rapidly in time, and by crossing
> over if, in fact, you did that very rapid crossover you really would
> be getting much more limited true comparative information and,
> obviously, you would be very substantially compromising any
> opportunity to really see if there is a survival effect, but even for
> progression or longer term or durable symptomatic relief comparisons
> you would be compromising that. So, I wouldn\'t think that the most
> informative crossover design would be one that would cross somebody
> over if they didn\'t show immediate symptom relief after the first
> assessment. That really wouldn\'t answer the question that we need to
> answer.
>
> DR. TEMPLE: Well, it was really offered as a way to verify the
> symptomatic benefit.
>
> DR. FLEMING: You raise a very good point. If this is available it is
> certainly going to be more difficult to do what would really be the
> more informative assessment as to whether or not there is truly
> clinical benefit. It would be easier to do something that would be
> very marginally informative, which would be crossing somebody over
> very rapidly in time.
>
> **Committee Discussion and Vote**
>
> DR. PRZEPIORKA: I think we are going to have actually more extensive
> discussion, but first I want to hear from Dr. Temple and Dr. Pazdur
> about anything else.
>
> \[No response\]
>
> Well, we have a number of issues that are set before us and the first
> question from the FDA is the FDA believes the relevance of the sum
> improvement data discussed above cannot be adequately evaluated with a
> randomized, blinded study with an adequate control arm. The two doses
> of ZD1839 show no difference in efficacy and are thus not adequate. Do
> you agree? Dr. Varricchio, do you have any opinions regarding this
> question in particular?
>
> DR. VARRICCHIO: I think that it is a soft claim of efficacy of symptom
> management in this situation. Obviously something is going on but you
> don\'t know why and what might have caused the improvement in symptom
> management. So, I feel to really have a strong basis for saying that
> this drug is the cause of the improvement in symptom management you do
> need a randomized, controlled trial with a real no drug arm, not this
> drug arm. Whether it is placebo or best standard care, that can be
> discussed.
>
> DR. PRZEPIORKA: Mr. Ohye?
>
> MR. OHYE: I would like to make first a general comment, if I may. I
> would like to compliment the sponsor for carrying out these trials
> because I know they are difficult, and also embarking on the expanded
> access. I think that is very humanitarian and the committee should go
> on record to say well done.
>
> I also think the FDA has done a good job in finding every blemish,
> every freckle, every micro-pimple in the trial, and that is their job
> because they have to look at this with an abundance of caution.
>
> My general comment is I think when we look at all these questions we
> have to look at the fifth question that was proposed, accelerated
> approval, and we have to think in terms of the requirements for
> accelerated approval that were so adequately or so well explained to
> us on page 3, third slide by Dr. Williams. We have to look at the
> standards there and we have to bear in mind that the evidence that we
> have to have is do the data show that it is reasonably likely to show
> a clinical benefit, not that it has to be proven beyond reasonable
> doubt.
>
> I think it goes without saying that we have met some of the other
> criteria that were dealing with a serious, life-threatening disease
> and that the question is whether it is reasonably likely to predict a
> clinical benefit. I think the data are very much in favor in that
> area. Thank you.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: I guess I will ask the biostatisticians, can you state
> with the information that is present that it did not have a negative
> impact, a negative aspect? Is that no?
>
> DR. FLEMING: Well, there are many issues here that we are going to be
> discussing and, as has already been pointed out, there are serious
> limitations in interpreting these data in the absence of
> randomization. The data establish some level of plausibility that
> there could be a quality of life impact and, to the extent that it
> establishes that, it makes it more implausible that it is a negative
> effect. But, in fact, the risk for biases here, as we will articulate
> shortly, are so substantial that one would have to be very cautious
> about what you interpreted when you are saying is there adequate
> evidence of causal positive influence of intervention on these quality
> of life measures.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Just a comment, I would like to come back to something
> that Grant mentioned in his slides that I think is very important and
> we can\'t lose track of. That is, the evidence for accelerated
> approval is not different than for ordinary approval. That is, we have
> to look for substantial evidence, and that is what I keep coming back
> to. Because of these potentials for serious biases in these studies I
> have a real problem coming to the conclusion that it is substantial
> evidence. My feeling is that obviously something is really going on.
> It is just too bad that we didn\'t have the direct randomized
> comparison so we can really know what the magnitude of that is. So, I
> just thought we ought to keep that in mind. I thought Grant had a very
> good point about that.
>
> DR. PRZEPIORKA: Dr. Varricchio?
>
> DR. VARRICCHIO: Just a thought that has occurred to me listening to
> this, if this drug did not have such a user-friendly toxicity profile
> we might not be considering some of the things we are considering.
> This is kind of low risk in terms of the toxicity profile, and maybe
> we are creeping out further out on the limb than we might if the drug
> had a more serious toxicity profile.
>
> DR. PRZEPIORKA: Dr. Blayney?
>
> DR. BLAYNEY: I would like to say two things. One, if this drug was
> more toxic, like in the ECOG study, it ought to be reflected in a
> decrement in the symptoms score. So, there is some reassurance, in my
> mind, that the lack of toxicity is reflected in the improvements here.
>
> Like Dr. George, I am convinced that there is a signal here. We have
> wrestled in the past with very similar sorts of problems. It looks
> like there is a signal. A lot of people tell me that there is a
> signal, and I think this drug ought to be available. I am wrestling,
> and perhaps I shouldn\'t\--that is your problem, wrestling with the
> regulatory and statutory burdens placed by the legislative branch on a
> government agency. So, that is where I have come down.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: This question is the main one in which you come to grips
> with the plausibility of the symptom benefit. So I have to ask a
> question just in response to something that went before. There isn\'t
> any doubt that there is an effect. We don\'t have any doubt that there
> is an effect on a surrogate, that surrogate being tumor shrinkage.
