Oncologic Drugs Advisory Committee

Questions to the Committee

September 24, 2002

NDA 21-399 ZD 1839 IIRESSA® (gefitinib)

AstraZeneca Pharmaceuticals LP


Indication: for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have previously received platinum-based chemotherapy


AstraZeneca has submitted a marketing application for the above indication for consideration of accelerated approval. Results from this ZD1839 New Drug Application (NDA) pose an unusual regulatory dilemma Before the Agencys action on this application, could act on this application for accelerated approval in patients with refractory NSCLC, results results became available from ZD1839 studies in patients with previously untreated NSCLC. Two large randomized trialsshowed no failed to show clinical benefit from the addition of ZD1839 to standard first-line cisplatin-based regimens.in these patients who were receiving chemotherapy. The Agency had expected that if ZD1839 received accelerated approval in refractory NSCLC, these trials would provide the post-approval evidence of ZD1839 clinical benefit. Such eEvidence of clinical benefit is requiredto allow for the conversion of the application status from accelerated approval to full approval. NowPresently, the Agency must consider the relevance of the tumor response data from the single-arm ZD1839 trials of patients with refractory NSCLC. Given the lack of ZD1839 clinical benefit in patients with previously untreated NSCLC, the dilemma is whether a 10% response rate in a 3rd line treatment is reasonably likely to predict clinical benefit.

The regulations and results are discussed in more detail below.

Regulatory Background

Regular marketing approval of oncology drugs requires substantial evidence of efficacy from well-controlled clinical trials. Guidance promulgated in the 1980's indicated that efficacy for cancer treatment should be demonstrated by prolongation of life, a better life, or an established surrogate for at least one of these. In 1992, Subpart H was added to the NDA regulations to allow accelerated approval (AA) for diseases that are serious or life-threatening where the new drug appears to provide benefit over available therapy. AA can be granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit. After AA, the applicant is required to perform a post-marketing study to demonstrate that treatment with the 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 the drug from the market. After AA of oncology drugs, clinical benefit has often been evaluated in patients with less refractory tumors, i.e., in first or second-line treatment settings.

Results of single-arm studies of chemotherapy resistant/refractory NSCLC

Response rate claims


Study 0039 evaluated Iressa ZD1839 treatment in 216 NSCLC patients, including 139 patients with tumors resistant or refractory to cisplatin and taxotere. These 139 patients were considered to have no available therapy. In this population, response rate serves as the surrogate endpoint for the AA claim. The response rate was 10.1% (95% CI: 5%,17%)

Symptom improvement claims

Patient symptoms were evaluated with the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L). This subscale is composed of seven 4-point questions that are summed for a total of 28 possible points. The applicant claims that clinical benefit is demonstrated by individuals showing a 28-day, 2-point improvement on the LCS of 28 day duration. The The applicant finds that aboutapproximately 40% of patients in Study 39 derive such benefit, and that the benefit correlates with response and survival. The FDA believes these results are not reliable because there is no concurrent, randomized, blinded control arm and the lack of a prospective plan for collecting and analyzing data on supportive care products (e.g., oxygen and pain medications) did not exist.


Results from randomized clinical studies in first-line treatment of NSCLC

Recently, the applicant provided FDA with analyses of two trials evaluating standard chemotherapy plus or minus ZD1839 in first-line treatment of NSCLC. These results are relevant because the FDA must determine whether a 10% ZD1839 response rate is reasonably likely to predict clinical benefit. The FDA must consider all available information on a drug product prior to making a regulatory decision. The lack of ZD1839 clinical benefit in the closely related first-line NSCLC setting could bear on this judgement must be considered in the FDAs regulatory decision-making process.

Approximately Despite about 350 patients per arm were entered on each trial.and aAdequate follow-up (about 240 events per arm) has been provided. nNeither sStudy 14 nor Study 17 showed a survival benefits for the addition of ZD1339 to chemotherapy.

Study 14 Survival


At Risk Events in Months 1-year

500 mg ZD1839 365 243 9.9 44%

250 mg ZD1839 365 248 9.9 42%

Placebo 363 236 11.1 45%


Study 17 Survival


At Risk Events in Months 1-year

500 mg ZD1839 347 246 8.7 38%

250 mg ZD1839 345 232 9.8 42%

Placebo 345 247 9.9 42%


Depending on the number of patients entered and subsequent events, Ddetection of a small survival benefit canmay be difficult. if the effect is small.However, for active drugs, a difference in response rate difference may be detected in these situations. It is usually easier to detect a response rate. In these studiesStudy 14 and 17, the addition of ZD1839 to chemotherapy did not also caused noresult in a significant improvement in response rates:

Study 14 Study 17

Response Rate Response Rate

500 mg ZD1839 49.7% 32.1%

250 mg ZD1839 50.1% 35.0%

Placebo 44.8% 33.6%


Questions to the Committee:

1. The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without 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?

2. Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?

3. More than 12,000 NSCLC patients have received ZD1839 under an expanded access protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.

4. Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.