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(solution) Pretend you are a member of the Regulatory Affairs team at a


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Pretend you are a member of the Regulatory Affairs team at a leading biotechnology company.

 

Your company has developed Herceptin, a recombinant DNA-derived, humanized monoclonal

 

antibody that targets the extracellular domain of the ErbB-2/HER2/neu receptor (i.e., human

 

epidermal growth factor receptor 2; ?HER2?).

 

?Approximately 25-30% of breast cancers overexpress HER2. Abnormal expression of

 

HER2/neu is frequently observed in a number of primary tumors, suggesting that

 

overexpression may contribute to transformation and tumorigenesis. HER2 receptor

 

overexpression has been correlated with poor

 

clinical outcome in patients with breast cancers?.

 

The company has recently completed multinational Phase II and Phase III clinical studies of the

 

product?s safety and efficacy. Given the favorable results, your company is now preparing a

 

Biomarker Qualification Submission to be certain that the proposed biomarker will be valid for:

 

a) patient inclusion/exclusion criteria in subsequent trials, b) determining the indicated

 

population in the product labeling, and c) supporting a marketing approval decision to market

 

the product to specific patient population(s). The company has specifically proposed that the

 

product be indicated for ?the treatment of patients with metastatic breast cancer who have

 

tumors that overexpress HER2?.

 

The Director of Regulatory Affairs has asked you to develop the Context of Use section of the

 

Biomarker Qualification Overview (as required for Section 2 of the Biomarker Qualification

 

Submission) for the relevant biomarker.

 

Assignment: Using only the information provided within this assignment, write the Context of

 

Use statement for the Biomarker Qualification Submission. Use the information and examples

 

described in Guidance for Industry E16 Biomarkers Related to Drug or Biotechnology Product

 

Development: Context, Structure, and Format of Qualification Submissions as well as the

 

?Biomarker Qualification Context of Use? information from the FDA website (attached here as a

 

reference) as a guide for composing the Context for Use statement. Additional sources will not

 

be necessary.

 

Your Context for Use statement should correctly address the following areas:

 

1. Identification of the biomarker (2 points)

 

2. Aspect of the biomarker that is measured and the form in which it is used for biological

 

interpretation (2 points)

 

3. Species and characteristics of animal or subjects studied (1 point)

 

4. Purpose of use (for the biomarker) in drug development (2 points)

 

5. Drug development circumstances for applying the biomarker (3 points)

 

6. Interpretation, and decision/action based on biomarker (5 points)

 

The assignment should be submitted as a well-written and clear document, typed (Microsoft

 

Word) using 11-point Arial font, double-spaced, with one-inch margins. Total length is limited to

 

5 pages (not including references). BACKGROUND INFORMATION:

 

?

 

?

 

?

 

?

 

? List of Abbreviations (2 pages)

 

Background of the Product (3 pages)

 

Overview of Phase II Study (2 pages)

 

Overview of Phase III Study (3 pages)

 

Protein Overexpression and Clinical Benefit (4 pages) Clinical Herceptin@

 

BLA 98-0369 Review 12.0 APPENDIX C - ABBREVIATIONS AC anthracycline plus cyclophosphamide chemotherapy ACH Herceptin@ ADCC antibody-dependent Am2 Amendment BLA Biologics CAD coronary Chemo chemotherapy CHF congestive cm centimeter CR complete response CRF Case Report Form CT computed CXR chest X-ray Dig. digoxin DOE dyspnea on exertion DVT deep venous thrombosis Echo echocardiogram ECG or EKG electrocardiogram EGFR endothelial FISH fluorescence H Herceptin@ HER2 human epidermal growth factor receptor 2 HEM/neu human epidermal growth factor receptor 2 HR heart rate plus AC

 

cell-mediated cytotoxicity 2 to the protocol H0648g pivotal study

 

License Application artery disease or atherosclerosis heart failure tomographic scan growth factor receptor

 

in siru hybridization 96 regimen Clinical Herceptin@

 