> Nobody has challenged that; we don\'t disagree with the numbers. The
> whole question is whether that is reasonably likely to predict
> clinical benefit.
>
> We have been offered by the company the option to believe that the
> evidence they have of symptomatic improvement is at least a basis for
> thinking it might correspond. So I have to ask my question. We are
> very accustomed to being suspicious of unblinded quality of life
> assessments as a general matter. One of the points that was made,
> although I must say not as strongly as I would have made it if I were
> the company, is that much of the symptom benefit is apparent before
> anybody knows whether there has been a tumor response. That is
> comparatively unusual, and we would be very interested in knowing
> whether that affects anybody\'s thinking about this or not because we
> are going to have to come to grips with it.
>
> DR. PRZEPIORKA: If I could just paraphrase what you just stated, what
> we need to actually ask ourselves is, looking at the symptom
> improvement data in isolation, there may not be enough there to say
> this is really real. But in terms of looking at the symptom
> improvement data together with the response data, does that make a
> more plausible story?
>
> DR. TEMPLE: Yes, and just one more point. Usually in refractory
> disease we have a history of accepting tumor response data as
> reasonably likely to correspond. The problem here is that in the
> first-line therapy where that question was tested\--nothing; no hint;
> no nothing. So, that makes it a somewhat unusual problem and the
> potential that you might believe a little bit in the symptom data. The
> question is, and Tom has been raising this, how should one believe in
> that. I was particularly interested in one feature of it which is that
> the symptom response appears to be reported before anybody knows there
> has been a tumor response and I wondered if that made people think one
> way or the other about it.
>
> DR. PRZEPIORKA: Dr. Reaman?
>
> DR. REAMAN: That certainly was very important for me, but equally
> important was the fact that there was a cessation of collecting
> symptom response data when patients progressed. So I don\'t know how
> you balance out those methodologic shortcomings.
>
> DR. PAZDUR: Let me just follow-up to Bob\'s question. Many of the
> drugs that we have gotten in for accelerated approval on a single-arm
> basis do not even have any attempt to look at quality of life data or
> symptom control. How would the committee view this in a refractory
> disease setting if we were simply dealing with a 10 percent response
> rate here, with the given confidence intervals, and that is all we
> had, period? Is that reasonably likely to predict clinical benefit if
> we didn\'t have the first-line data?
>
> We have approved drugs, for example CPT11, as Grant pointed out, with
> a very similar response rate. I am not going to cut hairs here between
> a 10 percent response rate and a 12 percent response rate or a 15
> percent response rate. Obviously, we felt comfortable enough giving
> accelerated approval to that drug. We didn\'t have the first-line data
> of CPT11 at the time of approval but, nevertheless, we felt
> comfortable enough to go ahead with that approval.
>
> So, pretend we didn\'t even have the symptom benefit analysis, would a
> 10 percent response rate be predictive, or reasonably likely to
> predict clinical benefit? And, then a question for you that we
> frequently get from sponsors is how low can you go?
>
> \[Laughter\]
>
> DR. PRZEPIORKA: Is that question number two, if I read question number
> two correctly? Let\'s finish one first and immediately go there. If
> there are no other questions, let\'s go ahead and take the vote. The
> question is, to rephrase this, the symptom improvement data discussed
> above cannot be adequately evaluated without a randomized trial. Do
> you agree? We will start with Dr. Martino. Please state your name
> before giving your vote.
>
> DR. MARTINO: Silvana Martino. Yes, I do agree.
>
> DR. PAZDUR: Could you repeat that?
>
> DR. PRZEPIORKA: The data cannot be evaluated adequately without a
> randomized trial. Do you agree?
>
> DR. MARTINO: Yes, I agree that it cannot be evaluated. I understood
> you correctly. Thank you.
>
> DR. BLAYNEY: Doug Blayney. No, I disagree.
>
> DR. VARRICCHIO: Claudette Varricchio. I agree.
>
> DR. BRAWLEY: Otis Brawley. I disagree.
>
> DR. PELUSI: Jody Pelusi. I disagree but I would put a little caveat in
> here. It would be really helpful to see those patients who then went
> off study, to really show us their quality of life data as well to
> help us balance that.
>
> DR. REAMAN: Gregory Reaman. I agree.
>
> DR. PRZEPIORKA: Donna Przepiorka. I agree.
>
> DR. FLEMING: Tom Fleming. I agree but I would like to actually expand
> a little bit on the rationale. I think interpreting symptomatic
> response data in this type of a setting is treacherous. It has long
> been recognized to be treacherous. The FDA has given a very clear
> articulation of all of the reasons.
>
> I would like to expand briefly on some of them. It is an open-label
> trial. Placebo effects clearly exist. The fact that there are some
> immediate improvements may well be due in part to therapy; undoubtedly
> are due in part to a placebo effect and not necessarily a true
> treatment effect. We don\'t know what the contributions are by
> ancillary care. I am bothered by the fact that we are not really doing
> an intention-to-treat analysis. We haven\'t truly looked at what is
> the symptomatic response across the board in all patients. Why is it
> not relevant to know what the symptom response is when someone
> progresses? Why do we stop assessing it at time to progression? To
> really understand this we should be fully assessing this.
>
> Then we get into these analyses about trying to provide credibility of
> response by looking at correlation with symptoms and vice versa and
> with survival. We have been down these pathways for 25 years in
> oncology research, recognizing how fallacious this reasoning may be.
> Response may simply be a marker for intrinsically better patients who
> would have had a better symptomatic outcome even without treatment.
