# Presentation: 719235

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

## FDA ZD1839 NDA Review Team

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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?

- ODAC Presentation: NDA 21-399

- 9/24/02

## Efficacy requirement for regular approval

- 1962 law: substantial evidence of efficacy from well controlled clinical trial_s_
- Efficacy is defined as clinical benefit

- ODAC Presentation: NDA 21-399

- 9/24/02

## DODP: Endpoints for Approval 

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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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)

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## DODP Accelerated Approval Using Response Rates 

- ODAC Presentation: NDA 21-399

- 9/24/02

## Evidence for Accelerated Approval

- _Substantial evidence_ from well controlled clinical trials regarding a surrogate endpoint
- NOT: _Borderline evidence_ regarding a clinical benefit endpoint

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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)

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## Medical Review Findings

- Martin Cohen, MD

## FDA Approved Drugs:                            NSCLC Stage IIIB/IV

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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trial 39 Pts refractory or intolerant

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trial 39 Responder Characteristics

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trial 39 Responder Characteristics

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trial 16: Prior Chemotherapy

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trial 16 Objective Response Rate

- ODAC Presentation: NDA 21-399

- 9/24/02

## Responder Characteristics

- ODAC Presentation: NDA 21-399

- 9/24/02

## Response Rate and Chemotherapy Progression

- ODAC Presentation: NDA 21-399

- 9/24/02

## Trials 39 & 16 AE’s

- ODAC Presentation: NDA 21-399

- 9/24/02

## Response Rates 

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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.

- ODAC Presentation: NDA 21-399

- 9/24/02

## Symptom Improvement Problems in Interpretation

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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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)

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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%

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- Baseline Score = 24

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- Baseline Score= 24

- Improved Score = 26

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## Patient LCS Profile - An Example

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## % of Patients Evaluated Over Time

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

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

_**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**

- ODAC Presentation: NDA 21-399

- 9/24/02

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

_**250 mg vs. Placebo**_**: HR 1.0  (0.8, 1.2)**
_**500 mg vs. Placebo**_**: HR 0.9  (0.8, 1.1)**

- ODAC Presentation: NDA 21-399

- 9/24/02

## Tumor Response and One-year Survival 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) |

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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

- ODAC Presentation: NDA 21-399

- 9/24/02

## 250 mg vs. Placebo: HR 1.0 (0.9, 1.2), P-value 0.6429

_**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**

- ODAC Presentation: NDA 21-399

- 9/24/02

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

_**250 mg vs. Placebo**_**: HR 0.85  (0.70, 1.03)**
_**500 mg vs. Placebo**_**: HR 0.86  (0.72, 1.04)**

- ODAC Presentation: NDA 21-399

- 9/24/02

## Tumor Response and One-year Survival 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) |

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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.

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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?

- ODAC Presentation: NDA 21-399

- 9/24/02

## 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.

- ODAC Presentation: NDA 21-399

- 9/24/02