NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products

NDA 21-399NDA 21-399 ZD1839 for Treatment of ZD1839 for Treatment of

NSCLCNSCLC

FDA ReviewFDA ReviewDivision of Oncology Drug Division of Oncology Drug

ProductsProducts

9/24/029/24/02 ODAC Presentation: NDA 21-399ODAC Presentation: NDA 21-399 22

Project Managers Amy BairdDotti 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.

FDA ZD1839 NDA Review TeamFDA ZD1839 NDA Review Team


Outline of FDA PresentationOutline of FDA Presentation

Regulatory Overview and Critical IssuesRegulatory Overview and Critical IssuesGrant Williams, MDGrant Williams, MD

Medical Review FindingsMedical Review FindingsMartin Cohen, MDMartin Cohen, MD

Statistical Review FindingsStatistical Review FindingsRajeshwari Sridhara, PhDRajeshwari Sridhara, PhD

Summary and Introduction of QuestionsSummary and Introduction of QuestionsGrant Williams, MDGrant Williams, MD


Study ResultsStudy Results1. Claim of symptom improvement from a 1. Claim of symptom improvement from a

study without a control armstudy without a control arm

2. Response rate (RR) of 10% in 139 2. Response rate (RR) of 10% in 139 patients with refractory NSCLCpatients with refractory NSCLC

3. No clinical benefit in two large controlled 3. No clinical benefit in two large controlled studies of first-line treatment of NSCLCstudies of first-line treatment of NSCLC

4. In view of #3, is the 10% RR in refractory 4. In view of #3, is the 10% RR in refractory NSCLC NSCLC reasonably likely to predict clinical reasonably likely to predict clinical benefitbenefit??


Efficacy requirement for Efficacy requirement for regular approvalregular approval

1962 law: substantial evidence of 1962 law: substantial evidence of efficacy from well controlled clinical efficacy from well controlled clinical trialtrialss

Efficacy is defined as clinical benefitEfficacy is defined as clinical benefit


DODP: Endpoints for DODP: Endpoints for Approval Approval

Approvals not based on SurvivalApprovals not based on Survival: : 67% (37/55) excluding accelerated 67% (37/55) excluding accelerated

approvalsapprovals 73% (48/66) of all approvals73% (48/66) of all approvals


Examples of Approvals Examples of Approvals Based on Tumor-Related Based on Tumor-Related

SymptomsSymptoms Symptoms from obstructive Symptoms from obstructive

esophageal cancer or lung cancer esophageal cancer or lung cancer Symptomatic prostate cancerSymptomatic prostate cancer Symptomatic cutaneous KS or Symptomatic cutaneous KS or

CTCLCTCL Bone morbidity from metastatic Bone morbidity from metastatic

cancer cancer


Problems with AZ symptom Problems with AZ symptom benefit claimsbenefit claims

No concurrent controlNo concurrent control Confounding palliative medicationsConfounding palliative medications Response correlation:Response correlation:

Patient and observer biasPatient and observer bias Assessment biasAssessment bias Shared baseline prognostic factors Shared baseline prognostic factors

(known and unknown)(known and unknown)


Accelerated approval Accelerated approval Serious or life-threatening diseaseSerious or life-threatening disease Drug must provide benefit over Drug must provide benefit over

available therapyavailable therapy Surrogate endpoint may be usedSurrogate endpoint may be used Surrogate endpoint must be Surrogate endpoint must be reasonably reasonably

likely to predict clinical benefitlikely to predict clinical benefit Post marketing studies must verify Post marketing studies must verify

clinical benefitclinical benefit


DODP Accelerated Approval Using DODP Accelerated Approval Using

Response RatesResponse Rates Drug Indication

Liposomal doxorubicin Kaposi's sarcoma, second lineDocetaxel Breast cancer, second lineIrinotecan Colon cancer, second lineCapecitabine Breast cancer, refractoryLiposomal cytarabine Lymphomatis meningitisTemozolomide Anaplastic astrocytoma, refractoryLiposomal doxorubicin Ovarian cancer, refractoryGemtuzumab ozogamicin AML, second line, elderlyImatinib mesylate CML: blast phase, accelerated

phase, or after failing interferonOxaliplatin Colon cancer after failing 5FU/LV

and irinotecan


Evidence for Accelerated Evidence for Accelerated ApprovalApproval

Substantial evidenceSubstantial evidence from well from well controlled clinical trials regarding a controlled clinical trials regarding a surrogate endpointsurrogate endpoint