>
> Essentially, when we look at a marker, let\'s say it is tumor response
> and a clinical endpoint, as I believe symptom improvement would be if
> we showed it, looking at whether there is a correlation is a necessary
> condition but not a sufficient condition for validity as a surrogate,
> meaning that if there isn\'t a correlation then one really does have a
> difficulty in being able to interpret whether or not, in fact, one
> basically would say it can\'t be a valid surrogate. But if there is a
> correlation between response and symptomatic improvement it just gets
> you in the door. It just means that there is now at least a
> possibility and, in fact, maybe only a limited possibility that it
> truly is representing treatment effect.
>
> Essentially what has long been recognized is when you have a class of
> agents and you are looking at validating a surrogate, you really need
> to have studies that look at the treatment effect on the marker and
> the treatment effect on the clinical endpoint to really understand,
> for that class of agents, if the effect on the marker is reliably
> telling you about the effect on the clinical endpoint.
>
> As we will say shortly, the sponsor did a remarkable job on the INTACT
> trials. I am very confused if they didn\'t have an intention of using
> those trials as the basis for establishing clinical benefit why the
> reliance in accelerated approval was just basically on the 39 trial.
> Why didn\'t we have a control arm, in essence, to be able to validate
> that there truly is a treatment effect on the symptom response?
>
> So, the bottom line is these data may well provide clues and
> encouragement for doing a properly controlled trial, certainly though,
> they can\'t be interpreted as providing adequate evidence to establish
> that treatment is actually influencing symptom relief, or even, the
> words the FDA has used, providing substantial evidence for such.
>
> DR. REDMAN: Scientifically, I think the answer to the question is yes,
> but also with the caveat based on the toxicity profile that the drug
> surely didn\'t have a negative impact on quality of life.
>
> DR. KELSEN: David Kelsen. I agree.
>
> DR. CARPENTER: John Carpenter. I think I disagree but that is only a
> partial disagreement. I don\'t think these numbers are really adequate
> but I am very influenced by the degree of improvement in symptoms
> without any knowledge of the response data.
>
> DR. CHESON: I am Bruce Cheson. I still have this feeling that when
> patients are off their chemotherapy they start feeling better and some
> of them just don\'t start feeling better within a month but they feel
> better over a longer period of time. With this study design, I think
> that the number of patients influenced by that is not discernible
> given the information we have. So I agree.
>
> DR. TAYLOR: Sarah Taylor. I agree.
>
> MR. SIMON: Tom Simon. I disagree.
>
> DR. PRZEPIORKA: Of the 14 votes, 9 agreed and 5 disagreed.
>
> I think Dr. Pazdur has already adequately stated the second question
> for us. Given the lack of clinical benefit in 2 large studies of
> ZD1839 in combination with standard first-line chemotherapy, is study
> 39 response rate of 10 percent in 139 patients with resistant or
> refractory non-small cell lung cancer reasonably likely to predict
> ZD1839 clinical benefit? Dr. Carpenter, do you have comments?
>
> DR. CARPENTER: John Carpenter. I am not too influenced by the Phase
> III results here because you are giving an anti-proliferative drug
> with 2 drugs that depend on cell proliferation for their efficacy. It
> is very much like giving hormonal therapy and chemotherapy for breast
> cancer where the response rate doesn\'t go up, and if you give them
> together they will change the outcomes. I think the model may be
> fairly true here so I would negate those 2 Phase III studies and say
> that what they tell us is that we didn\'t know how to study this drug,
> and I think everybody will agree that the most robust evidence all
> afternoon is that when you give this along with chemotherapy people
> don\'t do any better. There was no serious discussion of that.
>
> I think if we are going to undertake this right, we are going to have
> to look at the early studies just based on their own as a single
> agent. It seems to me that it is clear there is some prediction. What
> we don\'t get, because of the inadequacy of the trial data we have
> here, is how strong that signal is. But it is very clear that some
> people are getting better and some people are getting clinical benefit
> and at least nobody, so far, has picked out a way to identify those.
>
> I would submit to the company that if you look at who gets better on
> this drug, besides doing all the fancy gene analysis, if you took a
> simple immunoperoxidase stain and picked out slow-growing tumors
> everybody who gets better on this drug has a long and natural history
> in a tumor that grows slowly, and if you hypothesis were that people
> in the lowest quartile do better on this drug, you might figure out
> who gets better on this drug pretty quickly, and without doing too
> many elegant genetic studies.
>
> So, I think there is a signal. I think that 10 percent is hard as far
> as the response rate, and I think it is reasonably likely that that
> predicts clinical benefit. Given the inadequacy of the data we have, I
> would say yes.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Maybe I can delay some of my comments until item 4 when I
> guess we are going to discuss additional trial designs because that
> may provide some information about what we think about this first-line
> trial as providing evidence in this case. But I want to point out that
> it is certainly possible that an agent such as this, with a low
> toxicity profile could, indeed, provide clinical benefit as measured
> by symptom improvement or quality of life and have absolutely no
> effect on survival. If that were true then, of course, that is a
> clinical benefit. It is not survival benefit but I think sometimes the
> question is phrased as if we always mean survival and it is clear in
> the regulations and the way things are stated that it is not just
> overall survival. In fact, in this trial I asked the question earlier
> whether we had any information about quality of life or symptom
> improvement even in that first-line therapy and we have no evidence of
> that whatsoever at this point. So, it is clear that there is no
> survival benefit so it is certainly possible.
>
> Now, the question of whether it is reasonably likely to predict such
> things, then we run into an area of metaphysics and I can\'t give a
> probability of what reasonably likely is, but it is clearly possible
> that it could.
>
> DR. PRZEPIORKA: I will just weigh in with my two cents here. I don\'t
> know of anyone with non-small cell lung carcinoma whose cancer went
> away by itself or developed a PR by itself. So, very clearly there is
> activity here, and very clearly 10 percent is substantial as a
> third-line agent. I don\'t know that you could say for all non-small
> cell lung cancer. I think that is where some difficulty may arise, but
> very clearly there are patients who have derived clinical benefit from
> treatment with IRESSA. Dr. Cheson?
