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Trastuzumab [Genentech Inc.] Labeling Supplement to Include FISH Testing as a Method to Select Patients for Treatment

Trastuzumab [Genentech Inc.] Labeling Supplement to Include FISH Testing as a Method to Select Patients for Treatment. FDA Clinical Review December 5, 2001 Oncologic Drugs Advisory Committee Meeting. Objective of This sBLA.

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Trastuzumab [Genentech Inc.] Labeling Supplement to Include FISH Testing as a Method to Select Patients for Treatment

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  1. Trastuzumab [Genentech Inc.]Labeling Supplement to Include FISH Testing as a Method to Select Patients for Treatment FDA Clinical Review December 5, 2001 Oncologic Drugs Advisory Committee Meeting

  2. Objective of This sBLA • To add information on the use of fluorescence in situ hybridization (FISH) testing for HER2 amplification to the trastuzumab package insert

  3. Background: Trastuzumab • Original application approved September 1998 • Indications • Single agent use 2nd or 3rd line in metastatic breast cancer • In combination with paclitaxel first line in metastatic breast cancer

  4. Background: Trastuzumab • Indications (continued) • “HERCEPTIN should only be used in patients whose tumors have HER2 protein overexpression.” • Mechanism for antibody binding effect • FISH not performed

  5. Background: Trastuzumab • HER2 protein overexpression • “Data from both efficacy trials suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+).”

  6. Background: Trastuzumab • Immunohistochemical (IHC) detection of HER2 protein • Clinical Trial Assay (CTA) used to select patients for clinical trials • “HercepTest … has not been directly studied for its ability to predict HERCEPTIN treatment effect, but has been compared to CTA on over 500 breast cancer histology specimens…”

  7. Background: Trastuzumab • Immunohistochemical (IHC) detection of HER2 protein (cont.) • “Of specimens testing 2+ on HercepTest , only 34% would be expected to test at least 2+ on the CTA including 14% which would be expected to test 3+ on the CTA.”

  8. Background: Trastuzumab • Immunohistochemical (IHC) detection of HER2 protein (cont.) • “Of specimens testing 3+ on HercepTest, 94% would be expected to test at least 2+ on the CTA including 82% which would be expected to test 3+ on the CTA.”

  9. Postmarketing Commitment • Impetus: There was uncertainty regarding the optimal method for selection of patients who might benefit from trastuzumab therapy • 2+ or 3+ (vs) 3+ • Variability in immunohistochemistry results

  10. Postmarketing Commitment • “To assess the clinical outcome of patients selected for treatment on the basis of the DAKO test [HercepTest] and other HER2 diagnostics in the context of Herceptin clinical trials.”

  11. Regulatory Timeline for FISH sBLA • September 1998: Approval of trastuzumab • March 2000: Genentech informed FDA about results of exploratory, retrospective FISH analysis of clinical trial specimens. Rejected by FDA due to missing data (appeared to be non-random)

  12. Regulatory Timeline for FISH sBLA • August 2000: Genentech discusses proposal to minimize missing data by running FISH on previously stained slides • April 2001: sBLA for trastuzumab filed with CBER and sPMA for PathVysion filed with CDRH

  13. Regulatory Timeline for FISH sBLA • The sBLA under consideration today does not fulfill the postmarketing commitments. • Other trials, currently being conducted in the adjuvant setting, will address these commitments, but will not be complete for another 4-5 years.

  14. FDA Perception of the Field of HER2 Testing • HER2 assessment is not straightforward • Marked variability in results between different laboratories • Extensive off label use of other antibodies for IHC (aka “home brew” assays) • Extensive off label use of FISH

  15. FDA Perception of the Field of HER2 Testing • Misunderstanding, on the part of treating physicians, regarding the advantages and limitations of the various assay methodologies • Importance of reviewing the FISH data obtained from the clinical trial specimens, as it is unlikely that another randomized trial of this sort will be conducted.

  16. FISH sBLA: Nature of the Clinical Outcome Data • What they are not: Prospective, randomized, double-blinded, controlled multi-center trials providing data regarding the predictive capability of FISH and data regarding the comparability of FISH vs IHC. • Any conclusion drawn from these data should take into account the limitations of the studies conducted and filed in this sBLA.