NOT: NOT: Borderline evidenceBorderline evidence regarding a regarding a clinical benefit endpoint clinical benefit endpoint


Accelerated approvalAccelerated approval Serious or life-threatening diseaseSerious or life-threatening disease Drug must provide benefit over Drug must provide benefit over

available therapyavailable therapy Surrogate endpoint may be usedSurrogate endpoint may be used Surrogate endpoint must be Surrogate endpoint must be reasonably reasonably

likely to predict clinical benefitlikely to predict clinical benefit Post marketing studies must verify Post marketing studies must verify

clinical benefitclinical benefit


Drug must provide benefit Drug must provide benefit over available therapyover available therapy

Single arm trial design (all patients receive Single arm trial design (all patients receive ZD1839) dictates study of patients with no ZD1839) dictates study of patients with no available therapyavailable therapy

Drugs are currently available for first-line Drugs are currently available for first-line and second-line treatment of NSCLC and second-line treatment of NSCLC

The single arm design of Study 039 The single arm design of Study 039 restricts the accelerated approval analysis restricts the accelerated approval analysis to third-line NSCLC (139 patients)to third-line NSCLC (139 patients)


Reasonably likely to Reasonably likely to predict clinical benefitpredict clinical benefit

This is a judgement based on all This is a judgement based on all available evidenceavailable evidence

A response rate of about 10% has A response rate of about 10% has supported some AA’s (e.g., supported some AA’s (e.g., irinotecan)irinotecan)

Lack of clinical benefit in large, Lack of clinical benefit in large, randomized first-line studies must be randomized first-line studies must be consideredconsidered

Medical Review FindingsMedical Review Findings

Martin Cohen, MDMartin Cohen, MD


FDA Approved Drugs: FDA Approved Drugs: NSCLC Stage IIIB/IV NSCLC Stage IIIB/IV

First line - paclitaxel/cisplatinFirst line - paclitaxel/cisplatin

gemcitabine/cisplatingemcitabine/cisplatin

vinorelbine vinorelbine ++ cisplatincisplatin

Second line - docetaxelSecond line - docetaxel

NSCLC Stage IIIB/IVNSCLC Stage IIIB/IVSubmitted ZD1839 Clinical Submitted ZD1839 Clinical

TrialsTrials

Trial 39 - Third-line trial for Trial 39 - Third-line trial for accelerated approvalaccelerated approval

Trial 16 - Supporting second-line Trial 16 - Supporting second-line trialtrial

INTACT 1 and 2 - First-line trials to INTACT 1 and 2 - First-line trials to demonstrate clinical benefitdemonstrate clinical benefit

Trial DesignsTrial Designs

Phase II, Randomized, Double-Phase II, Randomized, Double-BlindBlind

ZD1839 250 mg/dayZD1839 250 mg/day

versusversus

ZD1839 500 mg/day ZD1839 500 mg/day

Trial 39 - Efficacy Trial 39 - Efficacy EndpointsEndpoints

Co-primary:Co-primary: Response rateResponse rate Disease related symptom Disease related symptom

improvementimprovement

(Assessment difficulty was (Assessment difficulty was recognized) recognized)


Trial 39 ITT Population Trial 39 ITT Population n=216n=216

Characteristic % of Patients

Performance status 0-1 80

Tumor Histology Squamous Adenocarcinoma Squamous & Adenocarcinoma

15667

Months from Dx (median) 20

Stage IV at diagnosis 50

Metastases at study entry 89


Trial 39 Pts refractory or Trial 39 Pts refractory or intolerantintolerant

Platinumrefractory/intolerant

Yes No

Yes 139 58Docetaxelrefractory/intolerant No 11 8


Trial 39 Responder Trial 39 Responder CharacteristicsCharacteristics

Characteristics of 22responders N (%)