>
> DR. CHESON: The response troubles me I guess. You can take the
> hematology out of the doctor but not the doctor\--you know, we deal
> with tumors that respond so it is a bit problematic. But just looking
> as someone who has done clinical research for a number of years, you
> would be hard-pressed to find a study in which the Phase III data,
> particularly response rates, were better than the Phase II data. So,
> this 10 percent, with confidence intervals going down to 5.6, may
> actually be optimistic in the grand scheme of things. So, that gives
> me significant room for pause about substantial clinical benefit. I
> thoroughly agree that some people really have had astounding benefit
> but what is that going to be when the drug is used to treat tens of
> thousands of patients?
>
> DR. PRZEPIORKA: Dr. Kelsen?
>
> DR. KELSEN: I agree with Dr. Pazdur\'s original comments, or I will
> try to answer his original comments. A 10 percent activity in
> third-line therapy in a variety of cell tumors, and colorectal is a
> really good example, is meaningful. Whether it is a surrogate for a
> higher level of benefit is difficult to say today, but it is a
> surrogate for activity and this drug does have activity, and the
> risk/benefit profile for this agent is substantially better than the
> risk/benefit profile for irinotecan and oxaliplatin.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: Certainly there is evidence here that there is biologic
> activity. The question is how impressive is that evidence and how
> reliable is it to indicate true clinical benefit? We have two studies.
> We have the 16 study and we have the 39 trial, and the 16 study\--just
> going back to what the team had intended, they were trying to discern
> between a 5 ruling out a 5 as an inadequate response rate, against a
> 20 percent response rate. So, according to their statistical criteria
> they needed to see a 13.3 percent response rate for success. They had
> less than that in the trial looking in the non-Japanese patients.
>
> As we had discussed earlier, if you focus on those people that, in
> fact, truly were first- and second-line progressors there was only 1
> responder. So, there is very limited information in that 16 trial
> about whether there is really an interesting or impressive response
> rate in third-line. We are left with the data in the 39 trial and
> essentially we are looking at the basis of that as 22 responses with,
> as Bruce was pointing out, confidence intervals that go down to 5
> percent. In fact, if you follow the protocol it is 97.5 percent
> confidence intervals that go below that.
>
> Then, as the FDA has pointed out, there are a lot of favorable
> characteristics in these people who responded. So, how impressive in
> the context of this trial are these responses? It appears, as has been
> presented to us, that the strategy that was in place here several
> months ago, prior to the release of the INTACT trials, was that the
> INTACT trials were going to give us the truth. Essentially, they were
> marvelous studies, absolutely fabulous studies conducted by the
> sponsor randomizing a thousand people per trial, getting 750 deaths
> per trial giving, in pair-wise comparisons, 500 deaths.

Essentially, these types of studies are incredibly informative and
reliable in their assessments allowing us to detect, with reliability,
even a 25 percent reduction or what would correspond to an improvement
in survival from 10 months to 13.3 months.

> What do the data show? The data show estimates that are slightly
> unfavorable, about a 10 percent increase in death rate in the 14 trial
> and no difference in death rate in the 17 trial. If you put this data
> together from these two studies, what you get is a remarkable level of
> precision. You have a thousand deaths per pairwise comparison to
> assess.
>
> So this is not just a matter of, we didn\'t achieve statistical
> significance. This is a matter of these studies nailed with great
> precision exactly what the true effect is going to be in first-line.
> Essentially, what that true effect is is a loss of one week in overall
> survival on a ten-month median for the control arm, a loss of one week
> at 500, a loss of two weeks at 250, with a precision two standard
> errors of within five weeks.
>
> What that means is these agents could be as unfavorable as reducing
> survival by six weeks and as favorable, best-case scenario, three-week
> improvement which is one-quarter the level of benefit that would
> correspond to what the study had sensitivity to detect.
>
> So I am left with a philosophical debate. These studies clearly
> conclusively establish providing consistent and compelling evidence
> that there is no effect on survival, not just that we have failed to
> achieve significance. There is no effect in the global population on
> survival. Response rates and TTP were also negative.
>
> What is the relevance? Clearly, it is always true that if you are
> really interested in survival effect in third-line that first-line
> results could give either false-positive or false-negative
> conclusions, false-positive being maybe you have an effect earlier on
> on survival if you deliver IRESSA earlier in time. If, in fact, the
> studies had been positive, would the sponsor be asking us to step back
> and reexamine their relevance to third line because you had agreed
> they would be relevant up-front.
>
> Yes; in fact, they could also be false negatives and that is the
> question that is validly being asked now. But hindsight is
> twenty-twenty. To say, in retrospect, gee, we can explain now why
> these results are providing compelling evidence of no-survival effect,
> aren\'t relevant to the third line, I would argue we should be
> incredibly cautious about that interpretation. That is clearly a
> data-driven interpretation.
>
> Yes; it may be true, but the bottom line is there clearly is relevance
> to those data and those data have to be factored in significantly.
> With that being factored in, it provides a great influence, I would
> argue on whether response rates in twenty-two responders in the
> uncontrolled 39 trial is compelling.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: I think I would look at the Phase III slightly
> differently but only from an interpretation standpoint. They show, as
> well as I can imagine, that if you add these two drugs together, the
> way they did, that there is simply a vanishingly small chance that
> there is any real improvement. Would you agree with that?
>
> DR. FLEMING: I agree.
>
> DR. CARPENTER: I think the question is limited by the way we asked it
> and so I don\'t think they tell us, necessarily, what the drug does in
> front-line therapy. They just tell us that the way we asked the
> question, or the way they asked the question, that we feel confident
> that, if you do it that way, there is no advantage to adding this
> drug. But I wouldn\'t, for a minute, conclude that if you asked the
> question differently with a different type of study that you would,
> necessarily, get the same answer.
