외국의 약물유전정보

Trastuzumab

미국 FDA   원본 보기 | 번역본 보기

1 INDICATIONS AND USAGE
1.1 Adjuvant Breast Cancer
Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
 - as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel 
 - as part of a treatment regimen with docetaxel and carboplatin
 - as a single agent following multi-modality anthracycline based therapy. 
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].

1.2 Metastatic Breast Cancer
Herceptin is indicated:
 - In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
 - As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].

1.3 Metastatic Gastric Cancer
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. 
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

11 DESCRIPTION
Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Herceptin is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Herceptin-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

14 CLINICAL STUDIES
14.1 Adjuvant Breast Cancer
The safety and efficacy of Herceptin in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open-label, clinical trials.
 - Studies 1 and 2
In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (Study 2) or was required to be performed at a reference laboratory (Study 1).
 - Study 3
In Study 3, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory.
Study 3 was designed to compare one and two years of three-weekly Herceptin treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable).

 

Table 10 Treatment Outcomes in Studies 2 and 3 as a Function of HER2 Overexpression or Amplification

 

Study 2

Study 3c

HER2 Assay

Resulta

Number of Patients

Hazard Ratio DFS (95% CI)

Number of Patients

Hazard Ratio DFS (95% CI)

IHC 3+

 

 

 

 

  FISH (+)

1170

0.42

(0.27, 0.64)

91

0.56

(0.13, 2.50)

  FISH (-)

51

0.71

(0.04, 11.79)

8

-

  FISH Unknown

51

0.69

(0.09, 5.14)

2258

0.53

(0.41, 0.69)

IHC<3+/

FISH(+)

174

1.01

(0.18, 5.65)

299b

0.53

(0.20, 1.42)

IHC unknown/

FISH(+)

-

-

724

0.59

(0.38, 0.93)

a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio 2.0) as performed at a central laboratory.

b All cases in this category in Study 3 were IHC 2+.

c Median follow-p duration of 12.6 months in the one-year Herceptin treatment arm.


14.2 Metastatic Breast Cancer
Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein.
 - Previously Untreated Metastatic Breast Cancer (Study 5)
Data from Study 5 suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) (see Table 12)

Table 12 Treatment Effects in Study 5 as a Function of HER2 Overexpression or Amplification

HER2 Assay Result

Number of Patients (N)

Relative Riskb for Time to Disease Progression (95% CI)

Relative Riskb for Motality

(95% CI)

CTA 2+ or 3+

469

0.49 (0.40, 0.61)

0.80 (0.64, 1.00)

  FISH (+)a

325

0.44 (0.34, 0.57)

0.70 (0.53, 0.91)

FISH (-)a

126

0.62 (0.42, 0.94)

1.06 (0.70, 1.63)

CTA 2+

120

0.76 (0.50, 1.15)

1.26 (0.82, 1.94)

  FISH (+)

32

0.54 (0.21, 1.35)

1.31 (0.53, 3.27)

  FISH (-)

83

0.77 (0.48, 1.25)

1.11 (0.68, 1.82)

CTA 3+

349

0.42 (0.33, 0.54)

0.70 (0.51, 0.90)

  FISH (+)

293

0.42 (0.32, 0.55)

0.67 (0.51, 0.89)

FISH (-)

43

0.43 (0.20, 0.94)

0.88 (0.39, 1.98)

a FISH testing results were available for 451 of the 469 patients enrolled on study.

b The relative risk represents the risk of progression or death in the Herceptin plus chemotherapy arm versus the chemotherapy arm.

 

 - Previously Treated Metastatic Breast Cancer (Study 6)
Herceptin was studied as a single agent in a multicenter, open-label, single-arm clinical trial (Study 6) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease.

14.3 Metastatic Gastric Cancer
All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%).
An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 14. 

 

Table 14 Exploratory Analyses by HER2 Status Using Updated Overall Survival Results

 

FC

(N=296)a

FC+H

(N=298)b

FISH+/IHC 0, 1+subgroup (N=133)

 

 

 No. Deaths / n (%)

57/71 (80%)

56/62 (90%)

 Median OS Duration (mos.)

8.8

8.3

 95% CI (mos.)

(6.4, 11.7)

(6.2, 10.7)

 Hazard ratio (95% CI)

1.33 (0.92, 1.92)

FISH+/IHC2+ subgroup (N=160)

 

 

 No. Deaths / n (%)

65/80 (81%)

64/80 (80%)

 Median OS Duration (mos.)

10.8

12.3

 95% CI (mos.)

(6.8, 12.8)

(9.5, 15.7)

 Hazard ratio (95% CI)

0.78 (0.55, 1.10)

FISH+ or FISH-/ IHC3+c subgroup (N=294)

 

 

 No. Deaths / n (%)

104/143 (73%)

96/151 (64%)

 Median OS Duration (mos.)

13.2

18.0

 95% CI (mos.)

(11.5, 15.2)

(15.5, 21.2)

 Hazard ratio (95% CI)

0.66 (0.50, 0.87)

a Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory subgroup analyses.

b Five patients on the Herceptin-containing arm who were FISH+, but IHC status unknown were excluded from the exploratory subgroup analyses.

c Includes 6 patients on chemotherapy arm, 10 patients on Herceptin arm with FISH-, IHC3+ and 8 patients on chemotherapy arm, 8 patients on Herceptin arm with FISH status unknown, IHC 3+.



(2018.4.30 업데이트)