Female sex (43%)* 18 (82)Adenocarcinoma (66%) 19 (86)Stage IV at diagnosis 13 (59)Dx to Randomization (mo)<1213-24>25

3 (14)12 (55) 7 (32)

3 to 5 prior chemo regimens 15 (68)* Percent of study population


Trial 39 Responder Trial 39 Responder CharacteristicsCharacteristics

Pt characteristic N Response rate

Platinum &Docetaxelrefractory/intolerant

14/139 10.1%

Not refractory/intolerant to both

8/77 10.4%

Symptom Assessment Symptom Assessment ProblemsProblems

- Patients and caregivers are - Patients and caregivers are unblinded unblinded

- Patients are informed of - Patients are informed of response response

- No prospective plan for - No prospective plan for managingmanaging

concomitant medicationconcomitant medication

Concomitant MedicationConcomitant Medication

NarcoticsNarcotics BronchodilatorsBronchodilators Antidepressants/Antidepressants/

AnxiolyticsAnxiolytics OxygenOxygen PrednisonePrednisone Transfusions/Transfusions/

ErythropoietinErythropoietin AntibioticsAntibiotics Cough SyrupCough Syrup


Trial 16 ITT Population Trial 16 ITT Population n=209n=209

Characteristic % of Patients

Performance status 0-1 87Tumor Histology Squamous Adenocarcinoma

2163

Months from Dx (median) 12Stage IV currently 79Caucasian/Japanese 49/49


Trial 16: Prior Trial 16: Prior ChemotherapyChemotherapy

Previous chemotherapy All patients (%)(n=209)

Platinum, 1st or 2nd line 100Progression on either 1st or2nd line

35

No progression on chemo 65


Trial 16 Objective Response Trial 16 Objective Response RateRate

Best Response Number (%)

CR 1 (0.5)

PR 38 (18.2)


Responder CharacteristicsResponder CharacteristicsCharacteristic N

Sex Male Female

18/148 (12)21/61 (34)

Origin Caucasian Japanese

11/102 (11)28/102 (27)

Histology Adeno Squamous

34/132 (26)3/43 (7)

Months from Dx Median (range)

14.9 (1.8 - 84.6)


Response Rate and Response Rate and Chemotherapy ProgressionChemotherapy Progression

No Progression Progression

Caucasian 9/62 (15%) 2/40 (5%)

Japanese 19/69 (28%) 9/33 (27%)


Trials 39 & 16 AE’sTrials 39 & 16 AE’s

AE 250 mg/d (%) 500 mg/d (%)

Diarrhea 44 62Rash 45 61Acne 30 24Dry skin 20 28Nausea 13 20Vomiting 9 14


Response RatesResponse Rates

Number %

Trial 39 Doubly refractory < doubly refractory

14/1398/77

10.1*10.4

Trial 16 Caucasian Japanese

11/10228/102

10.827.5

* 95% CI 5.6%,16.3%


Trial 39 Responding PatientsTrial 39 Responding Patients

Responders constitute a patient Responders constitute a patient population enriched for slowly population enriched for slowly growing, relatively non-biologically growing, relatively non-biologically aggressive cancers. aggressive cancers.

Median time from diagnosis to Median time from diagnosis to randomization was 19.5 months randomization was 19.5 months

Responders were predominantly P.S. Responders were predominantly P.S. 0-1 females with adenocarcinomas. 0-1 females with adenocarcinomas.


Symptom ImprovementSymptom Improvement Problems in Interpretation Problems in Interpretation

Not blinded (no comparator regimen)Not blinded (no comparator regimen) Concomitant medicationsConcomitant medications

Drug dose and schedule Drug dose and schedule information information not collectednot collected

? bias in responders? bias in responders

NDA 21-399: ZD1839 for NDA 21-399: ZD1839 for NSCLCNSCLC

Statistical Review FindingsStatistical Review Findings

Rajeshwari Sridhara, Ph.D.Rajeshwari Sridhara, Ph.D.


