Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Trazimera® 420 mg and Trazimera® 150 mg is a biosimilar medicinal product,that has been 2022-0077320
 demonstrated to be similar in quality, safety and efficacy to the reference medicinal product Herceptin.
More detailed information is available on the website of the Ministry of Health http://www.health.gov.il/hozer/dr_127.pdf

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03 
Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20 %-30 % of primary breast cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have shown that there is a broad variation of HER2-positivity ranging from 6.8 % to 34.0 % for IHC and 7.1 % to  42.6 % for FISH. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a shortened disease-free survival compared to patients whose tumours do not overexpress HER2.
The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in serum samples.

Mechanism of action

Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Detection of HER2 overexpression or HER2 gene amplification

Detection of HER2 overexpression or HER2 gene amplification in breast cancer trastuzumab should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section  4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Trazimera®  420 mg and Trazimera® 150 mg treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result.

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2: 
Table 2 Recommended Scoring System to Evaluate the IHC Staining Patterns in Breast Cancer 
Score      Staining pattern                                         HER2 overexpression assessment
0          No staining is observed or membrane staining is          Negative observed in < 10 % of the tumour cells
1+         A faint/barely perceptible membrane staining is          Negative detected in > 10 % of the tumour cells. The cells are only stained in part of their membrane.
2+         A weak to moderate complete membrane staining is         Equivocal detected in > 10 % of the tumour cells.
3+         Strong complete membrane staining is detected in         Positive > 10 % of the tumour cells.

In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to 
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 the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the HER2 gene per tumour cell if no chromosome 17 control is used.

In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus in greater than 50 % of tumour cells.

For full instructions on assay performance and interpretation please refer to the package inserts of validated FISH and CISH assays. Official recommendations on HER2 testing may also apply.

For any other method that may be used for the assessment of HER2 protein or gene expression, the analyses should only be performed by laboratories that provide adequate state-of-the-art performance of validated methods. Such methods must clearly be precise and accurate enough to demonstrate overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and strong (congruent with 3+) overexpression of HER2.

Detection of HER2 over expression or HER2 gene amplification in gastric cancer Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene amplification. IHC is recommended as the first testing modality and in cases where HER2 gene amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH technique must be applied. SISH technology is however, recommended to allow for the parallel evaluation of tumor histology and morphology. To ensure validation of testing procedures and the generation of accurate and reproducible results, HER2 testing must be performed in a laboratory staffed by trained personnel. Full instructions on assay performance and results interpretation should be taken from the product information leaflet provided with the HER2 testing assays used.

In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were defined as HER2 positive and thus included in the trial. Based on the clinical trial results, the beneficial effects were limited to patients with the highest level of HER2 protein overexpression, defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.

In a method comparison study (study D008548) a high degree of concordance (>95%) was observed for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.

HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using either SISH or FISH on fixed tumour blocks.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3: 


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Table 3 Recommended Scoring System to Evaluate the IHC Staining Patterns in Gastric Cancer 
Score       Surgical specimen -              Biopsy specimen –                  HER2 staining pattern                 staining pattern                   overexpression assessment
No reactivity or membranous      No reactivity or membranous
0           reactivity in < 10 % of tumour   reactivity in any tumour cell      Negative cells
Faint ⁄ barely perceptible     Tumour cell cluster with a faint ⁄ membranous reactivity in       barely perceptible membranous
1+           ≥ 10 % of tumour cells; cells reactivity irrespective of           Negative are reactive only in part of   percentage of tumour cells their membrane                 stained
Weak to moderate complete,     Tumour cell cluster with a weak basolateral or lateral         to moderate complete,
membranous reactivity in       basolateral or lateral
2+                                                                              Equivocal
≥ 10 % of tumour cells         membranous reactivity irrespective of percentage of tumour cells stained
Strong complete, basolateral Tumour cell cluster with a strong or lateral membranous          complete, basolateral or lateral
3+          reactivity in ≥ 10 % of tumour membranous reactivity                Positive cells                          irrespective of percentage of tumour cells stained