  17. FISH sBLA: Nature of the Clinical Outcome Data • What they are: Exploratory, retrospective data from two laboratory sites with provocative results which may warrant inclusion into the PI in some capacity

  18. FISH sBLA: Studies Conducted • Concordance study • Screened specimens (patients not necessarily treated, IHC score 0, 1+, 2+ or 3+) • Clinical Outcome study • Specimens from patients treated on thetrastuzumab clinical trials (IHC 2+ or 3+) • Validation study • Compare results between LabCorp and Press Lab

  19. Overview of Studies • FISH assay used: PathVysion by Vysis • Laboratory sites: Laboratory Corporation (LabCorp) and the laboratory of Dr. Michael Press (Press) • Specimens: Obtained from trastuzumab clinical trials H0648g, H0649g, H0650g

  20. FISH Testing Results:Success/Failure Rates • Concordance Study • LabCorp • 623 samples tested • 529 samples with a result [FISH (+) or FISH (-)] • 15% testing failure rate [i.e. no FISH result]

  21. FISH Testing Results:Success/Failure Rates • Clinical Outcome study • LabCorp and Press • 784 patient samples tested altogether • 618 tested by LabCorp • 244 tested by Press • 765 with FISH result • Testing failure rates • LabCorp = 14% • Press = 8%

  22. FISH Testing Results:Success/Failure Rates • Validation study • LabCorp and Press • 250 samples tested by both labs • 223 samples with a result by Press lab • 11% failure rate

  23. FISH Testing Results: Comparison of LabCorp and Press Labs • Different techniques • Lower FISH scores on samples at LabCorp • Discordant results (H0648g, 649g, and 650g) • 32% (37/116) of samples testing positive at Press tested negative at LabCorp • 2% (2/107) of samples testing positive at LabCorp tested negative at Press

  24. FISH Testing Results: Comparison of LabCorp and Press Labs • Estimate based upon exploratory analyses: 10-30% of LabCorp values in the range of 1.0-2.0 (FISH negative) may be patients who would benefit from trastuzumab therapy (3+ by CTA)

  25. FISH Testing ResultsConcordance Study • FDA analyses agreed with sponsor analyses • Moderate concordance (Kappa = 0.64) when CTA positive defined as 2+ and 3+ • Better concordance (Kappa = 0.80) when CTA positive defined as 3+ only

  26. FISH Testing ResultsConcordance Study • FISH testing missed 11% of the 3+ samples • FISH testing selected 4% of the 0-1+ samples • FISH testing was positive in 24% of 2+ samples

  27. FISH Testing ResultsConcordance Study • FDA exploratory analysis: concordance for clinical trial data (patients enrolled) showed consistent effect • 13% of 3+ samples were FISH negative • 34% of 2+ samples were FISH positive

  28. FISH Testing ResultsClinical Outcome Study • FDA analyses agreed with sponsor analyses • Special note: There are no clinical outcome data for patients who were IHC (0-1+) and either FISH (+) or FISH (-). • Studies H0648g and H0649g were analyzed.

  29. FISH Testing ResultsClinical Outcome Study • Endpoints assessed • Time to Progression (primary endpoint) • Overall Survival • Overall Response Rate

  30. H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo

  31. H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo

  32. H0648g Time to Progression, 3+ Trastuzumab + Chemo N = 176 Chemo N = 173

  33. H0648g Time to Progression, 2+ Trastuzumab + Chemo N = 59 Chemo N = 61

  34. H0648g Time to Progression, FISH (+) Trastuzumab + Chemo N = 164 Chemo N = 161

  35. H0648g Time to Progression, FISH (-) Trastuzumab + Chemo N = 62 Chemo N = 64

  36. H0648gTime to Progression,FISH (+)/3+ Trastuzumab + Chemo N = 148 Chemo N = 145

  37. H0648g Time to Progression, FISH (+)/2+ Trastuzumab + Chemo N = 16 Chemo N = 16

  38. H0648g Time to Progression, FISH (-)/3+ Trastuzumab + Chemo N = 21 Chemo N = 22

  39. H0648g Time to Progression, FISH (-)/2+ Trastuzumab + Chemo N = 41 Chemo N = 42

  40. H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo

  41. H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo

  42. H0648g Overall Survival Trastuzumab + Chemo vs Chemo

  43. H0648g Overall SurvivalTrastuzumab + Chemo vs Chemo

  44. H0648g Overall Survival, 3+ Trastuzumab + Chemo N = 176 Chemo N = 173

  45. H0648g Overall Survival, 2+ Trastuzumab + Chemo N = 59 Chemo N = 61

  46. H0648g Overall Survival, FISH (+) Trastuzumab + Chemo N = 164 Chemo N = 161

  47. H0648g Overall Survival, FISH (-) Trastuzumab + Chemo N = 62 Chemo N = 64

  48. H0648g Overall Survival, FISH (+)/3+ Trastuzumab + Chemo N = 148 Chemo N = 145

  49. H0648g Overall Survival, FISH (+)/2+ Trastuzumab + Chemo N = 16 Chemo N = 16

  50. H0648g Overall Survival, FISH (-)/3+ Trastuzumab + Chemo N = 21 Chemo N = 22

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