Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD01 
Herceptin subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.

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 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 
Herceptin 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 Herceptin 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 
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 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.

Clinical efficacy and safety

Metastatic breast cancer
Intravenous formulation

Herceptin 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 (Herceptin alone).

Herceptin 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 Herceptin. In the pivotal trial of docetaxel (100 mg/m2 infused over 1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-based adjuvant chemotherapy. Patients were treated with Herceptin until progression of disease.


The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been studied. However, Herceptin 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 Herceptin monotherapy and Herceptin 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 Herceptin, 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 metatstatic breast cancer

The efficacy results from the monotherapy and combination therapy studies are summarised in Table 3:

Table 3: Efficacy results from the monotherapy and combination therapy studies 
Parameter                Monotherapy                     Combination Therapy Herceptin1        Herceptin Paclitaxel2 Herceptin Docetaxel3 plus                    plus
2 paclitaxel             docetaxel3
N=172            N=68         N=77       N=92     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 Herceptin and anastrozole
Herceptin 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 Herceptin 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 Herceptin containing regimen after progression of disease.

Three -weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapy studies are summarised in Table 4:

Table 4: Efficacy results from the non-comparative monotherapy and combination therapy studies 
Parameter                       Monotherapy                               Combination Therapy Herceptin1    Herceptin2                Herceptin plus       Herceptin plus paclitaxel3           docetaxel4
N=105                N=72                 N=32                N=110
Response rate                 24 %                27 %                 59 %                 73 % (95 %CI)                     (15-35)             (14-43)              (41-76)              (63-81) Median duration of             10.1                7.9                   10.5                        13.4 response (months)           (2.8-35.6)         (2.1-18.8)              (1.8-21)                   (2.1-55.1) (range)
Median TTP                      3.4                7.7                   12.2                           13.6 (months) (95 %CI)            (2.8-4.1)          (4.2-8.3)              (6.2-ne)                       (11-16) Median Survival                 ne                 ne                     ne                            47.3 (months) (95 %CI)                                                                                     (32-ne) TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1.    Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3 weekly schedule 2.    Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule
3.    Study BO15935
4.    Study MO16419

Sites of progression

The frequency of progression in the liver was significantly reduced in patients treated with the combination of Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %; p=0.004). More patients treated with Herceptin 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)

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


-       Study BCIRG 006 study was designed to investigate combining Herceptin 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 BO16348 Study 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 study BO16348 following 12 months* and 8 years** median follow-up are summarized in the Table 5:

Table 5: Efficacy results from study BO16348

Median follow-up                      Median follow-up
12 months*                             8 years**
Parameter                             Observation      Herceptin            Observation      Herceptin N=1693           1 Year              N= 1697***         1 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 **Final analysis (including crossover of 52 % of patients from the observation arm to Herceptin) *** 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 Herceptin 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 Herceptin arm.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year Herceptin 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 Herceptin treatment.

In this final analysis, extending Herceptin 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 Herceptin 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 Herceptin, 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 studies NSABP B-31 and NCCTG N9831 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):
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 Herceptin 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 (Herceptin) 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 Herceptin in the control arm, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52 % decrease in the risk of disease recurrence. The addition of Herceptin 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→PH 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:
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 Herceptin. 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 Herceptin 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

Herceptin was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52 weeks.

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.

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 (Herceptin) arm and 4.6 percentage points (85.5 % versus 80.9 %) in favour of the DCarbH (Herceptin) 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 summarised in Table 10:

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**                    0.67                      0.77                     0.77 Hazard 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) 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)

Intravenous formulation
So far, no results are available which compare the efficacy of Herceptin 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 Herceptin with neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant Herceptin, 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 Herceptin, or neoadjuvant chemotherapy alone.



In study MO16432, Herceptin (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
- CMF on day 1 and 8 every 4 weeks for 3 cycles which was followed after surgery by
- additional cycles of adjuvant Herceptin (to complete 1 year of treatment) 
The efficacy results from Study MO16432 are summarized in Table 11. The median duration of follow-up in the Herceptin arm was 3.8 years.

