Trastuzumab

Pharmacotherapeutic group: cytostatics, monoclonal antibodies, ATC code: L01FD01 Trastuzumab is a recombinant humanised IgG1 monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2). HER2 overexpression is observed in 20–30% of primary breast cancers. Studies evaluating the frequency of HER2 positivity in gastric cancer using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) have demonstrated wide variability in HER2 positivity, ranging from 6.8% to 34.0% for IHC and 7.1% to 42.6% for FISH. Studies suggest that patients with breast cancer whose tumours overexpress HER2 have shorter disease-free survival than patients whose tumours do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) may be shed into the bloodstream and measured in serum samples. Mechanism of action Trastuzumab binds with high affinity and specificity to subdomain IV, a juxtamembrane region of the HER2 extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an HER2 activation mechanism. As a result, trastuzumab has been shown in both in vitro assays and animal studies to inhibit the proliferation of human tumour cells overexpressing HER2. In addition, 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 tumour cells compared with tumour 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 IHC-based assessment of fixed tumour tissue samples (see section 4.4). HER2 gene amplification should be detected by FISH or CISH using fixed tumour tissue samples. Patients are eligible for treatment if they demonstrate strong HER2 overexpression as scored 3+ by IHC, or a positive FISH or CISH result. To ensure accurate and reproducible results, testing must be performed in a specialised laboratory that can ensure validation of the test procedures. The recommended scoring system for evaluating IHC staining patterns is given in Table 2: Table 2: Recommended scoring system for evaluating IHC staining in breast cancer Score | Staining pattern | HER2 overexpression assessment 0 | No staining or membrane staining in < 10% of tumour cells | Negative 1+ | Faint/barely perceptible membrane staining in > 10% of tumour cells. Cells are stained only in part of their membrane. | Negative 2+ | Weak to moderate complete membrane staining in > 10% of tumour cells | Equivocal 3+ | Strong complete membrane staining in > 10% of tumour cells | Positive FISH testing is generally considered positive if the ratio of HER2 gene copy number to chromosome 17 copy number per tumour cell is ≥ 2, or if more than 4 HER2 gene copies per tumour cell are found when chromosome 17 is not used as a control. CISH testing is generally considered positive if more than 5 copies of the HER2 gene per nucleus are found in more than 50% of tumour cells. For full instructions on the performance of HER2 testing assays and interpretation of results, 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 to assess HER2 protein or gene expression, the analysis should be performed only by laboratories that provide adequate quality assurance of validated methods. Such methods must be sufficiently accurate and precise to demonstrate HER2 overexpression and to discriminate between moderate (corresponding to 2+) and strong (corresponding to 3+) levels of HER2 overexpression. 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 primary testing modality, and where HER2 gene amplification status is also required, silver in situ hybridisation (SISH) or FISH should be applied. SISH is recommended to allow parallel assessment of tumour histology and morphology. To ensure validation of test procedures and the generation of accurate and reproducible results, HER2 testing must be performed in a laboratory with trained personnel. The complete instructions for performing the assay and interpreting the results provided with the test in use should be followed. In the ToGA trial (BO18255), patients with HER2-positive tumours were defined as IHC3+ or FISH-positive and were enrolled in the study. Based on the study results, the beneficial effects were limited to patients with the highest level of HER2 protein overexpression, defined as IHC 3+ or IHC 2+ with a positive FISH result. In a systematic comparison study (study D008548), a high degree of concordance (> 95%) was observed between SISH and FISH methods for detecting HER2 gene amplification in patients with gastric cancer. HER2 overexpression should be detected by IHC-based assessment of fixed tumour tissue samples (see section 4.4). HER2 gene amplification should be detected by in situ hybridisation using SISH or FISH on fixed tumour tissue samples. The scoring system recommended for evaluating IHC staining is given in Table 3: Table 3: Recommended scoring system for evaluating IHC staining in gastric cancer Score | Surgical specimen – staining pattern | Biopsy specimen – staining pattern | HER2 overexpression assessment 0 | No reactivity or membrane reactivity in < 10% of tumour cells | No reactivity or membrane reactivity in any tumour cell | Negative 1+ | Faint/barely perceptible membrane reactivity in ≥ 10% of tumour cells; cells react only in part of their membrane | Tumour cell cluster with faint/barely perceptible membrane reactivity, irrespective of the percentage of stained tumour cells | Negative 2+ | Weak to moderate complete, basolateral or lateral membrane reactivity in ≥ 10% of tumour cells | Tumour cell cluster with weak to moderate complete, basolateral or lateral membrane reactivity, irrespective of the percentage of stained cells | Equivocal 3+ | Strong complete, basolateral or lateral membrane reactivity in ≥ 10% of tumour cells | Tumour cell cluster with strong complete, basolateral or lateral membrane reactivity, irrespective of the percentage of stained cells | Positive SISH or FISH is generally considered positive if the ratio of HER2 gene copy number to chromosome 17 copy number per tumour cell is ≥ 2. Clinical efficacy and safety Metastatic breast cancer In clinical trials, trastuzumab was used as monotherapy in patients with metastatic breast cancer whose tumours overexpressed HER2 and who had failed one or more chemotherapy regimens for their metastatic disease (trastuzumab alone). Trastuzumab was also used in combination with paclitaxel or docetaxel for the treatment of patients who had not received prior chemotherapy for their metastatic disease. Patients who had previously received adjuvant anthracycline-based chemotherapy were treated with paclitaxel (175 mg/m² as a 3-hour infusion) with or without trastuzumab. In the pivotal trial with docetaxel (100 mg/m² as a 1-hour infusion) with or without trastuzumab, 60% of patients had received prior adjuvant anthracycline-based chemotherapy. Patients were treated with trastuzumab until disease progression. The efficacy of trastuzumab in combination with paclitaxel in patients who had not received prior adjuvant anthracycline-based chemotherapy has not been studied. However, trastuzumab in combination with docetaxel was effective regardless of whether or not patients had received prior adjuvant anthracyclines. The eligibility criterion for inclusion in the pivotal trastuzumab monotherapy or trastuzumab plus paclitaxel trials was HER2 overexpression, determined by IHC-based testing for HER2 in fixed breast tumour tissue samples using the murine monoclonal antibodies CB11 and 4D5. Tissue was fixed in formalin or Bouin's fixative. These clinical trial assays were performed in a central laboratory using a 0 to 3+ scale. Patients classified as 2+ or 3+ staining were enrolled, while those with 0 or 1+ staining were excluded. More than 70% of enrolled patients demonstrated 3+ overexpression. The data suggest that the treatment benefit was greater in patients with higher levels of HER2 overexpression (3+). The principal HER2 testing method in the pivotal docetaxel trial with or without trastuzumab was IHC. A minority of patients were tested using FISH. In this trial, 87% of enrolled patients had IHC3+ disease and 95% had IHC3+ and/or FISH-positive disease. Weekly dosing in metastatic breast cancer Efficacy results from monotherapy and combination therapy studies are summarised in Table 4: Table 4: Efficacy results from monotherapy and combination therapy studies Parameter | Monotherapy | Combination therapy | Trastuzumab¹ n = 172 | Trastuzumab plus paclitaxel² n = 68 | Paclitaxel² n = 77 | Trastuzumab plus docetaxel³ n = 92 | Docetaxel³ n = 94 Response rate (95% CI) | 18% (13–25) | 49% (36–61) | 17% (9–27) | 61% (50–71) | 34% (25–45) Median duration of response (months) (95% CI) | 9.1 (5.6–10.3) | 8.3 (7.3–8.8) | 4.6 (3.7–7.4) | 11.7 (9.3–15.0) | 5.7 (4.6–7.6) Median time to progression (months) (95% CI) | 3.2 (2.6–3.5) | 7.1 (6.2–12.0) | 3.0 (2.0–4.4) | 11.7 (9.2–13.5) | 6.1 (5.4–7.2) Median survival (months) (95% CI) | 16.4 (12.3–ne) | 24.8 (18.6–33.7) | 17.9 (11.2–23.8) | 31.2 (27.3–40.8) | 22.74 (19.1–30.8) "ne" indicates that this value could not be estimated or has not yet been reached. 1. Study H0649g: IHC3+ patient subset 2. Study H0648g: IHC3+ patient subset 3. Study M77001: full analysis (intent-to-treat population), results at 24 months Trastuzumab plus anastrozole combination therapy Trastuzumab in combination with anastrozole was studied for use as first-line treatment in postmenopausal patients with HER2-overexpressing, hormone receptor-positive (i.e. oestrogen receptor [ER] and/or progesterone receptor [PR]-positive) metastatic breast cancer. Progression-free survival was doubled in the trastuzumab plus anastrozole arm compared with anastrozole alone (4.8 months versus 2.4 months). Of the other parameters, improvements in the combination arm were seen in overall response (16.5% versus 6.7%), clinical benefit rate (42.7% versus 27.9%), and time to progression (4.8 months versus 2.4 months). No difference was observed between the two arms with respect to time to response and duration of response. Median overall survival was 4.6 months longer in patients in the combination arm. This difference was not statistically significant; however, more than half of the patients in the anastrozole-alone arm crossed over to a trastuzumab-containing regimen following disease progression. Three-weekly dosing in metastatic breast cancer Table 5 summarises the results obtained from non-comparative monotherapy and combination therapy studies: Table 5: Efficacy results in non-comparative monotherapy and combination therapy studies Parameter | Monotherapy | Combination therapy | Trastuzumab¹ n = 105 | Trastuzumab² n = 72 | Trastuzumab plus paclitaxel³ n = 32 | Trastuzumab plus docetaxel⁴ n = 110 Response rate (95% CI) | 24% (15–35) | 27% (14–43) | 59% (41–76) | 73% (63–81) Median duration of response (months) (range) | 10.1 (2.8–35.6) | 7.9 (2.1–18.8) | 10.5 (1.8–21) | 13.4 (2.1–55.1) Median time to progression (months) (95% CI) | 3.4 (2.8–4.1) | 7.7 (4.2–8.3) | 12.2 (6.2–ne) | 13.6 (11–16) Median survival (months) (95% CI) | ne | ne | ne | 47.3 (32–ne) "ne" indicates that this value could not be estimated or has not yet been reached. 1. Study WO16229: loading dose 8 mg/kg body weight followed by 6 mg/kg body weight every 3 weeks 2. Study MO16982: loading dose 6 mg/kg body weight weekly × 3, followed by 6 mg/kg body weight every 3 weeks 3. Study BO15935 4. Study MO16419 Sites of disease progression In patients treated with trastuzumab plus paclitaxel, the frequency of progression in the liver was significantly reduced compared with paclitaxel alone (21.8% versus 45.7%; p = 0.004). More patients treated with trastuzumab and paclitaxel had progression in the central nervous system than those treated with paclitaxel alone (12.6% versus 6.5%; p = 0.377). Early breast cancer (adjuvant treatment) Early breast cancer is defined as non-metastatic primary invasive breast cancer. Adjuvant trastuzumab treatment was investigated in four large multicentre randomised clinical trials: Study BO16348 was designed to compare one and two years of three-weekly trastuzumab treatment versus observation in patients with HER2-positive early breast cancer following surgery, standard chemotherapy and radiotherapy (where applicable). A comparison between two years and one year of trastuzumab treatment was also performed. Patients allocated to trastuzumab received 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, which were assessed in a joint analysis, investigated the clinical