BLA 98-0369 Review ICU intensive IHC immunohistochemistty

 


 

JVD jugular venous distension NP jugular venous pressure MoAb or MAb monoclonal MRI magnetic NYHA class New York Heart Association 0? oxygen therapy PD progressive Plt platelet count PND paroxysmal PR partial response RBC red blood cell count rhuMAb HER2 care unit antibody

 

resonance imaging

 

Classification for congestive heart failure disease nocturnal recombinant dyspnea humanized RR respiratov SD stable disease SOB shortness of breath T paclitaxel TH Herceprin@ plus T VEGF vascular endothclial WBC white blood cell count XRT radiation anti-p185KRz monoclonal rate chemotherapy regimen groivth factor therapy 97 antibody = Herceptin@ Herceptin@

 

BLA 98-0369 Clinical Review 1 .O BACKGROUND

 

1.1 Introduction OF THE PRODUCT - HERCEPTIN@ Breast cancer is one of the most common malignancies

 

in women. It accounts for

 

approximately

 

l/3 of female cancer in the USA and therefore, remains a serious health

 

care problem. Approximately

 

2530%

 

of breast and ovarian cancers overexpress

 

HER2/neu. Abnormal expression of the HER2/neu is frequently observed in a number of

 

primary tumors, suggesting that overexpression

 

may contribute to transformation

 

and

 

tumorigenesis.

 

HEIWneu overexpression has been correlated with poor clinical outcome

 

in patients with breast and ovarian cancers. HER21neu overexpression

 

appears to be

 

associated with shorter disease-free inten.al, shorter overall survival, more rapid disease

 

progression

 

(higher incidence of metastasis),

 

and resistance to chemotherapy

 

in

 

retrospective studies. 1.2 HerceptinO

 

Herceptin@ (trastuzumab)

 

is a recombinant

 

DNA-derived

 

humanized

 

monoclonal

 

antibody that targets the extracellular dc*main of the ErbB-2/HerYneu

 

receptor.

 

It was

 

engineered by grafting the complementarity

 

determining regions of the parental murine

 

antibody (4D5) into the consensus framework of a human IgGl. Herceptin@ has been produced from CHO cells maintained in cell culture systems at

 

Genentech for human clinical trials sir,ce 1991. The entire cell culture process from

 

Master Cell Bank through final production contains no serum or other animal proteins. 1.2.1 BACKGROUN?)

 

The HER2 Receptor

 

The human epidermal grov& factor receptor 2 (ErbB-21 HER2p?85) is a member of Type I

 

family of growth factor tyrosine kinase receptors. The family also includes the

 

endothelial growth factor receptor (EGFR), HER3, and HER4 receptors. These receptors

 

are encoded by homeotic genes and share extensive sequence homology, suggesting a

 

similar mechanism of activation and signaling.

 

These receptors function by forming

 

hetero- and homo-dimers with members of the family.

 

The c-ErbB-21 HER2p?8S proto-oncogene encodes a 185 Kd trans-membrane

 

glycoprotein

 

that participates

 

in an interactive network of receptor-receptor

 

interactions.

 

These

 

interactions regulate cell fate, growth and proliferation, mainly through MAP and .-Kinases. 6 Clinical _- Herceptin@

 

BLA 98-0369 Review Current data indicate that HER2 acts as co-receptor or a shared signaling sub-unit,

 

prolonging and enhancing activation of proteins involved in signal transduction pathways

 

Normal Expression of Her2p?B?and Its Role in Embrvooenesis:

 

Immunohistochemistry

 

staining showed that HER2/neu is normally widely expressed in

 

differentiated adult and in fetal tissues derived from the three embry?onic germ layers.

 

High intensity staining was reported in the gastrointestinal tract (Press M. et al. Oncogene

 

1990) and the proximal tubules and loop of Henle of the urinary tract (Gullick W. et al.

 

Int. J. Cancer, 40246-254 (1987).

