1. Relapsed/Refractory Ovarian Cancer: Decision Points in Diagnosis and New Treatment Strategies Friday, March 24, 2006 Palm Springs Convention Center Primrose Ballroom C/D Palm Springs, California

2. Current Issues in the Management of Recurrent Ovarian Cancer Robert F. Ozols, MD, PhD Senior Vice President, Medical Science Fox Chase Cancer Center Philadelphia, Pennsylvania

3. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Current Management for Epithelial Ovarian Cancer  Surgical staging and cytoreduction at diagnosis  Postoperative chemotherapy for high-risk limited stage and all advanced stage patients  Chemotherapy –IV paclitaxel (175 mg/m 2 over 3 hrs) plus IV carboplatin (AUC 6.0-7.5) for 6 cycles –Intraperitoneal (IP) chemotherapy for optimal stage III “should be considered” 1  Vast majority of patients with advanced stage ovarian cancer will relapse 1. National Cancer Institute. NCI Clinical Announcement. January 2006.

4. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Potential for Relapse: Disease Stage and Diagnosis Disease StagePatients at Diagnosis, % Patients Who Will Relapse, % Low-risk early stage disease (Stage IA and IB, grade 1 and 2) 5< 5 High-risk early stage disease (Stage I, grade 3) 20 Stage II1030 Stage III, optimally debulked (< 1 cm residual) 4050-60 Stage III, suboptimally debulked (> 1 cm residual) 2070-80 Stage IV580-90

5. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Survival From Time of Recurrence Months From Progression Proportion Surviving, % Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200. 0 12 2436 48 60 0 20 40 60 80 100 Treatment GroupAliveDeadTotal Cisplatin/paclitaxel85214299 Carboplatin/paclitaxel87191278

6. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Patterns of Recurrence After Achieving a Complete Response  Median progression-free survival –18 months (suboptimal or stage IV) and 21-24 months (optimal stage III)  Serologic relapse –CA-125  in asymptomatic patients with normal physical exam and CT  Clinical relapse –Symptomatic with measurable disease –Asymptomatic with measurable disease –Symptomatic without measurable disease

7. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Treatment Considerations in Recurrent Ovarian Cancer  Definitions –Refractory disease: no response or incomplete response to platinum-based therapy –Relapsed disease: progression after clinical complete response –Platinum sensitive:  6 month platinum-free interval –Platinum resistant:  6 month platinum-free interval

8. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Effect of PFI on Response Rate Markman M, et al. J Clin Oncol. 1991;9:1801-1805. Months Response Rate (%) 27% 33% 59% 0 10 20 30 40 50 60 5-1213-24> 24

9. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Treatment Considerations in Recurrent Ovarian Cancer  Goals of therapy –Palliate symptoms –Prevent symptom development –Maintain quality of life –Increase progression-free survival –Prolong overall survival

10. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Selection of Therapy in Recurrent Ovarian Cancer  Platinum sensitivity or resistance  Length of disease-free interval  Disease volume  Sites of disease  Serologic relapse  Symptomatic vs asymptomatic disease  Residual toxicity from prior chemotherapy –Neuropathy –Myelosuppression –Allergic reactions  Patient preference –Schedule of administration –Importance of alopecia –Anticipated toxicity

11. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Treatment Modalities for Recurrent Ovarian Cancer  Chemotherapy –Primary modality  Surgery –Late relapse with potential for complete resection –Bowel obstruction  Radiation –Palliation for drug-resistant, symptomatic, isolated lesions

12. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Rising CA-125 in an Asymptomatic Patient  Highly predictive of clinical recurrence within median of 4-6 months 1,2  No evidence immediate chemotherapy superior to delayed chemotherapy at time of clinical progression –European randomized trial in progress –Gynecologic Oncology Group (GOG) randomizes patients to biologic agents 1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155:56-60. 2. Vergote IB, et al. Tumour Biol. 1992;13:168-174.

13. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Chemotherapy Principles in Recurrent Ovarian Cancer  Multiple agents have clinical activity –Activity superior in platinum-sensitive patients  Combinations are superior to single-agent platinum in platinum-sensitive patients  No established role for combinations in platinum-resistant disease  Management considerations –Length of treatment and “drug holidays” –Choice of combination in platinum-sensitive patients –Choice of drug in platinum-resistant patients

14. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Active Agents in Recurrent Ovarian Cancer  Carboplatin  Taxanes (q 3 wks vs q wk) –Paclitaxel –Docetaxel  Topotecan  Liposomal doxorubicin  Gemcitabine Less commonly used  Oral etoposide  Altretamine  Tamoxifen  Vinorelbine

15. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer  “Old standard” –Single-agent carboplatin  “New standard” –Paclitaxel plus carboplatin –Gemcitabine plus carboplatin  Other combinations under evaluation –Liposomal doxorubicin plus carboplatin –Biologic agents plus chemotherapy

16. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer ICON 4/AGO-OVAR 2.2  2 parallel randomized multicenter trials Parmar MK, et al. Lancet. 2003;361:2099-2106. Paclitaxel plus Platinum-based chemotherapy (n = 392) Platinum-based chemotherapy (n = 410) Patients with platinum- sensitive recurrent ovarian cancer (N = 802)

17. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Parmar MK, et al. Lancet. 2003;361:2099-2106. Paclitaxel plus platinum Conventional treatment Hazard ratio: 0.76; P =.0004 0 20 40 60 80 100 Time From Randomization (yrs) Progression-Free Survival (%) Patients at risk Paclitaxel plus platinum392179522517 Conventional treatment 4101574517 7 1 23 4 0 Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: PFS

18. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: OS Parmar MK, et al. Lancet. 2003;361:2099-2106. Paclitaxel plus platinum Conventional treatment Hazard ratio: 0.82; P =.0023 Proportion Surviving (%) Patients at risk Paclitaxel plus platinum392306167964318 Conventional treatment 410295150683311 0 20 40 60 80 100 1 23 4 0 5 Time From Randomization (yrs)

19. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Gemcitabine/Carboplatin vs Carboplatin  Randomized phase III trial  AGO OVAR, NCIC CTG, EORTC GCG Pfisterer J, et al. ASCO 2004. Abstract 5005. Gemcitabine (1000 mg/m 2 ) Days 1 and 8 Carboplatin (AUC = 4) day 1 (n = 178) Carboplatin (AUC = 5) Day 1 (n = 178) Patients with platinum-sensitive recurrent ovarian cancer ≥ 6 months out from initial platinum therapy (N = 356)

20. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Study Endpoints: OVAR 2.5 and ICON 4 ParameterGemcitabine/Carboplatin vs Carboplatin (OVAR 2.5) 1 Paclitaxel/Platinum vs Platinum (ICON 4) 2 ORR, %47.2 vs 30.966 vs 54 CR, %14.6 vs 6.2Not reported PFS, mos8.6 vs 5.812 vs 9  HR0.720.76 OS, mosNA*29 vs 24  HRNA0.82 1. Pfisterer J, et al. ASCO 2004. Abstract 5005. 2. Parmar MK, et al. Lancet. 2003;361:2099-2106. *Study not powered for overall survival.

21. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Platinum-Resistant Recurrent Ovarian Cancer  Weekly paclitaxel  Liposomal doxorubicin  Topotecan  Gemcitabine Which is better?  Few randomized trials have been performed –Topotecan vs paclitaxel –Liposomal doxorubicin vs topotecan –Gemcitabine vs liposomal doxorubicin

22. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan in Recurrent/Refractory Ovarian Cancer Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 100 90 80 70 60 50 40 30 20 10 0 020406080100120140160180200220240260 Weeks Since Randomization Pegylated liposomal Doxorubicin (n = 240) Topotecan (n = 241) Overall Survival (%) Median Survival Pegylated liposomal doxorubicin: 62.7 wks Topotecan: 59.7 wks Hazard ratio: 1.23 (95% CI: 1.01-1.50); P =.038

23. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan: Patients With Platinum-Refractory Disease 100 90 80 70 60 50 40 30 20 10 0 Weeks Since First Dose Overall Survival (%) Pegylated liposomal doxorubicin (n = 130) Topotecan (n = 125) No significant difference in survival HR: 1.069 (95% CI:.823-1.387); P =.618 0 20406080100120140160180200220240260 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

24. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer PLD vs Topotecan: Patients With Platinum-Sensitive Disease 100 90 80 70 60 50 40 30 20 10 0 020406080100120140160180200220240260 Weeks Since First Dose Overall Survival (%) Pegylated liposomal doxorubicin (n = 109) Topotecan (n = 110) Median Survival Pegylated liposomal doxorubicin: 107.9 wks Topotecan: 70.1 wks HR: 1.432 (95% CI: 1.066-1.923); P =.017 Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

25. clinicaloptions.com/oncology Relapsed/Refractory Ovarian Cancer Management of Recurrent Ovarian Cancer  Recurrent ovarian cancer a major clinical problem  Multiple therapeutic options –Surgery, radiation, chemotherapy –Combination chemotherapy superior in platinum-sensitive patients  New treatments needed to improve poor outcomes with current therapy