NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review

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					         NDA 21-399
ZD1839 for Treatment of
        NSCLC

        FDA Review
Division of Oncology Drug Products
          FDA ZD1839 NDA Review Team
           Project Managers                          Amy Baird
                                                     Dotti Pease

           Medical                                   Martin Cohen, M.D.
                                                     Grant Williams, M.D.
                                                     Richard Pazdur, M.D.

           Statistics                                Rajeshwari Sridhara, Ph.D.
                                                     Gang Chen, Ph.D.

           Chemistry & Manufacturing                 Chengyi Liang, Ph.D.
                                                     Richard Lostritto, Ph.D.

           Pharmacology & Toxicology                 William McGuinn, Ph.D.
                                                     David Morse, Ph.D.

           Clinical Pharmacology                     Sophia Abraham, Ph.D.
                                                     Atiqur Rahman, Ph.D.

           Division of Scientific Investigations     Khin U, M.D.


9/24/02                       ODAC Presentation: NDA 21-399                       2
          Outline of FDA Presentation

   Regulatory Overview and Critical Issues
     Grant Williams, MD

   Medical Review Findings
     Martin Cohen, MD

   Statistical Review Findings
     Rajeshwari Sridhara, PhD

   Summary and Introduction of Questions
     Grant Williams, MD


9/24/02                   ODAC Presentation: NDA 21-399   3
            Study Results
1. Claim of symptom improvement from a study
  without a control arm
2. Response rate (RR) of 10% in 139 patients
  with refractory NSCLC
3. No clinical benefit in two large controlled
  studies of first-line treatment of NSCLC
4. In view of #3, is the 10% RR in refractory
  NSCLC reasonably likely to predict clinical
  benefit?


9/24/02        ODAC Presentation: NDA 21-399     4
           Efficacy requirement for
                regular approval
         1962 law: substantial evidence of efficacy
          from well controlled clinical trials
         Efficacy is defined as clinical benefit




9/24/02              ODAC Presentation: NDA 21-399   5
 DODP: Endpoints for Approval

  Approvals not based on Survival:
           67% (37/55) excluding accelerated
            approvals
           73% (48/66) of all approvals




9/24/02              ODAC Presentation: NDA 21-399   6
Examples of Approvals Based on
   Tumor-Related Symptoms
   Symptoms from obstructive esophageal
    cancer or lung cancer
   Symptomatic prostate cancer
   Symptomatic cutaneous KS or CTCL
   Bone morbidity from metastatic cancer



9/24/02        ODAC Presentation: NDA 21-399   7
          Problems with AZ symptom
                benefit claims
   No concurrent control
   Confounding palliative medications
   Response correlation:
         Patient and observer bias
         Assessment bias
         Shared baseline prognostic factors (known
          and unknown)

9/24/02              ODAC Presentation: NDA 21-399    8
             Accelerated approval
         Serious or life-threatening disease
         Drug must provide benefit over available
          therapy
         Surrogate endpoint may be used
         Surrogate endpoint must be reasonably
          likely to predict clinical benefit
         Post marketing studies must verify clinical
          benefit

9/24/02              ODAC Presentation: NDA 21-399   9
          DODP Accelerated Approval Using
                    Response Rates
             Drug                           Indication
   Liposomal doxorubicin     Kaposi's sarcoma, second line
   Docetaxel                 Breast cancer, second line
   Irinotecan                Colon cancer, second line
   Capecitabine              Breast cancer, refractory
   Liposomal cytarabine      Lymphomatis meningitis
   Temozolomide              Anaplastic astrocytoma, refractory
   Liposomal doxorubicin     Ovarian cancer, refractory
   Gemtuzumab ozogamicin     AML, second line, elderly
   Imatinib mesylate         CML: blast phase, accelerated
                             phase, or after failing interferon
   Oxaliplatin               Colon cancer after failing 5FU/LV
                             and irinotecan
9/24/02             ODAC Presentation: NDA 21-399                 10
          Evidence for Accelerated
                 Approval
   Substantial evidence from well controlled
    clinical trials regarding a surrogate
    endpoint
   NOT: Borderline evidence regarding a
    clinical benefit endpoint