 

Recent studies (Lee I;. et al. Nature 378:394-396, 1995) demonstrated that espression of

 

HERXneu is crucial for cardiac and CN> development. Mice carrying the null allele died

 

at El 1 due to the lack of cardiac trabeculae formation. The development of cranial neuralcrest derived sensory ganglia as vell as the motor nerves, vas also compromised.

 

(Lee

 

K. et al. Nature 378:394-396 (1995).

 

Role of HER2?Is5 in Sirnal Transduction

 

The current literature supports a normal role for HERZneu as the preferred partner of all

 

the other fainily members (Karunagaran D. et al. Embo J:15: 253-264). Several ligands

 

have been characterized that bind the EGFR, HER3 and HER4. EGF and transforming

 

gro\-th factor-alpha (TGF-alpha) arc among the ligands for EGFR, and heregulin/NDF

 

(neu differentiation

 

factor) is the ligand for HER3 and HER4. No specific ligand for

 

HER2 has been found.

 

Ligand binding to the respecti1.e receptors induces a conformational

 

change of the

 

receptor, lvhich in turn results in a) ty.rosine autopl,.tsphorylation

 

and b) increased

 

binding affinity for the other receptors.

 

The increased binding affinity results in hetero/homodimer

 

formation. As a result of

 

ligand binding, the intracellular tyrosine kinases become activated and transphosphorylate

 

the

 

binding partner (e.g., HEIUp?*?). These events initiate the signal transduction

 

pathway. The ultimate step in all Erb family members? activation is mitogenesis.

 

HER 2 ?*? Overexprcssion

 

In humans, the oncogenic transformation

 

of HER2/neu has invariably correlated with

 

protein overexpression. Due to its constituti*e kinase activity, HER2/neu overexpression

 

results in enhanced tyrosine phosphorylation

 

activities. Constitutive

 

tyrosine kinase

 

activity leads to increased proliferation rate, resistance to TNFa, decreased expression of

 

adhesion molecules (E-cadherines and integrins) and increased vascular endothelial

 

growth factor (VEGF) secretion.

 

Mechanism of action of HerccntinQB

 

Herceptina acts in vitro by a dual mechanisms of action:

 

a) Biochemical: Exerted by binding to the HER2p?8s receptor. 7 Clinical Review HerceptinQ

 

BLA 98-0369 of

 

Herceptin binding to HER2p1*5 blocks dimer formation and induces down-regulation

 

the receptor. Both events lead to the blockade of the signal transduction pathway.

 

In addition, Herceptin has the following in vitro effects:

 

l

 

Cytostasis: inhibition of proliferation by interference with the mitogenic

 

activity of the HERZneu receptor due to the induction of the CDK2 kinase

 

protein, p 130;

 

inhibitor, ~27~? and the retinoblastoma-related

 

l

 

Reduction of the cellular resistance to TNFa;

 

l

 

Restoration of the expression of adhesion molecules (E-cadherines,

 

a2

 

integrins) involved in metastasis development and progression,

 

l

 

Reduction of VEGF production

 

Immunological:

 

Exerted by Fc binding to the FcgRIII of CD16+ cells.

 

In vitro studies demonstrated that HerceptinO, in the presence of PBMN, was able to

 

mediate ADCC (antibody-dependent

 

cell-mediated cytotoxicity). This effect was due to

 

binding of the MAb to the FcgRIII present on the surface of cytotoxic cells (NK, CDS+ T

 

cells, monocytes, macrophages, and activated PMN). It is postulated that in the in vivo

 

setting, Herceptin@ may recruit immune cells to the tumor site.

 

b) Clinical Review HerceptinO

 

BLA 98-0369 5.0 CLINICAL TRIAL H0649a - PHASE 2, SINGLE AIM STUDY

 

5.1 Title H0649g

 

A Multinational, Open-Label Study of Recombinant Humanized Anti-p1 85HEW

 

Monoclonal Antibody (rhuMAb HER2) in Patients with HER2/neu Overexpression Who

 

Have Relapsed Following One or Two Cytotoxic Chemotherapy Regimens for Metastatic

 

Breast Cancer

 

Conducted April 24, 1995 to June 4, 1997 5.2 Study design and conduct H0649g

 

5.2.1 Objectives H0649g

 

Primary endpoints of this study were the overall response rate defined as the sum

 

of the complete and partial responses and delineation of the safety profile of Herceptin@

 

as a single agent in patients with metastaric breast cancer.