Table 11: Efficacy results from MO16432

Parameter              Chemo +            Chemo only
Herceptin           (n=116)
(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 Herceptin arm was estimated in terms of 3-year event-free survival rate (65 % versus. 52 %).

Subcutaneous formulation

Study BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin subcutaneous formulation versus Herceptin intravenous formulation based on co-primary PK and efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, respectively). A total of 595 patients with HER2-positive, operable or locally advanced breast cancer (LABC) including inflammatory breast cancer received eight cycles of either Herceptin intravenous formulation or Herceptin subcutaneous formulation concurrently with chemotherapy (4 cycles of docetaxel, 75 mg/m2 intravenous infusion, followed by 4 cycles of FEC ([5-Fluorouracil, 500 mg/m2; epirubicin, 75 mg/m2; cyclophosphamide, 500 mg/m2 each intravenous bolus or infusion]), followed by surgery, and continued therapy with Herceptin intravenous formulation or Herceptin subcutaneous formulation as originally randomized for 10 additional cycles, for a total of one year of treatment.

The analysis of the efficacy co-primary endpoint, pCR, defined as absence of invasive neoplastic cells in the breast, resulted in rates of 40.7 % (95 % CI: 34.7, 46.9) in the Herceptin intravenous arm and 45.4 % (95 % CI: 39.2 %, 51.7 %) in the Herceptin subcutaneous arm, a difference of 4.7 percentage points in favour of the Herceptin subcutaneous arm. The lower boundary of the one-sided 97.5 % 

confidence interval for the difference in pCR rates was -4.0, establishing the non-inferiority of Herceptin subcutaneous for the co-primary endpoint

Table 12: Summary of pathological Complete Response (pCR)
Herceptin IV           Herceptin SC
(N = 263)              (N=260) pCR (absence ofinvasive neoplastic cells in breast               107 (40.7%)           118 (45.4%) Non-responders                                                 156 (59.3%)           142 (54.6%) Exact 95% CI for pCR Rate*                                (34.7; 46.9)          (39.2; 51.7) Difference in pCR (SC minus IV arm)                                          4.70 Lower bound one-sided 97.5% CI for the                                       -4.0 difference in pCR**
*Confidence interval for one sample binomial using Pearson-Clopper method **Continuity correction of Anderson and Hauck (1986) has been used in this calculation 
Analyses with longer term follow-up of a median duration exceeding 40 months supported the non- inferior efficacy of Herceptin subcutaneous compared to Herceptin intravenous with comparable results of both EFS and OS (3-year EFS rates of 73% in the Herceptin intravenous arm and 76% in the Herceptin subcutaneous arm, and 3-year OS rates of 90% in the Herceptin intravenous arm and 92% in the Herceptin subcutaneous arm).

For non-inferiority of the PK co-primary endpoint, steady-state trastuzumab Ctrough value at the end of treatment Cycle 7, refer to section 5.2. Pharmacokinetic Properties. For the comparative safety profile see section 4.8.

The final analysis at a median follow-up exceeding 70 months showed similar EFS and OS between patients who received Herceptin IV and those who received Herceptin SC. The 6-year EFS rate was 65% in both arms (ITT population: HR=0.98 [95% CI: 0.74;1.29]) and the OS rate, 84% in both arms (ITT population: HR=0.94 [95% CI: 0.61;1.45]).


Study MO28048 investigating the safety and tolerability of Herceptin subcutaneous formulation as adjuvant therapy in HER2 positive EBC patients who were enrolled in either a Herceptin subcutaneous vial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Herceptin subcutaneous administration system cohort (N=710 patients, including 21 patients receiving neoadjuvant therapy) resulted in no new safety signals. Results were consistent with the known safety profile for Herceptin intravenous and Herceptin subcutaneous formulations. In addition, treatment of lower body weight patients with Herceptin subcutaneous fixed dose in adjuvant EBC was not associated with increased safety risk, adverse events and serious adverse events, compared to the higher body weight patients. The final results of study BO22227 at a median follow-up exceeding 70 months were also consistent with the known safety profile for Herceptin IV and Herceptin SC, and no new safety signals were observed.