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 oftrastuzumab 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 andtrastuzumab 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 2022-0077320
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 trastuzumab 1                   Paclitaxel2                  Docetaxel3 trastuzuma                trastuzuma b plus                    b plus
N=172         paclitaxel2     N=77      docetaxel3         N=94
Response rate                18 %            49 %         17 %         61 %            34 % (95 %CI)                   (13 - 25)       (36 - 61)     (9 - 27)     (50-71)         (25-45) Median duration of            9.1             8.3           4.6          11.7            5.7 response (months)         (5.6-10.3)       (7.3-8.8)     (3.7-7.4)    (9.3 – 15.0)    (4.6-7.6) (95 %CI)
Median TTP                    3.2             7.1           3.0          11.7            6.1 (months) (95 %CI)          (2.6-3.5)      (6.2-12.0)     (2.0-4.4)    (9.2-13.5)      (5.4-7.2) Median Survival             16.4             24.8            17.9        31.2           22.74 (months) (95 %CI)        (12.3-ne)       (18.6-33.7) (11.2-23.8) (27.3-40.8) (19.1-30.8) TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1.   Study H0649g: IHC3+ patient subset
2.   Study H0648g: IHC3+ patient subset
3.   Study M77001: Full analysis set (intent-to-treat), 24 months results 
Combination treatment with trastuzumab and anastrozole trastuzumab has been studied in combination with anastrozole for first line treatment of MBC in HER2 overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor (PR)) positive postmenopausal patients. Progression free survival was doubled in the trastuzumab plus anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the improvements seen for the combination were for overall response (16.5 % versus 6.7 %); clinical benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4 months).
For time to response and duration of response no difference could be recorded between the arms.
The median overall survival was extended by 4.6 months for patients in the combination arm. The difference was not statistically significant, however more than half of the patients in the anastrozole alone arm crossed over to a trastuzumab containing regimen after progression of disease.

Sites of progression
The frequency of progression in the liver was significantly reduced in patients treated with the combination of trastuzumab and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %; p=0.004). More patients treated with trastuzumab and paclitaxel progressed in the central nervous system than those treated with paclitaxel alone (12.6 % versus 6.5 %; p=0.377).

Early breast cancer (adjuvant setting)

Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast.
In the adjuvant treatment setting, trastuzumab was investigated in 4 large multicentre, randomised, trials.
-        Study BO16348 was designed to compare one and two years of three-weekly trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of trastuzumab treatment versus one year of trastuzumab treatment was performed.
Patients assigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, 2022-0077320
            followed by
6 mg/kg every three weeks for either one or two years.
-          The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to investigate the clinical utility of combining trastuzumab treatment with paclitaxel following AC chemotherapy, additionally the NCCTG N9831 study also investigated adding trastuzumab sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.
-       The BCIRG 006 study was designed to investigate combining trastuzumab treatment with docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin in patients with HER2 positive EBC following surgery.

Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma of the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm in diameter.

In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or HER2 positive and lymph node negative with high risk features (tumor size > 1 cm and ER negative or tumor size > 2 cm, regardless of hormonal status).

In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors: tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological and/or nuclear grade 2-3, or age < 35 years).
The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up are summarized in Table 5:

Table 5 Efficacy Results from Study BO16348

Median follow-up                    Median follow-up
12 months*                            8 years**
Parameter                            Observation                         Observation N=1693           trastuzu          N= 1697***          trastuzu mab 1                              mab 1
Year                                Year
N = 1693                          N = 1702***