9/24/02          ODAC Presentation: NDA 21-399   11
             Accelerated approval
         Serious or life-threatening disease
         Drug must provide benefit over available
          therapy
         Surrogate endpoint may be used
         Surrogate endpoint must be reasonably
          likely to predict clinical benefit
         Post marketing studies must verify clinical
          benefit

9/24/02              ODAC Presentation: NDA 21-399   12
          Drug must provide benefit
            over available therapy
         Single arm trial design (all patients
          receive ZD1839) dictates study of
          patients with no available therapy
         Drugs are currently available for first-line
          and second-line treatment of NSCLC
         The single arm design of Study 039
          restricts the accelerated approval analysis
          to third-line NSCLC (139 patients)
9/24/02               ODAC Presentation: NDA 21-399   13
     Reasonably likely to predict
          clinical benefit
   This is a judgement based on all available
    evidence
   A response rate of about 10% has
    supported some AA’s (e.g., irinotecan)
   Lack of clinical benefit in large,
    randomized first-line studies must be
    considered


9/24/02         ODAC Presentation: NDA 21-399   14
Medical Review Findings

     Martin Cohen, MD
              FDA Approved Drugs:
              NSCLC Stage IIIB/IV

          First line -  paclitaxel/cisplatin
                       gemcitabine/cisplatin
                       vinorelbine + cisplatin
          Second line - docetaxel




9/24/02              ODAC Presentation: NDA 21-399   16
    NSCLC Stage IIIB/IV
Submitted ZD1839 Clinical Trials

Trial  39 - Third-line trial for
 accelerated approval
Trial 16 - Supporting second-line trial

INTACT 1 and 2 - First-line trials to
 demonstrate clinical benefit
        Trial Designs

Phase II, Randomized, Double-Blind
       ZD1839 250 mg/day
              versus
      ZD1839 500 mg/day
Trial 39 - Efficacy Endpoints

Co-primary:
 Response rate

 Disease related symptom improvement

  (Assessment difficulty was recognized)
          Trial 39 ITT Population n=216
Characteristic              % of Patients
Performance status 0-1           80
Tumor Histology
  Squamous                       15
  Adenocarcinoma                 66
  Squamous & Adenocarcinoma       7
Months from Dx (median)          20
Stage IV at diagnosis            50
Metastases at study entry        89
9/24/02          ODAC Presentation: NDA 21-399   20
 Trial 39 Pts refractory or intolerant

                                       Platinum
                                 refractory/intolerant
                                    Yes         No
   Docetaxel
                   Yes                 139       58
   refractory/
   intolerant       No                  11       8



9/24/02          ODAC Presentation: NDA 21-399        21
               Trial 39 Responder
                 Characteristics
          Characteristics of 22
               responders                                N (%)
    Female sex            (43%)*                         18 (82)
    Adenocarcinoma        (66%)                          19 (86)
    Stage IV at diagnosis                                13 (59)
    Dx to Randomization (mo)
    <12                                                   3 (14)
    13-24                                                12 (55)
    >25                                                   7 (32)
    3 to 5 prior chemo regimens                          15 (68)
   * Percent of study population
9/24/02                  ODAC Presentation: NDA 21-399             22
               Trial 39 Responder
                 Characteristics
          Pt characteristic              N           Response rate
   Platinum &            14/139                         10.1%
   Docetaxel
   refractory/intolerant
   Not refractory/        8/77                          10.4%
   intolerant to both


9/24/02              ODAC Presentation: NDA 21-399               23
Symptom Assessment Problems