 

Secondary endpoints were the duration of response, time to progression, time to

 

treatment failure, smival, and quality of life. Please refer to Appendix D for all

 

definitions..

 

52.2 H0639g

 

This is a Phase 2, open label, single arm study of HerceptinB conducted at 54

 

centers in the North America, Europe, and Australia/New Zealand. The target enrollment

 

was 200 patients.

 

Desizn 18 Clinical Herceptinm Review BLA 98-0369 5.2.3 Patient Selection H0649g

 

The selection criteria for patients was amended in May 1996. Below is a list of

 

the criteria from the original protocol and in its amended format.

 

Table 1. Selection criteria H0649g

 

Selection Original criteria protocol - April 1995 Age 18 or older Diagnosis Metastatic Prior chemotherapy

 

cancer for breast Final protocol - May 1996

 

18 or older Breast Cancer I 1 Progression g one regimen Breast Cancer 1 Progression following

 

two

 

for metastatic disease regimens Metastatic / regimens following

 

one or t~?o

 

for metastatic disease. if relapsed with metastases less than a year

 

following adjuvant therapy g if received high dose consolidation regimen adjuvant in the setting and one prior , rerimen for metastatic disease

 

1 Acceptable only if both primary

 

c Bilateral breast cancer HER2 positivity

 

Lift of tumor expectancy Measurable disease tumors are 2+ or 3+ or all metastatic metastatic sites are 3+ or 3+ for status sites are 2+ or 3+ for HER2 by IHC HER2 by IHC 2+ or 3+ by

 

immunohistochemistry 2+ or 3+ by > 3 months eliminated immunohistochemistry Mass at lcast I cm in greatest Mass at least I cm in greatest

 

dimension measurable

 

by physical, in 2

 

CT, or photos. . dimensions measurable

 

by physical, MRI, ultrasound, 600 b or bcner 60% or bener Creatinine Cl.7 eliminated Bilirubm 0,s eliminated White blood cell count > 3000 eliminated ?Intelet count -Iemoglobm > 80.000 eliminated > 8.5 eliminated < I I.0 Calcium or FISH dimension MRI, ultrasound,

 

performance only if both primary tumors are 2+ or 3+ or all dimensions

 

Kamofsky I 1 Acceptnblc in 2

 

CT, or photos. eliminated Radiation therapy Completed greater than 2 weeks Hormonal therapy Stopped more than 2 weeks prior eliminated prior lo entry

 

eliminated 10 entry

 

Brain metastases

 

Investigational agents Not allowed Allowed if stable after radiation

 

treatment Stopped therapy more than 30 Stopped therapy more than 30

 

days prior to entry days prior to entry 19 Clinical Herceptin@

 

BLA 984369 Review 6.0 CLINICAL TRIAL H0648g - PHASE 3, TWO ARM STUDY AND

 

THE COMPANION EXTENSION STUDY H0659g

 

6.1 Title H0648g

 

Chemotherapy and Antibody Response Evaluation (CARE): A Phase III, Multinational,

 

Randomized Study of Recombinant Humanized Anti-p1 85HEWMonoclonal Antibody

 

(rhuMAb HER2) Combined with Chemotherapy in Patients with HER2 Overexpression

 

who have not Received Cytotoxic Chemotherapy for Metastatic Breast Cancer.

 

Enrollment

 

ongoing. conducted from June 12, 1995 to March 7, 1997; patient follow up is still 6.2 Title H0659g

 

An additional study sen?es as and extension trial to HO648 and it is H0659g: An Open

 

Label Extension Study with Recombinant Humanized Anti-p] 85mK Monoclonal

 

Antibody (rhuMAb HER2) For Patients Whose Metastatic Breast Cancer Progressed

 

During Treatment on Study H0648g.