Disease-free survival
- No. patients with event           219 (12.9 %)       127 (7.5 %)     570 (33.6 %)         471 (27.7 %) - No. patients without event        1474 (87.1 %)    1566 (92.5 %)     1127 (66.4 %)       1231 (72.3 %) P-value versus Observation                     < 0.0001                             < 0.0001 Hazard Ratio versus Observation                  0.54                                 0.76 Recurrence-free survival
- No. patients with event           208 (12.3 %)       113 (6.7 %)     506 (29.8 %)         399 (23.4 %) - No. patients without event        1485 (87.7 %)    1580 (93.3 %)     1191 (70.2 %)       1303 (76.6 %) P-value versus Observation                     < 0.0001                             < 0.0001 Hazard Ratio versus Observation                  0.51                                 0.73 Distant disease-free survival
- No. patients with event           184 (10.9 %)        99 (5.8 %)     488 (28.8 %)         399 (23.4 %) - No. patients without event        1508 (89.1 %)    1594 (94.6 %)     1209 (71.2 %)       1303 (76.6 %) P-value versus Observation                     < 0.0001                             < 0.0001 Hazard Ratio versus Observation                  0.50                                 0.76 Overall survival (death)
- No. patients with event             40 (2.4 %)        31 (1.8 %)     350 (20.6 %)         278 (16.3 %) - No. patients without event        1653 (97.6 %)    1662 (98.2 %)     1347 (79.4 %)       1424 (83.7 %) P-value versus Observation                       0.24                                0.0005 Hazard Ratio versus Observation                  0.75                                 0.76 *Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary 
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**Final analysis (including crossover of 52 % of patients from the observation arm to trastuzumab) *** There is a discrepancy in the overall sample size due to a small number of patients who were randomized after the cut-off date for the 12-month median follow-up analysis

The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical boundary for the comparison of 1-year of trastuzumab versus observation. After a median follow-up of 12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95 % CI 0.44, 0.67) which translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage points (85.8 % versus 78.2 %) in favour of the trastuzumab arm.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year trastuzumab treatment is associated with a 24 % risk reduction compared to observation only (HR=0.76, 95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease free survival rate of 6.4 percentage points in favour of 1 year trastuzumab treatment.

In this final analysis, extending trastuzumab treatment for a duration of two years did not show additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years versus 1 year=0.99 (95 % CI: 0.87, 1.13), p-value=0.90 and OS HR=0.98 (0.83, 1.15); p-value= 0.78].
The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1 % versus 4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event in the 2- year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %).

In the NSABP B-31 and NCCTG N9831 studies trastuzumab was administered in combination with paclitaxel, following AC chemotherapy.

Doxorubicin and cyclophosphamide were administered concurrently as follows: 
- intravenous push doxorubicin, at 60 mg/ m2, given every 3 weeks for 4 cycles.

- intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4 cycles.
Paclitaxel, in combination with trastuzumab , was administered as follows: 
- intravenous paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given every week for 12 weeks.
or
- intravenous paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every 3 weeks for 4 cycles (day 1 of each cycle).

The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 trials at the time of the definitive analysis of DFS* are summarized in Table 6. The median duration of follow up was 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.

Table 6        Summary of Efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time of the definitive DFS analysis*

Parameter                    AC→P               AC→PH               Hazard Ratio vs (n=1679)            (n=1672)               AC→P
(95% CI) p-value
Disease-free survival
No. patients with event (%)            261 (15.5)           133 (8.0)           0.48 (0.39, 0.59) p<0.0001
Distant Recurrence
No. patients with event                193 (11.5)            96 (5.7)           0.47 (0.37, 0.60) p<0.0001
Death (OS event):

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No. patients with event                        92 (5.5)                62 (3.7)               0.67 (0.48, 0.92) p=0.014**
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
* At median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm ** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. AC→P 
For the primary endpoint, DFS, the addition of trastuzumab to paclitaxel chemotherapy resulted in a 52% decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % versus 75.4 %) in favour of the AC→PH ( trastuzumab ) arm.

At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to trastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapy resulted in a 52% decrease in the risk of disease recurrence. The addition of trastuzumab to paclitaxel chemotherapy also resulted in a 37% decrease in the risk of death.