>
> DR. FLEMING: You mean adding IRESSA first-line to a different
> combination; is that what you mean?
>
> DR. CARPENTER: I am talking about separating the IRESSA from the
> chemotherapy. I think what they did was to combine them as if it were
> a third chemotherapy drug and, like other third chemotherapy drugs, it
> didn\'t work and we feel pretty confident that it didn\'t.
>
> What I am saying is that answers that we have are limited by the way
> the questions were asked.
>
> DR. FLEMING: Just to clarify. Yes; I do agree that, in essence, we are
> limited to the interpretation of what these studies were designed to
> address. When the result is negative, to step back and try to assess
> why is very relevant. But to say they are not relevant to third-line
> is stepping back too far.
>
> DR. CARPENTER: I may have not stated my question right. Excuse me.
>
> DR. PRZEPIORKA: Dr. Brawley.
>
> DR. BRAWLEY: One possible design of the trial would be, for example,
> to take individuals treated with first-line chemotherapy who respond
> who have a very high likelihood of relapse and then giving them IRESSA
> at that point to see if it sort of prevents relapse or prevents
> recurrence. That is a question that has not been addressed and it
> may\--there is some scientific reason to believe it actually might
> work.
>
> But they really have not\--I mean, the drug\'s clinical benefit, in my
> mind, can be very different from does the tumor respond. So I think I
> have given you what my answer to No. 2 is going to be.
>
> DR. PRZEPIORKA: Dr. Pazdur.
>
> DR. PAZDUR: I wanted to kind of go over this question before you vote
> on it because I think there are several things here that the committee
> has to understand. First of all, when we are asking this question,
> this is tantamount to should the drug be approved on accelerated
> approval. It is Question No. 5 of the sponsor. So you could just skip
> that Question No. 5. This is it.
>
> We were rolling around on our merry way here in our Division with this
> 10 percent response rate and the symptom benefit. We believed that
> basically we weren\'t going to be taking a look at the symptom-benefit
> work per our previous discussion but we did look at this 10 percent
> response rate.
>
> Then we were kind of floored when the two large studies came into
> play. This is really what Tom was getting at here, that this is the
> point of the question. We are not asking about a 10 percent response
> rate. As I told Dave Kelsen, we approved a drug with a 12, 15 percent
> response rate. We already have that history of doing it. That is not
> the question here.
>
> The question is in the context of these two other trials. If we
> didn\'t have these trials, we probably wouldn\'t even be here. We
> would have already approved the drug on our merry way. We have this
> data here. We can\'t just ignore it. We have to take a look at the
> whole data package when we look at the approval of the drug.
>
> The question here is not the 10 percent response rate. It is in the
> context of these two other trials that are front-line trials. The
> observation that this drug does not work with chemotherapy is an
> observation. It is not an explanation, and I have not heard from the
> sponsor a viable explanation of why these trials have failed.
>
> If they would like to get up now and give it, I would like to hear it.
> George?
>
> DR. BLACKLEDGE: Well, Dr. Pazdur, I can hypothesize as well as anyone
> else. It is very clear that whatever effects you are seeing with
> doublet chemotherapy, you cannot, it appears, add to. That appears to
> be the case, whether it is another chemotherapy agent or whether it is
> a novel agent of this kind.
>
> I don\'t have the explanation yet, and I don\'t think anyone else
> does. All I can say is that it does seem to be an emerging pattern for
> both chemotherapy agents added as a triplet and also for novel agents
> added as a triplet.
>
> Whilst I don\'t think we can ignore the data, I do think that it looks
> an extraordinarily different situation from where we have clearly seen
> agents, noncytotoxic agents, giving real benefit as monotherapy in
> various different situations when they haven\'t shown any additional
> benefit in combination.
>
> So I am not sure I agree with Dr. Fleming completely. I think that,
> whilst you must take these data into effect, use as a monotherapy for
> clinical benefit and for response which leads to clinical benefit is a
> very, very different situation.
>
> DR. PAZDUR: One of the problems that I see with that answer, George,
> when you take a look at this drug when it is favorable to your
> situation, you may look at it as a chemotherapy drug. When it is not
> favorable to your situation, you take a look at it as a special agent
> here which is somewhat perplexing to me.
>
> I am fully aware of the doublet, triplet information in lung cancer.
> The question here, we have no other situation that I know in medical
> oncology, and I am having a tremendously difficult time trying to
> figure out why, in a first-line setting, you would not have some
> effect here.
>
> Obviously, AstraZeneca has gone on an extensive development program
> not only in lung cancer but in a myriad of diseases with chemotherapy
> and this agent, I assume, based on some preclinical rationale, we got
> the results of this trial. It has thrown a tremendous monkey-wrench
> here. What is the explanation? That is the essence of this question
> and that is what needs to be discussed here, not the 10 percent
> response rate.
>
> We have approved drugs. I don\'t know how low is low and how low you
> can go, but this is the issue here of the 10 percent rate, albeit it
> might even go down to 5 percent. I don\'t care. The question is these
> first-line data being there and that is the issue and that is the crux
> of why we brought this drug to the committee.
>
> DR. FLEMING: Could I add just briefly to Dr. Pazdur\'s question for
> the sponsor to respond to. If the sponsor didn\'t anticipate that the
> two first-line studies would, in fact, provide the validation of the
> surrogate effects, justifying the accelerated approval, what was the
> strategy since, essentially, the accelerated-approval strategy
> indicates that postmarketing studies would usually be under way.
>
> So, if you prospectively, before you saw the results of the first-line
> trial, already knew that those first-line results weren\'t going to be
> relevant to efficacy in third-line, what third-line comparative
> randomized studies were already under way as the basis for validating
> this accelerated approval in third-line?