 - Patients and caregivers are unblinded
 - Patients are informed of response
 - No prospective plan for managing
   concomitant medication
Concomitant Medication
   Narcotics
   Bronchodilators
   Antidepressants/Anxiolytics
   Oxygen
   Prednisone
   Transfusions/Erythropoietin
   Antibiotics
   Cough Syrup
   Trial 16 ITT Population n=209
           Characteristic                      % of Patients
   Performance status 0-1                           87
   Tumor Histology
     Squamous                                      21
     Adenocarcinoma                                63
   Months from Dx (median)                         12
   Stage IV currently                              79
   Caucasian/Japanese                             49/49
9/24/02        ODAC Presentation: NDA 21-399               26
     Trial 16: Prior Chemotherapy

 Previous chemotherapy        All patients (%)
                                  (n=209)
 Platinum, 1st or 2nd line          100
 Progression on either 1st or        35
 2nd line
 No progression on chemo             65


9/24/02         ODAC Presentation: NDA 21-399    27
      Trial 16 Objective Response
                  Rate

          Best Response             Number (%)
               CR                          1 (0.5)
               PR                       38 (18.2)




9/24/02          ODAC Presentation: NDA 21-399       28
          Responder Characteristics
           Characteristic                           N
           Sex
            Male                            18/148 (12)
            Female                          21/61 (34)
           Origin
             Caucasian                      11/102 (11)
             Japanese                       28/102 (27)
           Histology
             Adeno                         34/132 (26)
             Squamous                       3/43 (7)
           Months from Dx                14.9 (1.8 - 84.6)
             Median (range)
9/24/02             ODAC Presentation: NDA 21-399            29
             Response Rate and
          Chemotherapy Progression


                 No Progression Progression
     Caucasian    9/62 (15%)                      2/40 (5%)
     Japanese    19/69 (28%)                      9/33 (27%)



9/24/02           ODAC Presentation: NDA 21-399                30
              Trials 39 & 16 AE’s
             AE       250 mg/d (%) 500 mg/d (%)
          Diarrhea         44           62
          Rash             45           61
          Acne             30           24
          Dry skin         20           28
          Nausea           13           20
          Vomiting         9            14

9/24/02              ODAC Presentation: NDA 21-399   31
                   Response Rates

                                           Number      %
          Trial 39
           Doubly refractory                 14/139   10.1*
           < doubly refractory                8/77    10.4
          Trial 16
           Caucasian                         11/102   10.8
           Japanese                          28/102   27.5
     * 95% CI 5.6%,16.3%
9/24/02               ODAC Presentation: NDA 21-399           32
     Trial 39 Responding Patients

 Responders constitute a patient population
  enriched for slowly growing, relatively
  non-biologically aggressive cancers.
 Median time from diagnosis to
  randomization was 19.5 months
 Responders were predominantly P.S. 0-1
  females with adenocarcinomas.

9/24/02       ODAC Presentation: NDA 21-399   33
           Symptom Improvement
          Problems in Interpretation

   Not blinded (no comparator regimen)
   Concomitant medications
       Drug dose and schedule information
             not collected
   ? bias in responders


9/24/02          ODAC Presentation: NDA 21-399   34
NDA 21-399: ZD1839 for
        NSCLC

  Statistical Review Findings

     Rajeshwari Sridhara, Ph.D.
          Major Concerns in Trial IL0039

   Trial Design: Single Arm Trial to Eliminate < 5%
    Response; Trial sized to independently evaluate
    efficacy in the two ZD1839 treatment arms (250
    mg and 500 mg)
   Heterogeneity of patient population (third and
    second line patients)
   No Comparative Control Arm (no non-ZD1839
    arm)


9/24/02            ODAC Presentation: NDA 21-399   36
               Objective Tumor Response


         250 mg + 500 mg ZD1839 Treatment Arms
          (Third Line Patients Only):

             Total 14/139 ( 10.1 %) responses
               95% C.I.: 5.6 %, 16.3%




9/24/02                 ODAC Presentation: NDA 21-399   37
    Symptom Improvement - LCS Score

                                  Not at A little Some- Quite   Very
                                   all    bit      what a lot   much