The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→P H group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared with AC→P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001). At 8 years, the survival rate was estimated to be 86.9% in the AC→PH arm and 79.4% in the AC→P arm, an absolute benefit of 7.4% (95% CI 4.9%, 10.0%).
The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are summarized in Table 7 below:

Table 7 Final Overall Survival Analysis from the joint analysis of trials NSABP B-31 and NCCTG N9831
Parameter                             AC→P                AC→PH            p-value versus Hazard Ratio (N=2032)             (N=2031)              AC→P         versus
AC→P
(95% CI)
Death (OS event):
No. patients with event (%)        418 (20.6%)         289 (14.2%)            < 0.0001         0.64 (0.55, 0.74)
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54, 0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite  24.8% patients in the AC→P arm who crossed over to receive trastuzumab . At 8 years, the disease- free survival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit of 11.8% compared with the AC→P arm.

In the BCIRG 006 study trastuzumab was administered either in combination with docetaxel, following AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).

Docetaxel was administered as follows:
-    intravenous docetaxel - 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle) or
-    intravenous docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle) which was followed by:
-      carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over 30-60 minutes repeated every 3 weeks for a total of six cycles
 trastuzumab was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52 weeks.

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The efficacy results from the BCIRG 006 are summarized in Tables 8 and 9. The median duration of follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms.



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Table 8 Overview of Efficacy Analyses BCIRG 006 AC→D versus AC→DH Parameter                   AC→D               AC→DH             Hazard Ratio vs (n=1073)            (n=1074)             AC→D
(95% CI) p-value
Disease-free survival
No. patients with event                 195                  134           0.61 (0.49, 0.77) p<0.0001
Distant recurrence
No. patients with event                 144                  95            0.59 (0.46, 0.77) p<0.0001
Death (OS event)
No. patients with event                 80                   49            0.58 (0.40, 0.83) p=0.0024
AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval 

Table 9 Overview of Efficacy Analyses BCIRG 006 AC→D versus DCarbH
Parameter                   AC→D                DCarbH           Hazard Ratio vs (n=1073)            (n=1074)             AC→D
(95% CI)
Disease-free survival
No. patients with event                 195                  145           0.67 (0.54, 0.83) p=0.0003
Distant recurrence
No. patients with event                 144                  103           0.65 (0.50, 0.84) p=0.0008
Death (OS event)
No. patients with event                 80                   56            0.66 (0.47, 0.93) p=0.0182
AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and trastuzumab; CI = confidence interval

In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7 % versus 80.9 %) in favour of the AC→DH ( trastuzumab ) arm and 4.6 percentage points (85.5 % versus 80.9 %) in favour of the DCarbH ( trastuzumab ) arm compared to AC→D.

In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC→DH (AC→TH) arm, and 217/1073 in the AC→D (AC→T) arm had a Karnofsky performance status ≤90 (either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients (hazard ratio = 1.16, 95% CI [0.73, 1.83] for DCarbH (TCH) versus AC→D (AC→T); hazard ratio 0.97, 95% CI [0.60, 1.55] for AC→DH (AC→TH) versus AC→D).

In addition a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA) NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events and summarized in Table 10:



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Table 10 Post-Hoc Exploratory Analysis Results from the Joint Analysis NSABP B-31/NCCTG N9831* and BCIRG006 Clinical Studies Combining DFS Events and Symptomatic Cardiac Events 
AC→PH                     AC→DH                  DCarbH
(vs. AC→P)                (vs. AC→D)             (vs. AC→D)
(NSABP B-31 and            (BCIRG 006)             (BCIRG 006)
NCCTG N9831)*

Primary efficacy analysis
DFS Hazard ratios                   0.48                     0.61                    0.67 (95% CI)                    (0.39, 0.59)             (0.49, 0.77)            (0.54, 0.83) p-value                     p<0.0001                 p< 0.0001               p=0.0003 Long term follow-up efficacy analysis**
DFS Hazard ratios                      0.61                   0.72                     0.77 (95 % CI)                     (0.54, 0.69)           (0.61, 0.85)             (0.65, 0.90) p-value                       p<0.0001              p<0.0001                 p=0.0011 Post-hoc exploratory analysis with DFS and symptomatic cardiac events
Long term follow-up**Hazard                 0.67                   0.77                     0.77 ratios                     (0.60, 0.75)           (0.66, 0.90)             (0.66, 0.90) (95% CI)
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab CI = confidence interval
*
At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the AC→P arm and 2.0 years in the AC→PH arm
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range: 0.1 to 12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; Median duration of long term follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range: 0.0 to 12.6) arm and the DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH arm


Early breast cancer (neoadjuvant-adjuvant setting)
So far, no results are available which compare the efficacy of trastuzumab administered with chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting.