 

Enrollment conducted from December 1995 and is still ongoing. 6.3 Study design and conduct of H0648g

 

6.3.1 Ohicctives

 

Primarv en ,7inl

 

Time to disease progression was defined as the time from randomization until

 

documented disease progression or death. For patients who discontinued the study prior

 

to PD and had no assessment performed after baseline, time to progression was censored

 

at the time of last treatment date or date of study termination. All other patients were

 

censored at the time of last assessment.

 

Secondanr endooints

 

Overall response rate was defined as CR + PR sustained for 4 weeks.

 

Duration of major response was defined as time from initial CR or PR until PD or

 

death, whichever occurred first.

 

Time to treatment failure was defined as the time from randomization to whichever

 

of the following occurred first:

 

Documented PD

 

Treatment discontinuation due to adverse event

 

Patient?s request to discontinue study

 

Patient death

 

Commencement of concurrent immunotherapy, chemotherapy, or

 

hormonal therapy not specified in the protocol.

 

Survival was defined at the time from randomization to death.

 

Quality of Life as determined by a questionnaire which included the following: 31 Herceptin@

 

BLA 98-0369 Clinical Review EORTC

 

EORTC

 

Selected

 

Selected

 

Several QLQ-C30 Core Questionnaire, version 1

 

breast cancer module BR-23

 

items from the Breast Cancer Questionnaire BCQ

 

items from the National Health Institute Survey

 

original items 6.3.2 DesiPn H0648g

 

This was a Phase 3, open label, randomized study comparing therapy with HerceptinO

 

plus chemotherapy with chemotherapy alone and employing two different chemotherapy

 

regimens ?epending on the patient history of anthracycline use. The study was conducted

 

at 150 sites in North America, Europe, and Australia/New Zealand. The target

 

enrollment was 450 patients.

 

6.3.3 Maior amendments made to the studs H0638~ and selection criteria

 

H0648g began as a randomized double blind study with clearly outlined entry criteria; the

 

two arms of the trial were anthracyclinekyclophosphamide

 

(AC) chemotherapy

 

combined with herceptin and AC with placebo. However, multiple major changes in the

 

protocol were enacted during the conduct of the study, the majority of which were added

 

after 97 patients had enrolled. In its final form it was an open label study with relatively

 

broad entry criteria employing two different chemotherapy regimens. While there were

 

still two arms to the study (in terrns of randomization), there were 4 clinically distinct

 

subgroups: AC + Herceptin@, AC alone, paclitaxel (T) + Herceptin@, and paclitaxel (T)

 

alone. In addition, study H0659g was initiated in order to enable all patients from

 

H0648g meeting eligibility criteria for H0659g to receive Herceptin@. Below is a table

 

comparing the original and final study designs for H0648g: 32 Clinical Review Table 7. Herceptin@

 

BLA 98-0369 Comparison of original

 

_

 

.protocol and final protocol H0648r. Parameter H0648g original study

 

Initiated May 1995 H0648g final study

 

May 1996 Randomized

 

Blinding Herceptin vs placebo

 

Double Blind

 

Yes Herceptin vs control

 

Open label with blinded REC

 

No AC

 

6

 

450

 

Time to progression AC or T if prior anthracycline

 

at least 6 with no limit Placebo

 

Chemotherapy

 

Number of cycles of chemo

 

Target enrollment

 

Primary endpoint

 

Secondary endpoints KPS

 

HER2 expression

 

Prior anthracycline

 

(adjuvant)

 

Prior chemo for metastatic disease

 

Prior hormonal therapy for metastatic

 

disease

 

Prior radiation therapy for metastatic

 

disease

 

Bi-dimensionally

 

measurable disease

 

Bone metastases as sole site of disease

 

Brain metastases

 

Baseline labs and clinical studies VYHA Class Ill or IV CHF

 

Hcrccptin administration

 

relative

 

:hemo

 

rumor

 

assessment

 

extension times study H0659g to 450 Overall response

 