benefit of combining trastuzumab with paclitaxel after chemotherapy with an anthracycline plus cyclophosphamide (AC) regimen. In addition, study NCCTG N9831 evaluated sequential administration of trastuzumab after AC chemotherapy followed by paclitaxel (AC→P) in patients with HER2-positive early breast cancer following surgery. Study BCIRG 006 evaluated trastuzumab either in combination with docetaxel after AC chemotherapy or in combination with docetaxel plus carboplatin in patients with HER2-positive early breast cancer following surgery. In the HERA trial, early breast cancer was restricted to operable primary invasive adenocarcinoma of the breast with axillary node-positive disease, or axillary node-negative disease with a tumour at least 1 cm in diameter. In the joint analysis of NSABP B-31 and NCCTG N9831, early breast cancer was restricted to women with operable breast cancer at high risk, defined as HER2-positive with axillary node-positive disease, or HER2-positive with axillary node-negative disease and high-risk features (tumour size > 1 cm and ER-negative, or tumour size > 2 cm with any hormone receptor status). In study BCIRG 006, HER2-positive early breast cancer was defined as either node-positive disease or high-risk node-negative disease without axillary involvement (pN0) and at least one of the following features: tumour larger than 2 cm, oestrogen and progesterone receptor-negative, histological and/or nuclear grade 2–3, or age < 35 years. Efficacy results from study BO16348 at a median follow-up of 12 months* and 8 years** are presented in Table 6: Table 6: Efficacy results in study BO16348 Parameter | Median follow-up 12 months* | Median follow-up 8 years** | Observation n = 1,693 | Trastuzumab 1 year n = 1,693 | Observation n = 1,697*** | Trastuzumab 1 year n = 1,702*** Disease-free survival - Patients with event | 219 (12.9%) | 127 (7.5%) | 570 (33.6%) | 471 (27.7%) - Patients without event | 1,474 (87.1%) | 1,566 (92.5%) | 1,127 (66.4%) | 1,231 (72.3%) p-value versus observation | < 0.0001 | | < 0.0001 | Hazard ratio versus observation | 0.54 | | 0.76 | Recurrence-free survival - Patients with event | 208 (12.3%) | 113 (6.7%) | 506 (29.8%) | 399 (23.4%) - Patients without event | 1,485 (87.7%) | 1,580 (93.3%) | 1,191 (70.2%) | 1,303 (76.6%) p-value versus observation | < 0.0001 | | < 0.0001 | Hazard ratio versus observation | 0.51 | | 0.73 | Distant disease-free survival - Patients with event | 184 (10.9%) | 99 (5.8%) | 488 (28.8%) | 399 (23.4%) - Patients without event | 1,508 (89.1%) | 1,594 (94.6%) | 1,209 (71.2%) | 1,303 (76.6%) p-value versus observation | < 0.0001 | | < 0.0001 | Hazard ratio versus observation | 0.50 | | 0.76 | Overall survival (deaths) - Patients with event | 40 (2.4%) | 31 (1.8%) | 350 (20.6%) | 278 (16.3%) - Patients without event | 1,653 (97.6%) | 1,662 (98.2%) | 1,347 (79.4%) | 1,424 (83.7%) p-value versus observation | 0.24 | | 0.0005 | Hazard ratio versus observation | 0.75 | | 0.76 | * Co-primary endpoint of disease-free survival of 1-year trastuzumab versus observation crossed the pre-defined statistical boundary. ** Final analysis (including 52% of patients in the observation arm who crossed over to trastuzumab). *** Discrepancy in the total number of patients enrolled is due to a small number of patients who were enrolled after the data cut-off date at the 12-month median follow-up. At the interim efficacy analysis comparing one year of trastuzumab treatment versus observation, the efficacy results crossed the pre-specified statistical boundary. After a median follow-up of 12 months, the hazard ratio for disease-free survival was 0.54 (95% CI 0.44–0.67), translating to an absolute treatment benefit, in terms of two-year disease-free survival, of 7.6 percentage points (85.8% versus 78.2%) in favour of the trastuzumab arm. A final analysis was performed at a median follow-up of 8 years and showed that one year of trastuzumab treatment is associated with a 24% risk reduction compared with observation alone (hazard ratio 0.76, 95% CI 0.67–0.86). This translates to an absolute treatment benefit, in terms of