Results Increased median PFS 2.8 months No apparent increased survival. HR=0.985 CR+PR=46% Gemzar vs 36% control Independently Assessed Increased toxicity, mainly hematologic, requiring increased RBC & platelet transfusions and use of growth factors

2004 International Consensus Conference on Ovarian Cancer

Gynecological Cancer Intergroup (GCIG) GOG (USA), RTOG (USA), NCI-US (USA), NCIC-CTG (Canada), MRC/NCRI (UK), SGCTG (Scotland), AGO-OVAR (Germany), ANZGOG (Australia – New Zealand), EORTC (Europe), GEICO (Spain), GINECO (France), NSGO (Scandinavia), JGOG (Japan)

Issue # 1 Are there regimens that increase survival in this setting in RCTs ? ICON-4 Study Taxol & Carboplatin Lancet Vol 361 June 21, 2003 Pegylated Liposomal Doxorubicin FDA Review of Doxil SNDA, Doxil Package Insert

ICON-4 Study Taxol & Carboplatin Carbo +Taxol vs Platinum based CT without a Taxane Rec/Relapsed Advanced Ovarian Cancer after Platinum Based CT Platinum Sensitive 802 Patients HR for Death =0.82, P=0.02 –Lancet Vol 361 June 21, 2003

Pegylated Liposomal Doxorubicin vs Topotecan Advanced Ovarian Cancer Recurrent after Platinum Based CT Stratified Plat. Sens. vs Plat. Insens. 474 Patients HR for Death=0.82, P=0.05 Plat Sens. Subgroup HR for Death= 0.7, P=0.017 FDA Review of Doxil SNDA, February 2005 Doxil Package Insert

2004 International Consensus Conference on Ovarian Cancer “There is an impact of post recurrence/progression therapy on overall survival (OS).” Annals Oncology 16 (Supplement 8) viii 7-viii 12

2004 International Consensus Conference on Ovarian Cancer “the unanimous answer is … there is … an impact on overall survival. One need look no further than … the ICON4 trial”. Thigpen Ann Oncol 16 (suppl 8) viii 13-viii 19, 2005

ISSUE #2 Are there regimens that increase survival in RCTs in the patient population in the Gemzar RCT setting, if given post progression? The FDA knows of no such regimens. Probably of interest only if there is imbalance between treatment groups.

Post Study Chemotherapy (PSC) GCb (n=178) Cb (n=178 PSC 135 (75.8%) 129 (72.5%) No PSC 43 (24.2%) 49 (27.5%) PSC Status Known Drug 71 Drug 43 No Drug 49 No Drug PCS known in 66.3% of study patients 13 (10.8%) of Cb patients with Known PCS Status crossed to Gemzar 0 GCb patients with Known PSC Status received Gemzar after prog.

Post Study Chemotherapy DRUGN RowsGemzar/ Carbo Carbo TOPOTECAN PLATINUM DOXIL TAXANE ETOPOSIDE ALKYLATING AGT ANTHRACYLINE178 9 GEMCITABINE13013 PROVERA 30 3

Issue # 3 Is it likely there would be a Gemzar survival effect in the Gemzar RCT if it were expanded? HR for death=0.985 Probability of Stat. Sig. Survival increase if 177 more deaths were added is 0.01 (Cox unstratified) or 0.15 (Cox stratified)

Issue # 4 Is improved PFS an adequate basis for drug approval in this setting?

2004 Consensus Conf Ovarian Ca First-Line CT Adv. Dis. “Advanced first-line: Both PFS and OS are important endpoints to understand the full impact of any new treatment. Thus, either may be designated as the primary end point. Regardless of which is selected, the study should be powered so both PFS and OS can be appropriately evaluated.” Annals Oncology 16 (Supplement 8) viii 7-viii 12

2004 Consensus Conf Ovarian Ca Second-Line CT Adv. Dis. “Post-recurrence/progression trials: The choice of the primary end point needs to be fully justified with appropriate power calculations. Symptom control/quality of life (for early relapse) and OS (for late relapse) may be the preferred primary end points, although PFS should still be used in the assessment of new treatments. Whatever the primary end point, the ability of the study design to detect important differences in survival should be formally addressed.” Annals Oncology 16 (Supplement 8) viii 7-viii 12

2004 Consensus Conf Ovarian Ca Second-Line CT Adv. Dis. "For phase III trials in the second-line setting, progression-free survival does not seem to be a good surrogate for survival: there are several examples where progression-free survival was significantly improved, with no survival impact. It can be argued that some of these studies were underpowered to detect survival improvements; however, the weight of evidence to consider progression-free survival a surrogate for survival, and thus a primary end point in the second-line setting, is not strong as yet.

2004 Consensus Conf Ovarian Ca Second-Line CT Adv. Dis. (Continued) In the recurrent disease setting, overall survival remains an important primary end point (particularly if more costly or toxic therapy is being offered). Progression-free survival data remain of interest but are unlikely to be sufficiently persuasive to shift practice patterns. Furthermore, since the rationale for treating patients with relapsed disease is a desire to improve symptoms and thus quality of life, an adequate measure of these factors would also

2004 Consensus Conf Ovarian Ca Second-Line CT Adv. Dis. (Continued) be an appropriate primary end point for randomized trials. However, no universally and acknowledged and standardized system of symptom measurement analysis is readily available. GCIG will continue, through its working groups, to build a consensus on how meaningful improvements in disease-related symptoms can be quantified.“ Annals Oncology 16 (Supplement 8) viii20-viii29, 2005