>
> DR. BLACKLEDGE: We had no randomized third-line studies underway. The
> reason for that is that when we planned Study 39, we discussed
> extensively with our investigators about possibilities of
> randomization. They advised us that, certainly within the context of
> the United States, that would be extremely difficult to carry out.
>
> In addition to that, the studies that we carried out in third-line
> were validation of the Phase I data that we saw where we unexpectedly
> saw responses and it seemed logical to carry out a Phase II in that
> setting. That is the basis that we went forward with accelerated
> approval.
>
> Now, we are clearly faced with a difficult situation. I don\'t think
> any one of us expected the results that we saw in the INTACT studies
> although, in fact, if you look at other data that has emerged since we
> started them, maybe you might have expected that we wouldn\'t see that
> effect.
>
> I don\'t believe it invalidates, however, the response that we see and
> the strong suggestive evidence, but not proven evidence, of a clinical
> benefit linked to those responses.
>
> DR. FLEMING: Just in completing the response, then, to this response,
> your approach in the INTACT trials was remarkable. You did a
> remarkable effort to come forward with outstanding trials to establish
> whether or not there were effects on survival and other clinical
> endpoints in first line.
>
> As a result, it seems to be a paradox that you have mounted the
> accelerated approval in third-line based on the 39 trial without any
> backup plan for how you were going to, in fact, be able to validate as
> accelerated approval requires, it surely leaves me to think you
> actually were anticipating a favorable result in INTACT that would
> serve as a basis for validating and, in which case, if we then took
> that logic to the limit, we would say, you did view that there would
> be relevance to what you see in third-line in the first-line trials to
> the third-line indication.
>
> DR. BLACKLEDGE: We have never linked the third-line submission with
> the first-line submission. Clearly, if there was a positive result, we
> would have been very pleased with that and so would the patients. But
> this is not the only clinical-trial program that we are carrying out.
> We are carrying out trials with monotherapy in adjuvant situation.
>
> We have maintenance studies going on and we would be more than happy,
> as we have described earlier, and as our investigators have described
> earlier, to attempt to validate the data that you have seen today from
> Trial 39 in a randomized setting.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: John Carpenter. Since we seem to be pressing in on this
> question of should we approve this drug or not, I wanted to get a
> couple of comments in if it is okay. I think that we could all
> speculate on the reason that the third-line therapies don\'t\--I mean,
> the first-line therapies don\'t validate the results seen as a
> third-line drug. But that may be because of the mechanisms of action
> of the drugs and they would be counterproliferative.
>
> That is an hypothesis but it certainly is a testable one. It seems
> very clear that slowing indolent tumors are the ones that get better
> here.
>
> If this drug\--and I will be very favorable towards this drug with the
> limited evidence that we have, partially because there is no viable
> competitor in this situation. But I think there is a whole flood of
> studies that could be done to elicit out the way to use this drug. You
> could study performance-status-2 patients and test this versus
> anything since nothing else works very well.
>
> I think there is a study of vinoralbine in older patients. That is
> certainly doable. You can use it in a short period before front-line
> chemotherapy with a crossover. You could use it as an adjuvant with a
> placebo control after frontline chemotherapy and sort this out. All
> these things are easily doable.
>
> You can do the proliferation assay and see if you can predict who gets
> better on this. All those are easily doable studies. So I think I am
> going to come out in favor of making this available with the proviso
> that a bunch of studies about just how to use this drug need to be
> done and should be done.
>
> DR. PRZEPIORKA: So, Dr. Pazdur, I think your question is not just is
> there any evidence for clinical benefit for this drug, but do the
> results of the two randomized trials actually suggest more or less
> that the results that we see in the single-arm study makes a
> difference.
>
> I have to actually weigh in with Dr. Carpenter. I think it is very
> clear there is clinical benefit in the single-arm study, but I think
> the questions being asked in the randomized studies are completely
> different questions. Although we don\'t know why, I am not sure we
> actually know that the inhibition of the kinase is actually the
> mechanism of action that this drug uses because there doesn\'t seem to
> be any correlation with EGFR expression.
>
> I don\'t know that anybody right now could actually answer your
> question about why the combination does not work because I don\'t
> think we have enough information available.
>
> DR. TEMPLE: Maybe everybody said this and maybe it is clear to
> everybody, but we need to be quite sure. As Rick said, if all we had
> was the response rate in third-line, we might not even have brought it
> here because we have been approving drugs with reasonable response
> rates in refractory disease on the basis of that right along.
>
> We were, however, surprised by a negative result in first-line which,
> as everybody has noted, was a complete surprise to everyone or they
> wouldn\'t have done the trials. The fundamental question is does that
> shake your belief that a 10 percent response rate is reasonably likely
> to predict clinical benefit, just to be clear.
>
> That is why we are asking you, because we would ordinarily have been
> comfortable with that response rate. Should we not be comfortable
> anymore because of those trials? That is really the question.
>
> DR. PRZEPIORKA: With all due respect to the statisticians, I think
> what we have heard from the clinicians, both from the sponsor and on
> the committee discussing is we don\'t think the results of the
> randomized trials are that clinically relevant to our opinion of the
> single-arm trial.
>
> But I could take a vote and let you know for sure.
>
> DR. PAZDUR: That\'s appropriate.
>
> DR. PRZEPIORKA: So the question is, given the lack of clinical benefit
> in the randomized trial, do you still think that the response rate of
> 10 percent using ZD1839 is likely to predict clinical benefit?
>
> Dr. Martino.
>
> DR. MARTINO: Yes; I do. I am discouraged, but not totally devastated.
>
> DR. BLAYNEY: Doug Blayney. Yes.
>
> DR. VARRICCHIO: Claudette Varricchio. Yes.
>
> DR. BRAWLEY: Otis Brawley. Yes.
>
> DR. PELUSI: Jody Pelusi. Yes.