eight-year disease-free survival, of 6.4 percentage points in favour of one year of trastuzumab treatment. This final analysis did not demonstrate that extending trastuzumab treatment to two years further improved outcomes compared with one year of treatment [intent-to-treat (ITT) hazard ratio for disease-free survival of 2 years versus 1 year = 0.99 (95% CI 0.87–1.13), p-value = 0.90, and hazard ratio for overall survival = 0.98 (0.83–1.15), p-value = 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the two-year treatment arm (8.1% versus 4.6% in the one-year treatment arm). More patients in the two-year treatment arm experienced at least one Grade 3 or 4 adverse event (20.4%) than in the one-year treatment arm (16.3%). In studies NSABP B-31 and NCCTG N9831, trastuzumab was given in combination with paclitaxel following AC chemotherapy. Doxorubicin and cyclophosphamide were administered concurrently as follows: - doxorubicin 60 mg/m² administered intravenously every 3 weeks for 4 cycles. - cyclophosphamide 600 mg/m² administered intravenously over 30 minutes 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, administered weekly for 12 weeks or - intravenous paclitaxel — 175 mg/m² as a continuous intravenous infusion, administered every 3 weeks for 4 cycles (on day 1 of each cycle). The efficacy results of the joint analysis of NSABP B-31 and NCCTG N9831 at the time of the final disease-free survival analysis* are summarised in Table 7. The median duration of follow-up was 1.8 years for 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 NSABP B-31 and NCCTG 9831 at the time of the final disease-free survival analysis* Parameter | AC→P (n = 1,679) | AC→PH (n = 1,672) | Hazard ratio vs. AC→P arm (95% CI) p-value Disease-free survival Patients with event (%) | 261 (15.5) | 133 (8.0) | 0.48 (0.39; 0.59) p < 0.0001 Distant recurrence Patients with event | 193 (11.5) | 96 (5.7) | 0.47 (0.37; 0.60) p < 0.0001 Death (number of events for overall survival assessment) 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 * The median duration of follow-up was 1.8 years for patients in the AC→P arm and 2.0 years for patients in the AC→PH arm. ** The p-value for overall survival did not cross the pre-specified statistical boundary for the AC→PH versus AC→P comparison. For the primary endpoint, disease-free survival, the addition of trastuzumab to paclitaxel resulted in a 52% reduction in the risk of disease recurrence. The hazard ratio translates to an absolute benefit, in terms of the estimated three-year disease-free survival rate, of 11.8 percentage points (87.2% versus 75.4%) in favour of the AC→PH (trastuzumab) arm. A disease-free survival analysis performed at the time of an updated safety analysis with a median follow-up of 3.5–3.8 years confirmed the magnitude of the benefit shown in the final disease-free survival analysis. Despite cross-over to trastuzumab treatment in the control arm, the addition of trastuzumab to paclitaxel resulted in a 52% reduction in the risk of disease recurrence. The addition of trastuzumab to paclitaxel also resulted in a 37% reduction in the risk of death. The pre-planned final analysis of overall survival from the joint analysis of NSABP B-31 and NCCTG N9831 was performed after 707 deaths had occurred (median follow-up of 8.3 years in the AC→PH group). Treatment with AC→PH resulted in a statistically significant improvement in overall survival compared with AC→P (stratified hazard ratio = 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 overall survival results from the joint analysis of NSABP B-31 and NCCTG N9831 are summarised in Table 8 below: Table 8: Final overall survival analysis from the joint analysis of NSABP B-31 and NCCTG N9831 Parameter | AC→P (n = 2,032) | AC→PH (n = 2,031) | p-value versus AC→P | Hazard ratio versus AC→P (95% CI) Death (number of events for overall survival assessment): 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 At the final overall survival analysis from the joint analysis of NSABP B-31 and NCCTG N9831, a disease-free survival analysis was also performed. The updated disease-free survival results (stratified hazard ratio = 0.61; 95% CI [0.54; 0.69]) showed a similar disease-free survival benefit to the final primary disease-free survival analysis, despite 24.8% of patients in the AC→P arm crossing over to trastuzumab treatment. 