Oncologic Drugs Advisory Committee

**Questions to the Committee**

September 24, 2002

NDA 21-399 ZD 1839 IRESSA^®^ (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

**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 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 2-point improvement on
the LCS of 28 day duration The applicant finds that approximately 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 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 must be considered in the FDA's regulatory decision-making
process.

Approximately 350 patients per arm were entered on each trial.Adequate
follow-up (about 240 events per arm) has been provided. Neither Study 14
nor Study 17 showed survival benefits for the addition of ZD1339 to
chemotherapy.

**Study 14 Survival**

Median

> [At Risk]{.underline} [Events]{.underline} [in Months]{.underline}
> [1-year]{.underline}

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**

Median

> [At Risk]{.underline} [Events]{.underline} [in Months]{.underline}
> [1-year]{.underline}

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,
detection of a small survival benefit may be difficult. However, for
active drugs, a difference in response rate difference may be detected
in these situations. In Study 14 and 17, the addition of ZD1839 to
chemotherapy did not result in a significant improvement in response
rates:

**Study 14 Study 17**

> **[Response Rate]{.underline} [Response Rate]{.underline}**

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.