1 SNDA Gemzar plus Carboplatin Treatment of Late Relapsing Ovarian Cancer

2 Proposed Indication Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy

3 Pivotal Trial A Randomized Open Label Phase 3 Study Comparing Gemcitabine Plus Carboplatin Versus Carboplatin Monotherapy in Patients with Advanced Epithelial Ovarian Carcinoma Who Failed First-Line Platinum-Based Therapy

4 Dosing -Gemzar plus Carboplatin: Gemzar 1000 mg/m2 on Days 1 and 8 and carboplatin AUC 4 -Carboplatin Alone: Carboplatin AUC 5 administered on Day 1 Cycles are repeated every 21-days.

5 Regulatory Background -Study was not conducted under an IND. -Protocol had not been reviewed by DODP -Pre NDA Meeting 12/21/04. Issue: Is PFS an appropriate endpoint -Pre NDA Meeting 3/23/05. Further discussion of PFS and a sensitivity analysis plan

6 Submitted Clinical Studies Phase 3 - Pivotal trial Phase 2 - Gemzar + carboplatin in identical dose and schedule in an identical patient population. 40 patients. Investigator reported response rate 62.5% Phase 1/2 - Varying gemzar and carboplatin doses. Identical patient population. 25 patients. Response rate 40.0%

7 Participating groups -AGO -EORTC -NCIC-CTG -14 sites in China, India, Italy, Venezuela and Peru - No U.S. sites

8 Main Inclusion Criteria -Females  18 years old with ovarian cancer not amenable to curative surgery or radiation therapy -Relapsed disease > 6 months after discontinuation of 1 st line platinum-containing therapy -ECOG PS < 2 -Adequate marrow reserve -Measurable or evaluable disease

9 Study Plan -Treatment continues for 6 cycles until disease progression, intolerable toxicity, or other relevant reason to discontinue treatment. -Diagnostic studies (radiology, physical exam or ultrasound) every other cycle. -30 day poststudy follow-up disease evaluation. -Independent review of CT scans and MRI’s

10 Efficacy Endpoints Primary - PFS Secondary - Survival - RR & Duration - Q of L

11 Patient and Disease Characteristics Patient Groups were comparable for: Age Ethnicity Performance status Platinum-free interval Ovarian Cancer Histology Tumor Differentiation Stage at Diagnosis Pretreatment Tumor Burden

12 Prior Chemotherapy GCb n=178 n (%) Cb N=178 n (%) Platinum+paclitaxel + others122 (68.5)120 (67.4) Platinum+docetaxel + others 3 (1.7) 7 (3.9) Platinum + Non-taxane 51 (28.7) 49 (27.5) Carboplatin only 2 (1.1)

13 PFS Primary Analysis Scans were not routinely performed after a single post-study evaluation. Investigator clinical judgment determined the timing of progression assessment. Non-progressors were censored at last visit date. New therapy did not always imply progression. Missing studies did not affect progression date.

14 PFS –Sponsor Primary Analysis GC (N=178)C (N=178) Censored13% Median (mo) (95% CI) 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) HR 0.72 (0.57, 0.90) p=0.0038

15 PFS – Sponsor Primary Analysis HR 0.72 (0.57, 0.90) p=0.0038

16 Sensitivity Analysis for PFS Non-progressing patients, patients with missing scans prior to progression and patients who died after an extended lost to follow up time were censored at their last complete diagnostic evaluation. Patients who began a new therapy prior to progression were censored on the day that the therapy was initiated.

17 PFS–Sponsor Sensitivity Analysis GC (N=178)C (N=178) Censored74%57% Median (mo) (95% CI) 6.9 (6.3, NE) 5.6 (5.0, 5.9) HR 0.47 (0.32, 0.68) p=0.001

18 PFS – FDA Analysis

19 Response Rate GC (N=178) C (N=178) p RR CR PR 47.2% 14.6% 32.6% 30.9% 6.2% 24.7%

20 Post Study Chemotherapy GC 178 pts C 178 pts Post-study Chemo75.8%72.5% Specific Drugs Known41%40% Post study Gemzar0%10.1%* * Denominator = 129 patients

21 Survival HR 0.98 (0.78, 1.24) p=0.898

22 Treatment Dose Intensity Treatment Arm Percent (%) of Planned Mean Dose Gemcitabine Day 1 Gemcitabine Day 8 Carboplatin Day Carboplatin98

23 Grade 3/4 Hematologic Toxicity

24 Grade 3/4 Non-laboratory toxicity

25 Efficacy Conclusions Gemcitabine plus carboplatin treatment significantly prolonged PFS and increased response rate compared to carboplatin alone. Caveat: Progression was not independently reviewed. Also response was not completely independently reviewed. There was no significant increase in survival. Caveat: Post-study chemotherapy may confound survival interpretation.

26 Safety Conclusions Grade 3 and 4 toxicities were primarily hematologic and were more frequent with G/C treatment. Toxicities were consistent with the single agent toxicity of each drug. No new safety concerns

27 ODAC Question Is a significant improvement in PFS and RR, with no increase in overall survival, at the cost of some additional toxicity, an adequate basis for drug approval for treatment of patients with advanced ovarian cancer who have relapsed at least 6 months after completion of platinum- based therapy ?

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