In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was designed to investigate the clinical efficacy of concurrent administration of trastuzumab with neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant trastuzumab , up to a total treatment duration of 1 year. The study recruited patients with newly diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant trastuzumab , or neoadjuvant chemotherapy alone.

In study MO16432, trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3 weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy  as follows:

-   Doxorubicin 60mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles, which was followed by
-   Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles,
 which was followed by
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    -    CMF on day 1 and 8 every 4 weeks for 3 cycles



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which was followed after surgery by
-   additional cycles of adjuvant trastuzumab (to complete 1 year of treatment) 
The efficacy results from study MO16432 are summarised in Table 11. The median duration of follow- up in the trastuzumab arm was 3.8 years

Table 11 Efficacy Results from MO16432
Parameter                  Chemo +              Chemo only trastuzum             (n=116) ab
(n=115)

Event-free survival                                                              Hazard Ratio (95% CI)
No. patients with event                     46                 59              0.65 (0.44, 0.96) p=0.0275
Total pathological complete             40%                  20.7%                P=0.0014 response* (95% CI)                   (31.0, 49.6)          (13.7, 29.2) Overall survival                                                             Hazard Ratio (95 % CI)
No. patients with event                22                   33             0.59 (0.35, 1.02) p=0.0555
* defined as absence of any invasive cancer both in the breast and axillary nodes 
An absolute benefit of 13 percentage points in favour of the trastuzumab arm was estimated in terms of 3-year event-free survival rate (65 % versus 52 %).

Metastatic gastric cancer
 trastuzumab has been investigated in one randomised, open-label phase III trial ToGA (BO18255) in combination with chemotherapy versus chemotherapy alone.


Chemotherapy was administered as follows:
-   capecitabine - 1000 mg/m2 orally twice daily for 14 days every 3 weeks for 6 cycles (evening of day 1 to morning of day 15 of each cycle) or
-   intravenous 5-fluorouracil - 800 mg/m2/day as a continuous intravenous infusion over 5 days, given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)

Either of which was administered with:

-   cisplatin - 80 mg/m2 every 3 weeks for 6 cycles on day 1 of each cycle.
The efficacy results from study BO18225 are summarized in Table 12: Table 
12 Efficacy Results from BO18225
Parameter                  FP         FP +H       HR (95 % CI)        p-value N = 290      N = 294
Overall Survival, Median             11.1         13.8      0.74 (0.60-0.91)     0.0046 months
Progression-Free Survival,            5.5           6.7     0.71 (0.59-0.85)     0.0002 Median months
Time to Disease Progression,          5.6           7.1     0.70 (0.58-0.85)     0.0003 Median months
Overall Response Rate, %            34.5 %        47.3 %      1.70a (1.22,       0.0017 2.38)
26
Duration of Response, Median          4.8           6.9    0.54 (0.40-0.73)     < 0.0001 2022-0077320 months


FP + H: Fluoropyrimidine/cisplatin + trastuzumab

FP: Fluoropyrimidine/cisplatin a Odds ratio

Patients were recruited to the trial who were previously untreated for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction not amenable to curative therapy. The primary endpoint was overall survival which was defined as the time from the date of randomization to the date of death from any cause. At the time of the analysis a total of 349 randomized patients had died: 182 patients (62.8 %) in the control arm and 167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the underlying cancer.

Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79) for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group.

