Results

1
Results

• Increased median PFS 2.8 months
• No apparent increased survival. HR0.985
• CRPR46 Gemzar vs 36 control
• Independently Assessed
• Increased toxicity, mainly hematologic,
• requiring increased RBC platelet
• transfusions and use of growth factors

2
2004 International ConsensusConference on
Ovarian Cancer
3
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)

4
Issue 1Are 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, 2-1-05
• Doxil Package Insert

5
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, P0.02
• Lancet Vol 361 June 21, 2003

6
Pegylated Liposomal Doxorubicin vs Topotecan

• Advanced Ovarian Cancer
• Recurrent after Platinum Based CT
• Stratified Plat. Sens. vs Plat. Insens.
• 474 Patients
• HR for Death0.82, P0.05
• Plat Sens. Subgroup
• HR for Death 0.7, P0.017
• FDA Review of Doxil SNDA, February
  2005
• Doxil Package Insert

7
2004 International ConsensusConference on
Ovarian Cancer

• There is an impact of post recurrence/progressio
  n therapy on overall survival (OS).
• Annals Oncology 16 (Supplement 8) viii 7-viii
  12

8
2004 International ConsensusConference 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

9
ISSUE 2Are 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.

10
Post Study Chemotherapy (PSC)

• 
  GCb (n178) Cb (n178
• PSC 135
  (75.8) 129 (72.5)
• No PSC 43
  (24.2) 49 (27.5)
• PSC Status Known 116
  120
• 
  73 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.

11
Post Study Chemotherapy

• DRUG N Rows Gemzar/ Carbo
• 
  Carbo
• TOPOTECAN 54 31 23
• PLATINUM 45 22 23
• DOXIL 32 16 16
• TAXANE 37 17 20
• ETOPOSIDE 30 21 9
• ALKYLATING AGT. 44 14 28
• ANTHRACYLINE 17 8 9
• GEMCITABINE 13 0 13
• PROVERA 3 0 3

12
Issue 3 Is it likely there would be a Gemzar
survival effect in the Gemzar RCT if it were
expanded?

• HR for death0.985
• Probability of Stat. Sig. Survival increase if
• 177 more deaths were added is
• 0.01 (Cox unstratified) or
• 0.15 (Cox stratified)

13
Issue 4Is improved PFS an adequate basis for
drug approval in this setting?
14
2004 Consensus Conf Ovarian CaFirst-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

15
2004 Consensus Conf Ovarian CaSecond-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

16
2004 Consensus Conf Ovarian CaSecond-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.

17
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

18
2004 Consensus Conf Ovarian CaSecond-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