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Trastuzumab [Genentech Inc.]Labeling Supplement to
Include FISH Testing as a Method to Select Patients for
TreatmentFDA Clinical Review
December 5, 2001
Oncologic Drugs Advisory Committee Meeting
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
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
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
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+).”
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…”
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.”
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.”
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
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.”
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)
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
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.
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
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.
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.
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
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 the
trastuzumab clinical trials (IHC 2+ or 3+)• Validation study–Compare results between LabCorp and
Press Lab
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
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]
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%
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
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
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)
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
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
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
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.
FISH Testing ResultsClinical Outcome Study
• Endpoints assessed–Time to Progression (primary
endpoint)
–Overall Survival
–Overall Response Rate
H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo
Subgroup Relative Risk
95% CI N
3+ 0.42 0.33, 0.55 349
2+ 0.82 0.54, 1.24 120
FISH (+) 0.44 0.34, 0.57 325
FISH (-) 0.66 0.45, 0.99 126
H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo
Subgroup Relative Risk
95 %CI N
FISH+/3+ 0.42 0.32, 0.55 293
FISH+/2+ 0.72 0.31, 1.64 32
FISH-/3+ 0.40 0.19, 0.87 43
FISH-/2+ 0.86 0.53, 1.38 83
H0648g Time to Progression, 3+
Trastuzumab + Chemo
N = 176
Chemo
N = 173
H0648g Time to Progression, 2+
Trastuzumab + Chemo
N = 59
Chemo
N = 61
H0648g Time to Progression, FISH (+)
Trastuzumab + Chemo
N = 164
Chemo
N = 161
H0648g Time to Progression, FISH (-)
Trastuzumab + Chemo
N = 62
Chemo
N = 64
H0648gTime to Progression,FISH (+)/3+
Trastuzumab + Chemo
N = 148
Chemo
N = 145
H0648g Time to Progression, FISH (+)/2+
Trastuzumab + Chemo
N = 16
Chemo
N = 16
H0648g Time to Progression, FISH (-)/3+
Trastuzumab + Chemo
N = 21
Chemo
N = 22
H0648g Time to Progression, FISH (-)/2+
Trastuzumab + Chemo
N = 41
Chemo
N = 42
H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo
Subgroup Relative Risk
95% CI N
3+ 0.42 0.33, 0.55 349
FISH+/3+ 0.42 0.32, 0.55 293
FISH-/3+ 0.40 0.19, 0.87 43
H0648g Time to ProgressionTrastuzumab +Chemo vs Chemo
Subgroup Relative Risk
95% CI N
2+ 0.82 0.54, 1.24 120
FISH+/2+ 0.72 0.31, 1.64 32
FISH-/2+ 0.86 0.53, 1.38 83
H0648g Overall SurvivalTrastuzumab + Chemo vs Chemo
Subgroup Relative Risk
95% CI N
3+ 0.70 0.54, 0.92 349
2+ 1.09 0.71, 1.58 120
FISH (+) 0.69 0.53, 0.91 325
FISH (-) 1.07 0.70, 1.63 126
H0648g Overall SurvivalTrastuzumab + Chemo vs Chemo
Subgroup Relative Risk
95% CI N
FISH+/3+ 0.57 0.51, 0.89 293
FISH+/2+ 0.98 0.41, 2.35 32
FISH-/3+ 0.94 0.42, 2.11 43
FISH-/2+ 1.15 0.70, 1.89 83
H0648g Overall Survival, 3+
Trastuzumab + Chemo
N = 176
Chemo
N = 173
H0648g Overall Survival, 2+
Trastuzumab + Chemo
N = 59
Chemo
N = 61
H0648g Overall Survival, FISH (+)
Trastuzumab + Chemo
N = 164
Chemo
N = 161
H0648g Overall Survival, FISH (-)
Trastuzumab + Chemo
N = 62
Chemo
N = 64
H0648g Overall Survival, FISH (+)/3+
Trastuzumab + Chemo
N = 148
Chemo
N = 145
H0648g Overall Survival, FISH (+)/2+
Trastuzumab + Chemo
N = 16
Chemo
N = 16
H0648g Overall Survival, FISH (-)/3+
Trastuzumab + Chemo
N = 21
Chemo
N = 22
H0648g Overall Survival, FISH (-)/2+
Trastuzumab + Chemo
N = 41
Chemo
N = 42
H0648g Overall SurvivalTrastuzumab + Chemo vs Chemo
Subgroup Relative Risk
95% CI N
3+ 0.70 0.54, 0.92 349
FISH+/3+ 0.57 0.51, 0.89 293
FISH-/3+ 0.94 0.42, 2.11 43
H0648g Overall SurvivalTrastuzumab + Chemo vs Chemo
Subgroup Relative Risk
95 %CI N
2+ 1.09 0.71, 1.58 120
FISH+/2+ 0.98 0.41, 2.35 32
FISH-/2+ 1.15 0.70, 1.89 83
H0648g Overall Response RateTrastuzumab + Chemo vs Chemo
T+C
2+,3+
C
2+,3+
T+C
3+
C
3+
T+C
2+
C
2+
FISH
(+)54% 30% 55% 28% 50% 56%
FISH
(-)40% 38% 62% 55% 29% 29%
FISH
Any45% 29% 49% 27% 32% 34%
H0649g Overall Response Rate
• Single agent trastuzumab
• Single arm study assessment of response rate.
• Without comparator arm, it is difficult to assess the meaning of time to progression and survival.
H0649g Overall Response RateSingle Agent Trastuzumab
CTA 3+ CTA 2+ All
FISH (+) 22% 11% 20%
FISH (-) 0% 0% 0%
All 19% 6% 14%
Conclusions
• Inter-laboratory variability in test results can be seen with FISH testing as evidenced by the differences observed between two selected laboratories in these studies.
• There is an expected failure rate for obtaining a result by the HER2 FISH assay.
Conclusions
• Concordance between FISH and CTA testing is moderate–Between 11% and 13% of patients
who might benefit from trastuzumab (IHC 3+) would not be selected by FISH–Nearly 4% of patients who would
not have been eligible for the clinical trials (IHC 0-1+), test positive by FISH
Conclusions
• It is not possible to determine the utility of treating patients whose tumors test FISH (+) and IHC (0-1+), because they were not enrolled onto these clinical trials.
Conclusions
• There are insufficient data to definitively describe the predictive capability of FISH as the first and only test to identify patients who would benefit from trastuzumab therapy.
Conclusions
• Direct comparative statements of equivalence or superiority between FISH and IHC cannot be made.
Conclusions
• The clinical outcome study in a pre-selected population indicates that FISH appears to be a useful method for selection of patients who are known to be IHC 2+ or 3+ .
Potential Questions to Address Postmarketing
• Do patients whose tumors test as FISH (+) and either IHC 0, 1+, or 2+ benefit from trastuzumab therapy?
• How much inter-laboratory variability exists in the community for FISH and IHC testing of HER2?
• What types of educational programs targeting oncology professionals need to be in place to optimize testing and interpretation of results?