In an exploratory subgroup analysis performed in the ToGA (BO18255) trial there was no apparent benefit on overall survival with the addition of trastuzumab in patients with ECOG PS 2 at baseline [HR
0.96 (95 % CI 0.51-1.79)], non-measurable [HR 1.78 (95 % CI 0.87-3.66)] and locally advanced disease [HR 1.20 (95 % CI 0.29-4.97)].

Paediatric population

See section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties


The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or other tumor types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab IV. A two- compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 15).
MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the final population PK model, in addition to primary tumor type, body-weight, serum aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.

The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated with the approved q1w and q3w dosing regimens are shown in Table 13 (Cycle 1), Table 14 (steady- state), and Table 15 (PK parameters).


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Table 13 Population Predicted Cycle 1 PK Exposure Values (median with 5th - 95th Percentiles) for trastuzumab IV Dosing Regimens in MBC, EBC and AGC Patients
Cmin            Cmax             AUC0-21days
Regimen     Primary tumor type       N
(µg/mL)         (µg/mL)           (µg.day/mL)

28.7               182                 1376
MBC                805
(2.9 - 46.3)        (134 - 280)         (728 - 1998)
8mg/kg +                                               30.9                176                 1390 6mg/kg q3w            EBC                390
(18.7 - 45.5)        (127 - 227)        (1039 - 1895)
23.1                132                1109
AGC                274
(6.1 - 50.3)        (84.2 – 225)        (588 – 1938)
37.4                76.5               1073
MBC                805
4mg/kg +                                             (8.7 - 58.9)        (49.4 - 114)        (597 – 1584)
2mg/kg qw                                               38.9                 76.0               1074
EBC                390
(25.3 - 58.8)        (54.7 - 104)        (783 - 1502)


Table 14 Population Predicted Steady State PK Exposure Values (median with 5th - 95th Percentiles) for trastuzumab IV Dosing Regimens in MBC, EBC and AGC Patients


Time to
Primary tumor                      Cmin,ss*           Cmax,ss**     AUCss, 0-21days   steady- Regimen                           N type                          (µg/mL)             (µg/mL)       (µg.day/mL)       state*** (week)
44.2                179            1736
MBC            805                                                                 12 (1.8 - 85.4)         (123 - 266)    (618 - 2756)
8mg/kg +                                          53.8                184             1927 EBC            390                                                                 15 6mg/kg q3w                                     (28.7 - 85.8)        (134 - 247)    (1332 -2771) 32.9                 131           1338
AGC            274                                                                  9 (6.1 – 88.9)         (72.5 -251)    (557 - 2875)
63.1                 107           1710
MBC            805                                                                 12    4mg/kg +                                     (11.7 - 107)         (54.2 - 164)   (581 - 2715)
2mg/kg qw                                         72.6                 115            1893
EBC            390                                                                 14 (46 - 109)          (82.6 - 160)   (1309 -2734)



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*Cmin,ss – Cmin at steady state
**Cmax,ss = Cmax at steady state
*** time to 90% of steady-state


Table 15 Population Predicted PK Parameter Values at Steady State for Trastuzumab IV Dosing Regimens in MBC, EBC and AGC Patients
Total CL range from Cmax,ss to   t1/2 range from Cmax,ss to
Primary                                                         Cmin,ss Regimen                         N                  Cmin,ss tumor type
(L/day)                         (day)
MBC   805              0.183 - 0.302                      15.1 - 23.3 8mg/kg +
6mg/kg q3w                      EBC   390              0.158 - 0.253                     17.5 – 26.6 AGC   274              0.189 - 0.337                      12.6 - 20.6 
4mg/kg +                      MBC   805              0.213 - 0.259                      17.2 - 20.4
2mg/kg qw                      EBC   390              0.184 - 0.221                      19.7 - 23.2

Trastuzumab washout
Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the population PK model. The results of these simulations indicate that at least 95% of patients will reach concentrations that are <1 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% washout) by 7 months.

Circulating shed HER2 ECD

The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD level had faster nonlinear clearance (lower Km) (P< 0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC and EBC patients and no apparent impact on trastuzumab clearance was observed.