Paediatric population

See section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by the subcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kg maintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for the co primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous compared to the Herceptin intravenous dose adjusted by body weight.


The mean Ctrough during the neoadjuvant treatment phase, at the pre dose Cycle 8 time point, was higher in the Herceptin subcutaneous arm (78.7 µg/mL) than the Herceptin intravenous arm (57.8 µg/mL) of the study. During the adjuvant phase of treatment, at the pre-dose Cycle 13 time point, the mean Ctrough values were 90.4 µg/mL and 62.1 µg/mL, respectively. Based on the observed data in study BO22227, steady state with the intravenous formulation was reached at cycle 8. With Herceptin subcutaneous formulation, concentrations were approximately at steady-state following Cycle 7 dose (pre-dose Cycle 8) with small increase in concentration (<15%) up to cycle 13. The mean Ctrough at the subcutaneous pre- dose cycle 18 was 90.7 µg/mL and is similar to that of cycle 13, suggesting no further increase after cycle 13.

The median Tmax following subcutaneous administration was approximately 3 days, with high interindividual variability (range 1-14 days). The mean Cmax was expectedly lower in the Herceptin subcutaneous formulation (149 μg/mL) than in the intravenous arm (end of infusion value: 221 μg/mL).

The mean AUC0-21 days following the Cycle 7 dose was approximately 10 % higher with the Herceptin subcutaneous formulation as compared to the Herceptin intravenous formulation, with mean AUC values of 2268 µg/mL•day and 2056 µg/mL•day, respectively. The AUC0-21 days following Cycle 12 dose was approximately 20 % higher with the Herceptin subcutaneous formulation than the Herceptin intravenous dose, with mean AUC values of 2610 µg/mL•day and 2179 µg/mL•day, respectively. Due to the significant impact of body weight on trastuzumab clearance and the use of a fixed dose for the subcutaneous administration the difference in exposure between subcutaneous and intravenous administration was dependent on body weight: in patients with a body weight < 51 kg, mean steady state AUC of trastuzumab was about 80% higher after subcutaneous than after intravenous treatment whereas in the highest BW group (> 90 kg) AUC was 20% lower after subcutaneous than after intravenous treatment.

A population PK model with parallel linear and nonlinear elimination from the central compartment was constructed using pooled Herceptin SC and Herceptin IV PK data from the phase III study BO22227 to describe the observed PK concentrations following Herceptin IV and Herceptin SC administration in EBC patients. Bioavailability of trastuzumab given as the subcutaneous formulation was estimated to be 77.1%, and the first order absorption rate constant was estimated to be 0.4 day-1.
Linear clearance was 0.111 L/day and the central compartment volume (Vc) was 2.91 L. The Michaelis-Menten parameter values were 11.9 mg/day and 33.9 µg/mL for Vmax and Km, respectively.
Body weight and serum alanine aminotransferase (SGPT/ALT) showed a statistically significant influence on PK, however, simulations demonstrated that no dose adjustments are required in EBC patients. The population predicted PK exposure parameter values (median with 5th - 95th Percentiles) for Herceptin SC dosing regimens in EBC patients are shown in Table 13 below.

Table 13 Population Predicted PK Exposure Values (median with 5th - 95th Percentiles) for the Herceptin SC 600 mg Q3W Dosing Regimen in EBC patients

Primary tumor                                     Cmin               Cmax             AUC0-21days type and            Cycle         N
Regimen                                      (µg/mL)            (µg/mL)           (µg.day/mL) 
28.2                79.3              1065
Cycle 1       297
EBC 600 mg                                   (14.8 - 40.9)       (56.1 - 109)       (718 - 1504) Herceptin SC         Cycle 7 q3w                                          75.0                149               2337 (steady       297 state)                 (35.1 - 123)        (86.1 - 214)      (1258 - 3478) 


Trastuzumab washout

Trastuzumab washout period was assessed following subcutaneous 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.