>
> DR. REAMAN: Gregory Reaman. Yes.
>
> DR. PRZEPIORKA: Donna Przepiorka. Yes.
>
> DR. FLEMING: Thomas Fleming. No.
>
> DR. REDMAN: Bruce Redman. Yes.
>
> DR. KELSEN: Dave Kelsen. Yes.
>
> DR. CARPENTER: John Carpenter. Yes.
>
> DR. CHESON: Bruce Cheson. No.
>
> DR. TAYLOR: Sarah Taylor. No.
>
> MR. SIMON: Tom Simon. Yes.
>
> DR. PRZEPIORKA: The vote is 11 yes and 3 no.
>
> The third question regards the expanded-access protocol. We had some
> discussion regarding expanded access and single-patient exemptions and
> single-patient protocols. So, Dr. Temple, Dr. Pazdur, if you just want
> to set the stage regarding specifically what that means, especially
> for the new members, of the committee, that might be helpful.
>
> DR. WILLIAMS: This question becomes a little more difficult after your
> answer to No. 2. We will have to decide what to do with your answer to
> No. 2. Theoretically, supposing the drug is not approved, there is the
> issue of expanded access. I think the company has mentioned that they
> would have to reexamine to determine whether they thought it was
> ethical.
>
> We had two ODACs where we discussed expanded access and we talked
> about the level of activity that should be seen, et cetera. If this
> were to be of such a level of activity that we would not approve it
> for accelerated approval, the question would be would it still be
> indicated to allow widespread expanded access.
>
> I guess we could go ahead and have that discussion as you wish.
>
> DR. PRZEPIORKA: Comments? Dr. Kelsen?
>
> DR. KELSEN: Actually, I was initially heartened and then a little bit
> taken aback by two contradictory comments from the sponsor. First, I
> thought I heard that it would be very straightforward to perform a
> confirmatory trial either before accelerated approval, while the
> expanded-access program was open, or after accelerated approval, that,
> in either case, it would be quick to achieve definitive opinions to
> clear the air because patients would readily approve randomized to a
> study in which they initially did not receive the drug and then, at
> sometime, they received the drug.
>
> That is what actually swayed me quite a bit because I could see you
> doing that before accelerated approval with the expanded-access
> program wide open.
>
> Then I was a little taken aback by the answer that we got that the
> reason that we didn\'t see Phase III data right up front today, which
> would have clearly answered the question, is that it was felt that
> patients wouldn\'t accept such a randomization.
>
> Maybe it would help if the sponsor could clarify their position.
>
> DR. BLACKLEDGE: What I was referring to, Dr. Kelsen, was the situation
> two years ago when we began our trial program and the expanded-access
> program. We have been in regular discussions with both the FDA, with
> NORD, with medical ethicists and patient advocates to review the
> expanded-access program as we move along.
>
> We are certainly not going to make any instant decisions and we would
> want to discuss the situation extremely carefully with all those
> people, particularly the FDA. Of course, we would want to be in a
> situation where we were able to carry out a confirmatory study.
>
> We didn\'t speak to the patients about the original randomization. We
> spoke to investigators at that time. But now you are hearing from
> investigators who would take part in those studies that they feel, in
> view of the changed environment and changed need, that it would be
> possible to carry that out.
>
> Now, we want to work together with all the involved stakeholders to
> make sure that we come to a happy resolution of this. We began the
> expanded-access program in the anticipation that one day we would stop
> it. Clearly, we would like to do that as soon as possible because we
> would like to see the drug approved with accelerated approval.
>
> We would also like to do the confirmatory study as quickly as possible
> and, therefore, we would like to achieve some kind of balance so that
> we could do the study and yet not deprive patients of the benefit that
> they are gaining.
>
> DR. PRZEPIORKA: Just a comment. I recall, in our discussions, that the
> program should be set up so that patients who are eligible for any
> studies would not be allowed in the expanded-access program. I think
> that is a very valid way to continue if this program does stay open.
> But I think it is also very important, now that we have seen the
> response rates and that there may be certain subsets of patients in
> whom the response rate is highest and others in whom there is no
> response, and especially there is no valid reason to use it with
> chemotherapy, that that is something that absolutely has to be given
> to the patients prior to their making a decision to take this drug.
>
> DR. PAZDUR: Donna, we have corrected the informed consents to reflect
> these recent INTACT trials.
>
> I do want to mention one thing. There are 12,000 patients on
> expanded-access trials which is a huge number of questions. There are
> a huge number of patients and there are a huge number of questions
> that are unanswered about this drug.
>
> I want to step back. This is something that we are trying to encourage
> sponsors to do is to start looking at other trials that could be done
> within the context of a more expanded research program with a
> particular drug. Even if they were not meant for registration or to
> fulfill a new indication, or even to just give us more idea about what
> would be a better use of this drug, specific populations, populations
> that this drug would not work in, rather than just giving everyone,
> 12,000 patients, this drug.
>
> The best way to get information for everyone in society is for
> patients to be going on clinical trials. We would like to work with
> sponsors more to design other trials. For example, in the third-line
> setting, could we have used a point analysis of time to progression
> where patients could have gone on a chemotherapy regimen that their
> doctors agreed to versus this drug and cross over at the time of
> progression to IRESSA looking at a time-to-progression endpoint.
>
> Everybody would get the drug. Some people would get it a little later
> than the others, but one would have access and get more information on
> this drug.
>
> We really would like to emphasize the best way for us to get
> information is randomized trials and is to look at trials in a more
> close way. I think this would give us much more confidence in
> approving drugs in the long term.
>
> DR. PRZEPIORKA: Any other comments on Question 3? Hearing none, let\'s
> move on to No. 4. Regardless of whether ZD1839 is granted accelerated
> approval for treating non-small-cell lung carcinoma, additional trials
> may be needed. Please discuss any potential study designs that will
> demonstrated ZD1839 provides clinical benefit to non-small-cell lung
> cancer patients.
