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

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


• Indications (continued)

–“HERCEPTIN should only be used in patients whose tumors have HER2 protein overexpression.”

•Mechanism for antibody binding effect

• FISH not performed


• 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+).”


• 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…”


• 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.”


• 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)


• 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


• 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]


• 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%


• 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 missed 11% of the 3+ samples

• FISH testing selected 4% of the 0-1+ samples

• FISH testing was positive in 24% of 2+ samples


• 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



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



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



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


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



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



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



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?

Documents

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