Duration of response

 

Survival at one year Time to progression

 

Overall response

 

Duration of response

 

Survival at one year 60 or better

 

2+ or 3+; Ab 4D5

 

No

 

No

 

> 2 weeks prior 60 or better

 

2+ or 3+, Ab 4D5 or CBI 1

 

Yes

 

No

 

No limit > 2 weeks prior NT limit Yes

 

No Yes

 

Yes, lytic lesions only No

 

Creatmine < 1.7

 

Bilirubin < 2.0

 

Protime < 14

 

W?BC > 3500

 

Platelets > 100,000

 

Hgb > IO

 

Calcium > II.0

 

FEV, > 60% of predicted

 

Cardiac EF > 45%

 

No

 

Herceptin given one day prior

 

to chemo for all cycles Yes if treated and stable

 

?Suitable candidates for receiving

 

concomitant cytotoxic chemotherapy

 

as evidenced by screening lab

 

assessments of hematologic, renal,

 

hepatic, and metabolic functions.? Weeks 8, 17,26,36,52,

 

every 12 weeks

 

No then No limit

 

Herceptin give day prior

 

then at the same time as

 

subsequent cycles

 

Weeks 8,20,32,44,56,

 

weeks

 

Yes, initiated November for first cycle

 

chemo for

 

then every I2

 

1995 According to the sponsor, enrollment on the trial was very slow and they had deterrnined

 

that the reasons related to investigator and patient concerns. The sponsor decided that the

 

above outlined amendments were necessary in order to improve the rate of enrollment.

 

However, this resulted in a study which was difficult to analyze for a variety of reasons.

 

Below are listings of the reasons proposed by the sponsor for making the extensive

 

modifications of the ongoing clinical trial and problems which this created for the

 

analysis of the study. 33 Clinical Review Herceptin@

 

BLA 98-0369 7.0 Relationship

 

Betx-een

 

and Clinical Benefit

 

T.evel of HER2/peu protein Level of HERZ/neu Protein Overexpression overexpression As discussed earlier in the document, the tumor samples of patients with metastatic

 

cancer were tested for the presence of HER2/neu protein over-expression by

 

immunohistochemistry

 

(IHC). Two different antibodies w?ere employed. breast 4D5 antibody - binds to the extracellular domain of

 

HERYneu and is the parent antibody of Herceptin CB 11 antibody - binds to the intracellular domain of HERYneu Parenthetically, the PMA for the test kit, HercepTest. with the proposed indication for the

 

selection of patients appropriate for treatment with Herceptina was simultaneously under

 

review by, the FDA. The test kit used a polyclonal antibody Lvhich binds to the

 

intracellular domain. For all the abo e assays, tumor samples were scored as 0, l+, 2+ or

 

3+. Only patients with scores of 2+ or 3+ were enrolled into studies HOG49g (Phase 2)

 

and H064Q (Phase 3).

 

We examined the data (FD.4 data sets) for differences in the efficacy endpoints (time to

 

progression and response rate) between patients who were 2+ 1s. 3+ overexpressers of

 

the HER2ineu protein by IHC testing. There was one patient scored as l+ by the protein

 

assay and 2-e by FISH who vas entered on study as an exemption; she did not have a

 

tumor response and progressed by week 8. For purposes ofthe analysis she is included as

 

a 2+ overespresser.

 

The distribution of patients who were 2+ or 3+ lvas comparable between the two study

 

arms of H0648g. The data appear below in Table 29. Table 29. Percent of patients testing 2+ or 3+ by IHC in study H0648g and H0649g.

 

HER2 ACH

 

N = 143

 

% (n) AC

 

N = 138

 

% (n) I-H

 

N = 92

 

%(n) T

 

N = 96

 

% (n) H+Chcmo

 

N = 235

 

% (n) Chemo

 

N = 234

 

% (n) H (6495)

 

N = 713

 

___ 2+ 24% 3 0% 26% 30% 25% 26% 22% 3+ (35)

 

76% (42)

 

70% (24)

 

74% (19)

 

80% (59)

 

75% (61)

 

74% (108) (96) (68) (77) (176) (173) (50)

 

78%

 

(172) Sccire - The data for the overall response rate

 

score (2+ vs. 3+) appear in Table 30.