Major Concerns in Trial IL0039Major Concerns in Trial IL0039

Trial Design: Single Arm Trial to Eliminate Trial Design: Single Arm Trial to Eliminate < 5% Response; Trial sized to < 5% Response; Trial sized to independently evaluate efficacy in the two independently evaluate efficacy in the two ZD1839 treatment arms (250 mg and 500 ZD1839 treatment arms (250 mg and 500 mg)mg)

Heterogeneity of patient population (third Heterogeneity of patient population (third and second line patients)and second line patients)

No Comparative Control Arm (no non-No Comparative Control Arm (no non-ZD1839 arm)ZD1839 arm)


Objective Tumor ResponseObjective Tumor Response

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

Total 14/139 ( 10.1 %) responses Total 14/139 ( 10.1 %) responses

95% C.I.: 5.6 %, 16.3%95% C.I.: 5.6 %, 16.3%


Symptom Improvement - LCS Symptom Improvement - LCS ScoreScore

Not atNot at A littleA little Some-Some- QuiteQuiteVeryVery

allall bit bit what what a lota lotmuchmuch

1. I have been short of breath1. I have been short of breath 0 0 1 1 2 2 3 3 4 4

2. I am losing weight2. I am losing weight 0 0 1 1 2 2 3 3 4 4

3. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 3 3 4 4

4. I have been coughing4. I have been coughing 0 0 1 1 2 2 3 3 4 4

5. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 3 3 4 4

6. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 3 3 4 4

7. Breathing is easy for me7. Breathing is easy for me 0 0 1 1 2 2 3 3 4 4



Not atNot at A littleA little Some-Some- QuiteQuite VeryVery

allall bit bit what what a lota lot muchmuch

1. I have been short of breath1. I have been short of breath 0 0 1 1 2 2 3 3 4 4

2. I am losing weight2. I am losing weight 0 0 1 1 2 2 3 3 4 4

3. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 3 3 4 4

4. I have been coughing4. I have been coughing 0 0 1 1 2 2 3 3 4 4

5. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 3 3 4 4

6. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 3 3 4 4


00 2828





1. I have been short of breath1. I have been short of breath 00 1 1 2 2 3 3 4 4

2. I am losing weight2. I am losing weight 0 0 1 1 2 2 33 4 4

3. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 33 4 4

4. I have been coughing4. I have been coughing 00 1 1 2 2 3 3 4 4

5. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 33 4 4

6. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 33 4 4


00 2828

Baseline Score = 24





1. I have been short of breath1. I have been short of breath 00 1 1 2 2 3 3 4 4

2. I am losing weight2. I am losing weight 0 0 1 1 2 2 33 44

3. My thinking is clear3. My thinking is clear 0 0 1 1 2 2 33 44

4. I have been coughing4. I have been coughing 00 1 1 2 2 3 3 4 4

5. I have a good appetite5. I have a good appetite 0 0 1 1 2 2 33 4 4

6. I feel tightness in my chest6. I feel tightness in my chest 0 0 1 1 2 2 33 4 4


00 2828

Baseline Score= 24 Improved Score = 26


Symptom Improvement RateSymptom Improvement Rate

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

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


Patient LCS Profile - An ExamplePatient LCS Profile - An Example


Patient LCS Profile - An ExamplePatient 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


% of Patients Evaluated Over % of Patients Evaluated Over TimeTime

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

WEEKS

% o

f P

AT

IEN

TS

250 mg

500 mg


Critical IssuesCritical Issues Efficacy with respect to Objective Tumor Efficacy with respect to Objective Tumor

Response with ZD1839 could be as low Response with ZD1839 could be as low as 5.6% (lower 95% CL = 5.6%).as 5.6% (lower 95% CL = 5.6%).

Symptom Improvement not Symptom Improvement not interpretable without control data.interpretable without control data.