>
> I think we had some initial ones. If anyone wants to underscore their
> favorite design or indication, now is the time to discuss it.
>
> Dr. Blayney?
>
> DR. BLAYNEY: Given what we have seen and our experience, I think it
> would be reasonable to ask the question, front-line in untreated
> patients, does this drug offer a benefit over\--pick your
> chemotherapy. I would probably pick a good performance status,
> relatively good prognosis, patient population.
>
> But I think, from my point of view, that is an ethical question to
> ask.
>
> DR. PRZEPIORKA: Dr. Martino?
>
> DR. MARTINO: I want to simply follow up on that. There is a design in
> front-line that has been mentioned around the table and that is
> actually looking at a new agent\--this would be the new agent\--in
> place of chemotherapy. I think that would allow us to, first of all,
> look at this agent up-front but, also, if it turns out to be as good
> as and, perhaps, better than chemotherapy, would be a nice
> alternative.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Just a comment about the crossover designs that have been
> mentioned or the early and late IRESSA, say, in the third-line
> setting, there are a lot of problems with that. I just wanted to make
> sure everybody is aware of that, that it might be easy to get\--it
> might be a practical issue of getting patients on the study but there
> is a real serious problem with\--you, first of all, have to be very
> careful about the time to progression, making sure the blinding is
> working properly so you are not biased in deciding when somebody has
> progressed so that they can get IRESSA or something.
>
> But just the whole issue of how soon you do that is going to cause you
> to be very limited in your kinds of conclusions. If that were the kind
> of follow-up study, I would be kind of skeptical of whether whatever
> came out of that would really prove or validate the clinical benefit
> of IRESSA.
>
> So that just kind of bothers me. It is possible to do but it would
> need to be carefully thought out.
>
> DR. PRZEPIORKA: Dr. Varricchio?
>
> DR. VARRICCHIO: I would to suggest that, given the hints that have
> come from the trials that we have been hearing about, that any
> subsequent trial be designed so that it could look at stratifications
> in the analysis that might let you be able to begin to look at
> predicting which subset of people this drug would be most effective to
> be used in.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: This is a difficult issue because whether accelerated
> approval is granted or not, the efficacy has not been established. The
> issue on the table here was not whether full approval should occur. It
> is whether accelerated approval should occur.
>
> So whether or not FDA grants accelerated approval, it is recognized
> that efficacy has not been established and there needs to be a timely
> conduct of adequate and well-controlled studies to achieve that
> evidence.
>
> Many of us have argued for a long time that accelerated approval has
> many advantages and disadvantages, advantages if there is adequate
> evidence to establish plausibility of benefit, it provides earlier
> access. However, at the risk of providing earlier access to
> interventions that haven\'t been truly proven to have a favorable
> benefit-to-risk profile and also, at the significant risk of being
> able to do a timely assessment\--i.e., if there is accelerated
> approval, we had already heard from the sponsor that they had
> reservations about mounting the Phase III comparative or Phase IV
> postmarketing comparator trials without accelerated approval.
>
> Now, if there is accelerated approval with wide access, not
> access\--an expanded access limited to those people who wouldn\'t be
> eligible for a study but to anyone who would choose to get access, is
> it logical to think that we are going to be able to mount a truly
> informative randomized comparative study to reliably assess effects on
> clinical endpoints.
>
> It could be argued, well, sure we will do a crossover study. As Dr.
> George has pointed out, they can be very problematic in
> interpretation, particularly if you offer crossover at a relatively
> early point in time. So let\'s suppose, based on what I am hearing,
> that people are not so willing to take a failure in first-line and, in
> any way, argue that that should give us less confidence in third-line.
>
> I think I would ask, then, under that logic if accelerated approval is
> granted, give me a third-line trial that is a randomized comparative
> study that will truly establish in a timely way efficacy on clinical
> endpoints. That is going to take several hundred patients properly
> randomized and followed for an adequate duration of time to be able to
> meaningfully establish the benefits at least on symptoms and,
> potentially, even on survival.
>
> I have serious concerns as to how that is really, truly going to be
> something that can be done in a timely way as the regulations require
> if, in fact, accelerated approval is granted.
>
> DR. PRZEPIORKA: Mr. Ohye?
>
> MR. OHYE: When accelerated approval is granted, it is only granted in
> the United States. So there is Canada and other countries where this
> study can be carried out. I would also like to add that, before I
> retired, I was a competitor of AstraZeneca. As a competitor, I was
> very much impressed with the level of research that they are able to
> carry out because they have research centers in Sweden, which is a
> major scientific center, and they have research centers in the U.K.
> and in the United States.
>
> So, with this worldwide capability and the brain power that they have
> available, I have every confidence that they would be able to come to
> an agreement with the agency on the appropriate study and carry it out
> in a timely fashion.
>
> DR. FLEMING: And you are confident that the results that would be done
> in other settings would be truly relevant? We have already seen the
> differences in ethnicity with the Japanese and U.S. That doesn\'t
> cause you any concern?
>
> MR. OHYE: I think the challenge has been set down before the company
> and, while I can\'t speak for the company, I have competed against
> this company and I know that their capabilities are formidable.
>
> DR. PAZDUR: Tom, the drug is approved in Japan, so doing the trial in
> Japan would not be an option. The EU community; we have accepted
> lung-cancer trials from Western Europe and even Eastern Europe. So we
> feel confident in that aspect of quality of data and comparable
> results to the U.S.
>
> DR. PRZEPIORKA: Hearing no further comments, I will adjourn the
> meeting. Thank you.
>
> \[Whereupon, at 3:35 p.m., the meeting was adjourned.\]

\- - -