1. I have been short of breath       0         1        2   3    4
2. I am losing weight                0         1        2   3    4
3. My thinking is clear              0         1        2   3    4
4. I have been coughing              0         1        2   3    4
5. I have a good appetite            0         1        2   3    4
6. I feel tightness in my chest      0         1        2   3    4
7. Breathing is easy for me          0         1        2   3    4



9/24/02                 ODAC Presentation: NDA 21-399                38
    Symptom Improvement - LCS Score

                                  Not at A little Some- Quite   Very
                                   all    bit      what a lot   much

1. I have been short of breath       0         1        2   3     4
2. I am losing weight                0         1        2   3     4
3. My thinking is clear              0         1        2   3     4
4. I have been coughing              0         1        2   3     4
5. I have a good appetite            0         1        2   3     4
6. I feel tightness in my chest      0         1        2   3     4
7. Breathing is easy for me          0         1        2   3     4
                                     0                           28

9/24/02                 ODAC Presentation: NDA 21-399                 39
    Symptom Improvement - LCS Score
          Baseline Score = 24

                                   Not at A little Some- Quite   Very
                                    all    bit      what a lot   much

1. I have been short of breath        0         1        2   3     4
2. I am losing weight                 0         1        2   3     4
3. My thinking is clear               0         1        2   3     4
4. I have been coughing               0         1        2   3     4
5. I have a good appetite             0         1        2   3     4
6. I feel tightness in my chest       0         1        2   3     4
7. Breathing is easy for me           0         1        2   3     4
                                      0                           28

9/24/02                  ODAC Presentation: NDA 21-399                 40
    Symptom Improvement - LCS Score
          Baseline Score= 24                                 Improved Score = 26

                                   Not at A little Some- Quite           Very
                                    all    bit      what a lot           much

1. I have been short of breath        0         1        2        3        4
2. I am losing weight                 0         1        2        3        4
3. My thinking is clear               0         1        2        3        4
4. I have been coughing               0         1        2        3        4
5. I have a good appetite             0         1        2        3        4
6. I feel tightness in my chest       0         1        2        3        4
7. Breathing is easy for me           0         1        2        3        4
                                      0                                   28

9/24/02                  ODAC Presentation: NDA 21-399                         41
           Symptom Improvement Rate

   250 mg and 500 mg ZD1839 Treatment Arms
    (Third line patients only):

         45/139 (32.4 %) with symptom
          improvement per sponsor definition of
          improvement on the LCS scale




9/24/02              ODAC Presentation: NDA 21-399   42
          Patient LCS Profile - An Example




9/24/02            ODAC Presentation: NDA 21-399   43
          Patient LCS Profile - An Example

                                              1. Short of Breath
                                              2. Losing Weight
                                              3. Thinking is Clear
                                              4. Been Coughing
                                              5. Good Appetite
                                              6. Tightness in Chest
                                              7. Breathing Easy




9/24/02            ODAC Presentation: NDA 21-399                      44
 % of Patients Evaluated Over Time

                          100
                           90
                           80
          % of PATIENTS




                           70
                           60
                                                                                         250 mg
                          50
                                                                                         500 mg
                          40
                          30
                          20
                          10
                           0
                                0   1   2 3   4   5   6   7   8 9 10 11 12 13 14 15 16
                                                          WEEKS




9/24/02                                       ODAC Presentation: NDA 21-399                       45
                Critical Issues
     Efficacy with respect to Objective Tumor
      Response with ZD1839 could be as low as
      5.6% (lower 95% CL = 5.6%).

     Symptom Improvement not interpretable
      without control data.

