ONTRUZANT Powder for concentrate for solution for infusion Ref.[7133] Active ingredients: Trastuzumab

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 trastuzumab 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:

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.

Detection of HER2 overexpression or HER2 gene amplification in gastric cancer

Only an accurate and validated assay should be used to detect HER2 overexpression 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.

Table 3. Recommended scoring system to evaluate the IHC staining patterns in gastric cancer:

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:

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.

Three-weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapy studies are summarised in Table 5.

Table 5. Efficacy results from the non-comparative monotherapy and combination therapy studies:

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 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, 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 tumours 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 (tumour size >1 cm and ER negative or tumour 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 6.

Table 6. Efficacy results from Study BO16348:

* 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 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 7. 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 7. 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^*:

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→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 8 below.

Table 8. Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG N9831:

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 the 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.

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. 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 9. Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH:

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval

Table 10. Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH:

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 summarised in Table 11.

Table 11. 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:

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 60 mg/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 trastuzumab (to complete 1 year of treatment)

The efficacy results from Study MO16432 are summarized in Table 12. The median duration of follow-up in the trastuzumab arm was 3.8 years.

Table 12. Efficacy results from MO16432:

* 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 13.

Table 13. Efficacy results from BO18225:

FP + H: fluoropyrimidine/cisplatin + trastuzumab
FP: fluoropyrimidine/cisplatin
^a Odds ratio

Patients 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 were recruited to the trial. 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 (IHC2+/FISH+ or IHC3+). 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 IHC2+/FISH+ group and the HR was 0.58 (95% CI 0.41-0.81) in the IHC3+/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

The European Medicines Agency has waived the obligation to submit the results of studies with trastuzumab in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 for information on paediatric use).