Symptom Improvement possibly Symptom Improvement possibly confounded by concomitant medication confounded by concomitant medication effect and patient characteristicseffect and patient characteristics


Results of Randomized, Controlled, Results of Randomized, Controlled, Phase III Studies in First-line Phase III Studies in First-line

NSCLC PatientsNSCLC Patients Study IL0014: Study IL0014:

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

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

Gemcitabine + Cisplatin + Placebo; N = 363Gemcitabine + Cisplatin + Placebo; N = 363


250 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.4382



250 mg vs. Placebo: HR 1.0 (0.8, 1.2)

500 mg vs. Placebo: HR 0.9 (0.8, 1.1)


Tumor Response and One-year Tumor Response and One-year Survival Rates in Trial IL0014Survival Rates in Trial IL0014

Treatment Arm Response Rate(95% C.I.)

% KM Survival Estimate at 1 yr

(S.E.)

Chemo + ZD1839 250 mg

50.1%(44.7%, 55.6%)

43.75 (2.61)

Chemo +ZD1839 500 mg

49.7%(44.2%, 55.2%)

41.51(2.59)

Chemo + Placebo

44.8%(39.3%, 50.4%)

44.87 (2.64)


Results of Randomized, Controlled, Results of Randomized, Controlled, Phase III Studies in First-line Phase III Studies in First-line

NSCLC PatientsNSCLC Patients Study IL0017: Study IL0017:

Taxol + Carboplatin + ZD1839 250 mg; N = Taxol + Carboplatin + ZD1839 250 mg; N = 347347

Taxol + Carboplatin + ZD1839 500 mg; N = Taxol + Carboplatin + ZD1839 500 mg; N = 345345

Taxol + Carboplatin + Placebo; N = 345Taxol + Carboplatin + Placebo; N = 345





250 mg vs. Placebo: HR 0.85 (0.70, 1.03)

500 mg vs. Placebo: HR 0.86 (0.72, 1.04)


Tumor Response and One-year Tumor Response and One-year Survival Rates in Trial IL0017Survival Rates in Trial IL0017

Treatment Arm Response Rate(95% C.I.)

% KM Survival Estimate at 1 yr

(S.E.)

Chemo + ZD1839 250 mg

35.0%(29.6%, 40.6%)

37.57 (2.60)

Chemo +ZD1839 500 mg

32.1%(27.0%, 37.7%)

41.89 (2.67)

Chemo + Placebo

33.6%(28.1%, 39.3%)

42.22 (2.66)


Results of Phase III StudiesResults of Phase III Studies No Statistically Significant Difference with No Statistically Significant Difference with

respect to Overall Survival between ZD1839 respect to Overall Survival between ZD1839 treated group and Placebo treated group in treated group and Placebo treated group in the two well conducted, placebo controlled, the two well conducted, placebo controlled, randomized studies in over 2000 patients. randomized studies in over 2000 patients.

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

Summary of FDA FindingsSummary of FDA Findings

Grant Williams, MDGrant Williams, MD


Study ResultsStudy Results1. Claim of symptom improvement from a 1. Claim of symptom improvement from a

study without a control armstudy without a control arm

2. Response rate (RR) of 10% in 139 2. Response rate (RR) of 10% in 139 patients with refractory NSCLCpatients with refractory NSCLC

3. No clinical benefit in two large controlled 3. No clinical benefit in two large controlled studies of first-line treatment of NSCLCstudies of first-line treatment of NSCLC

4. In view of #3, is the 10% RR in 4. In view of #3, is the 10% RR in refractory NSCLC refractory NSCLC reasonably likely to reasonably likely to predict clinical benefitpredict clinical benefit??


Questions to the Questions to the CommitteeCommittee

1. Can symptom improvements claimed 1. Can symptom improvements claimed for ZD1839 be adequately assessed for ZD1839 be adequately assessed without a control arm?without a control arm?

2. Given negative studies in first-line 2. Given negative studies in first-line treatment of NSCLC, is the 10% RR in treatment of NSCLC, is the 10% RR in refractory NSCLC reasonably likely to refractory NSCLC reasonably likely to predict clinical benefit?predict clinical benefit?

3. Discuss expanded access3. Discuss expanded access

4. Discuss design of additional trials.4. Discuss design of additional trials.

Documents

NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products