     Symptom Improvement possibly confounded
      by concomitant medication effect and patient
      characteristics
9/24/02            ODAC Presentation: NDA 21-399     46
     Results of Randomized, Controlled,
    Phase III Studies in First-line NSCLC
                  Patients
   Study IL0014:

         Gemcitabine + Cisplatin + ZD1839 250 mg; N = 365

         Gemcitabine + Cisplatin + ZD1839 500 mg; N = 365

         Gemcitabine + Cisplatin + Placebo; N = 363



9/24/02                ODAC Presentation: NDA 21-399         47
            250 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.4382
            500 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.3041




9/24/02   ODAC Presentation: NDA 21-399                             48
                         250 mg vs. Placebo: HR 1.0 (0.8, 1.2)
                         500 mg vs. Placebo: HR 0.9 (0.8, 1.1)




9/24/02   ODAC Presentation: NDA 21-399                          49
Tumor Response and One-year Survival
        Rates in Trial IL0014
Treatment Arm         Response Rate             % KM Survival
                       (95% C.I.)                Estimate at 1 yr
                                                     (S.E.)
Chemo +                    50.1%                  43.75 (2.61)
ZD1839 250 mg         (44.7%, 55.6%)
Chemo +                    49.7%                  41.51(2.59)
ZD1839 500 mg         (44.2%, 55.2%)
Chemo +                    44.8%                  44.87 (2.64)
Placebo               (39.3%, 50.4%)


9/24/02         ODAC Presentation: NDA 21-399                    50
     Results of Randomized, Controlled,
    Phase III Studies in First-line NSCLC
                  Patients
   Study IL0017:

         Taxol + Carboplatin + ZD1839 250 mg; N = 347

         Taxol + Carboplatin + ZD1839 500 mg; N = 345

         Taxol + Carboplatin + Placebo; N = 345




9/24/02                 ODAC Presentation: NDA 21-399    51
            250 mg vs. Placebo: HR 1.0 (0.9, 1.2), P-value 0.6429
            500 mg vs. Placebo: HR 1.0 (0.8, 1.2), P-value 0.6710




9/24/02   ODAC Presentation: NDA 21-399                             52
                 250 mg vs. Placebo: HR 0.85 (0.70, 1.03)
                 500 mg vs. Placebo: HR 0.86 (0.72, 1.04)




9/24/02   ODAC Presentation: NDA 21-399                     53
Tumor Response and One-year Survival
        Rates in Trial IL0017
Treatment Arm         Response Rate             % KM Survival
                       (95% C.I.)                Estimate at 1 yr
                                                     (S.E.)
Chemo +                    35.0%                  37.57 (2.60)
ZD1839 250 mg         (29.6%, 40.6%)
Chemo +                    32.1%                  41.89 (2.67)
ZD1839 500 mg         (27.0%, 37.7%)
Chemo +                    33.6%                  42.22 (2.66)
Placebo               (28.1%, 39.3%)


9/24/02         ODAC Presentation: NDA 21-399                    54
          Results of Phase III Studies
   No Statistically Significant Difference with
    respect to Overall Survival between ZD1839
    treated group and Placebo treated group in the
    two well conducted, placebo controlled,
    randomized studies in over 2000 patients.

   No difference between ZD1839 treated arm and
    Placebo treated arm with respect to secondary
    endpoints including response rate and time to
    progression in both the studies.


9/24/02           ODAC Presentation: NDA 21-399      55
Summary of FDA Findings


     Grant Williams, MD
             Study Results
1. Claim of symptom improvement from a
  study without a control arm
2. Response rate (RR) of 10% in 139
  patients with refractory NSCLC
3. No clinical benefit in two large controlled
  studies of first-line treatment of NSCLC
4. In view of #3, is the 10% RR in refractory
  NSCLC reasonably likely to predict clinical
  benefit?

9/24/02         ODAC Presentation: NDA 21-399    57
    Questions to the Committee
1. Can symptom improvements claimed
  for ZD1839 be adequately assessed
  without a control arm?
2. Given negative studies in first-line
  treatment of NSCLC, is the 10% RR in
  refractory NSCLC reasonably likely to
  predict clinical benefit?
3. Discuss expanded access
4. Discuss design of additional trials.
9/24/02       ODAC Presentation: NDA 21-399   58