 

achieved a significantly higher tumor

 

AC or paclitaxel compared with those O/b(n) (responses sustained for at least 4 weeks) by IHC

 

The patients with tumors which scored as 3+

 

response rate when treated with Herceptin@ plus

 

treated with AC or paclitaxel alone: 53% vs 36% 73 Herceptin@

 

BLA 98-0369 Clinical Review for ACH 3+ vs AC 3+, respectively and 44% vs 14% for TH 3+ vs T 3+, respectively. The benefit for the patients who were 3+, again, was greater for those in the paclitaxel

 

subgroup. Patients with tumors which scored as 2+ treated with the same regimens

 

showed no difference in response rate between those treated with Herceptin plus

 

chemotherapy and those treated with chemotherapy alone: 40% vs 43% for ACH 2+ vs

 

AC 2+, respectively and 2 1% vs 16% for TH 2+ vs T 2+, respectively. Table 30. Response rate by IHC score for HER2/neu protein expression H0649g. The denominator

 

and score.

 

HER2 score of

 

responders

 

2+ (CR+PR)

 

3+ (CR+PR) H0648g and

 

value (n) appears in Table 29 for each corresponding subgroup ACH AC TH T % (N) % (N) % (N) % (N) % (N) % (N) % (N) 40%

 

(14)

 

53%

 

(57) 43% 2I% 16% 32 % 34 % J% .(5)

 

4-t%

 

GO) (3)

 

14% (19)

 

49% (21)

 

27X0 (11) (87) (46) (2)

 

17%

 

(29) (18)

 

36%

 

(35) H+Chemo Chemo H We also examined the time to progression for 2+ vs 3+ patients and found that there v~as

 

no difference in time to progression for patients with 2+ tumors ( p > 0. IO), but there was

 

a significant increase in time to progression for those with 3+ tumors (p < 0.001).

 

Statistical testing for an interaction (i.e. testing of the difference between the differc-ces

 

of the cumes) vvas significant with a p 1,alue < 0.05. The curves for time to progression

 

appear in Figures 11 and 12 and the median time to progression v*alues are in Table 3 1.

 

Table 31. Median time to progression

 

HER2 score ACH of 2+ 1?s 3+ patients enrolled on HO648 months AC

 

months TH

 

months T

 

months 2+ (CR+PR)

 

95% Cl 7.6

 

5.3. 10.1 7.1

 

4.8.9.7 4.4

 

3.2.6.6 3.2

 

2.0, 5.6 3+ (CR+PR)

 

9s!! Cl 7.3

 

7.1. 9.8 4.9

 

4.5. 6.9 7.1

 

6.7. 12.0 2.2

 

I .s, 4.3 by IHC These studies (H0649g and H0648g) were not designed to test whether or not there was a

 

relationship between the impact of Herceptina on time to pr -gression, response rate, or

 

survival and the extent of HER2 overexpression (2+ vs. 3+); therefore, this analysis is

 

exploratory in nature. There were far fewer patients with tumors that scored 2+ and this

 

affects the power of such an analysis. Nonetheless, the observed difference in clinical

 

outcome and the interaction of the level of overexpression were significant. 74 Clinical HerceptinQ, Review BLA Time to Progression , b - 5 Her 2+ Patients I I I I 10 15 20 25 I Time to Progression

 

Figure 11. Time to progression Herccptin plus chemotherapy (Months) for patients whose tumors were scored as 2+ for protein vs chemotherapy alone. 75 98-0369 Study H0638g . overexpression. Clinical Herceptin@J Review BLA Time to Progression 0 5 Her 3+ Patients I 1 10 15 J Time to Progression

 

Figurr

 

tlerceptin 1 20 vs chcmolhcrap). alone....

 


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