te, basolateral or lateral membranous reactivity in ≥ 10% of tumour cells
Tumour cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained
Positive
In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to the chromosome 17 copy number is greater than or equal to 2.
Clinical efficacy and safety
Metastatic breast cancer
Trastuzumab has been used in clinical trials as monotherapy for patients with MBC who have tumours that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic disease (trastuzumab alone).
Trastuzumab has also been used in combination with paclitaxel or docetaxel for the treatment of patients who have not received chemotherapy for their metastatic disease. Patients who had previously received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused over 3 hours) with or without trastuzumab. In the pivotal trial of docetaxel (100 mg/m2 infused over 1 hour) with or without trastuzumab, 60% of the patients had received prior anthracycline-based adjuvant chemotherapy. Patients were treated with trastuzumab until progression of disease.
The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been studied. However, trastuzumab plus docetaxel was efficacious in patients whether or not they had received prior adjuvant anthracyclines.
The test method for HER2 overexpression used to determine eligibility of patients in the pivotal trastuzumab monotherapy and trastuzumab plus paclitaxel clinical trials employed immunohistochemical staining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin's fixative. This investigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among those patients with higher levels of overexpression of HER2 (3+).
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or without trastuzumab, was immunohistochemistry. A minority of patients was tested using fluorescence in-situ hybridisation (FISH). In this trial, 87% of patients entered had disease that was IHC3+, and 95% of patients entered had disease that was IHC3+ and/or FISH-positive.
Weekly dosing in metastatic breast cancer
The efficacy results from the monotherapy and combination therapy studies are summarised in table 4.
Table 4 Efficacy results from the monotherapy and combination therapy studies
Parameter
Monotherapy
Combination therapy
Trastuzumab1
N = 172
Trastuzumab plus paclitaxel2
N = 68
Paclitaxel2
N = 77
Trastuzumab plus docetaxel3
N = 92
Docetaxel3
N = 94
Response rate (95%CI)
18%
(13-25)
49%
(36-61)
17%
(9-27)
61%
(50-71)
34%
(25-45)
Median duration of response (months) (95%CI)
9.1
(5.6-10.3)
8.3
(7.3-8.8)
4.6
(3.7-7.4)
11.7
(9.3–15.0)
5.7
(4.6-7.6)
Median TTP (months) (95%CI)
3.2
(2.6-3.5)
7.1
(6.2-12.0)
3.0
(2.0-4.4)
11.7
(9.2-13.5)
6.1
(5.4-7.2)
Median Surviva |
