sNDA 20-262

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sNDA 20-262

• TAXOL
• for
• ADJUVANT BREAST CANCER THERAPY

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REVIEW TEAM
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PROPOSED INDICATION

• TAXOL is indicated for the adjuvant treatment of
  node-positive breast cancer administered
  sequentially to standard combination therapy.

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A Phase III Intergroup Study INT-0148Doxorubici
n Dose Escalation With or Without TAXOL, As
Part Of the Cyclophosphamide/Doxorubicin
Adjuvant Chemotherapy Regimen For Node Positive
Breast Cancer Participating GroupsCALGB ECOG
NCCTG SWOG
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Intergroup (0148)
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Accrual By Study Arm
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FDA Analysis of DFS All Patients and Major
Subgroups
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FDA Analysis of DFS All Patients and Major
Subgroups
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Disease Free SurvivalEstrogen Receptor Negative
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FDA Analysis of DFS All Patients and Major
Subgroups
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Disease Free SurvivalEstrogen and/or
Progesterone Positive
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FDA Analysis of DFS All Patients and Major
Subgroups
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Disease Free SurvivalSubset Tamoxifen Therapy
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Three Year DFS(Kaplan-Meier Estimate)
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Patterns of Recurrence

• Cut-off Date Set. 30, 1998
• Distant Recurrence 368 (12)
• AC 202 (13)
• ACT 166 (11)
• Local Recurrence 189 (6)
• AC 104 (7)
• ACT 85 (5)
• Simultaneous Recurrence 16 (lt1)
• AC 9 (lt1)
• ACT 7 (lt1)

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Survival Analysis

• Cut-off DateSept. 30, 1998
• Dead 342/3121 (11)
• AC 192 (12)
• ACT 150 (10)
• Alive 2779/3121 (89)
• AC 1359 (88)
• ACT 1420 (90)

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Overall SurvivalER Negative
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Overall SurvivalE and/or PR Positive
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Overall SurvivalSubset Tamoxifen Therapy
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Adverse Events Reported During Taxol Therapy
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Treatment Discontinuation Secondary to
Toxicity(AC vs. ACT)

• ACT
• 15 patients withdrew during AC
• 81 patients withdrew during Taxol

• AC
• 17 patients withdrew

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DEATHS WITHIN 30 DAYS (AC vs. ACT)

• ACT 2 Deaths
• Brain Infarct Subsequent to Sepsis
• Hypersensitivity Reaction

• AC 1 Death
• Respiratory Failure

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ISSUES TO CONSIDER

• Overall, results of the trial are very positive
• Effects of Taxol on DFS and OS are strong
• Results of Subset Analyses based on receptor
  status
• large number of patients and events
• these subsets are medically plausible
• positive overall results driven by receptor
  negative subgroup
• Cytotoxic agents are not without toxicity
• Four additional cycles of chemotherapy

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RECOMMENDATION FOR APPROVAL Taxol AC in
patients with ER-/PR- tumors

• Improvement in DFS
• 3 Year DFS 67.3 ACT vs 56.8 AC
• Hazard Ratio 0.66 (0.53 - 0.83)
• P-value 0.0003
• Improvement in OS
• Hazard Ratio 0.69 (0.53 - 0.91)
• P-value 0.0079

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RECOMMENDATION CONTINUED FOLLOW-UPTaxol
sequential to AC in patients with ER and/or PR
tumors who received Tamoxifen

• No Improvement in DFS
• 3 Year DFS 81.9 ACT vs. 82.7 AC
• Hazard Ratio 0.98 (0.77 - 1.25)
• P-value 0.87
• No Improvement in OS
• Hazard Ratio 0.89 (0.60 - 1.32)
• P-value 0.57

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