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 study BCIRG 006, trastuzumab was given 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 a 1-hour intravenous infusion administered every 3 weeks for 4 cycles (on day 2 of the first docetaxel cycle and day 1 of subsequent cycles) or - intravenous docetaxel — 75 mg/m² as a 1-hour intravenous infusion administered every 3 weeks for 6 cycles (on day 2 of the first cycle and day 1 of subsequent cycles) followed by: - carboplatin at a target AUC = 6 mg/mL/min administered as a 30–60-minute intravenous infusion, repeated every 3 weeks for a total of 6 cycles. Trastuzumab was administered weekly concurrently with chemotherapy and subsequently every 3 weeks, for a total of 52 weeks. Efficacy results from study BCIRG 006 are summarised in Tables 9 and 10. The median 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: Summary of efficacy analysis in study BCIRG 006, AC→D versus AC→DH arm Parameter | AC→D (n = 1,073) | AC→DH (n = 1,074) | Hazard ratio vs. AC→D arm (95% CI) p-value Disease-free survival Patients with event | 195 | 134 | 0.61 (0.49; 0.77) p < 0.0001 Distant recurrence Patients with event | 144 | 95 | 0.59 (0.46; 0.77) p < 0.0001 Death (number of events for overall survival assessment) 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 Table 10: Summary of efficacy analysis in study BCIRG 006, AC→D versus DCarbH arm Parameter | AC→D (n = 1,073) | DCarbH (n = 1,074) | Hazard ratio vs. AC→D arm (95% CI) p-value Disease-free survival Patients with event | 195 | 145 | 0.67 (0.54; 0.83) p = 0.0003 Distant recurrence Patients with event | 144 | 103 | 0.65 (0.50; 0.84) p = 0.0008 Death (number of events for overall survival assessment) 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 In study BCIRG 006, for the primary endpoint of disease-free survival, the hazard ratio translates to an absolute benefit, in terms of the estimated three-year disease-free survival rate, 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 with the AC→D arm. In study BCIRG 006, 213/1,075 patients in the DCarbH (TCH) arm, 221/1,074 patients in the AC→DH (AC→TH) arm and 217/1,073 patients in the AC→D (AC→T) arm had a Karnofsky performance status ≤ 90 (either 80 or 90). No disease-free survival benefit was observed in this patient subgroup (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 combining data from the joint analysis of clinical studies NSABP B-31/NCCTG N9831* and study BCIRG 006, combining events for disease-free survival and symptomatic cardiac events; results are summarised in Table 11: Table 11: Results of post-hoc exploratory analyses of data from the joint analysis of clinical studies NSABP B-31/NCCTG N9831* and study BCIRG 006, combining events for disease-free survival and symptomatic cardiac events | AC→PH (vs. AC→P) (NSABP B-31 and NCCTG N9831)* | AC→DH (vs. AC→D) (BCIRG 006) | DCarbH (vs. AC→D) (BCIRG 006) Primary efficacy analysis – Hazard ratios for disease-free survival (95% CI) p-value | 0.48 (0.39; 0.59) p < 0.0001 | 0.61 (0.49; 0.77) p < 0.0001 | 0.67 (0.54; 0.83) p = 0.0003 Efficacy analysis after long-term follow-up** – Hazard ratios for disease-free survival (95% CI) p-value | 0.61 (0.54; 0.69) p < 0.0001 | 0.72 (0.61; 0.85) p < 0.0001 | 0.77 (0.65; 0.90) p = 0.0011 Post-hoc exploratory analysis combining disease-free survival and symptomatic cardiac events – Long-term follow-up** Hazard ratios (95% CI) | 0.67 (0.60; 0.75) | 0.77 (0.66; 0.90) | 0.77 (0.66; 0.90) A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab * At the time of the final disease-free survival analysis. The median duration of follow-up was 1.8 years for patients in the AC→P arm and 2.0 years for patients in the AC→PH arm. ** Median duration of long-term follow-up for the joint analysis of clinical studies was 8.3 years (range: 0.1 to 12.1) in the AC→PH arm and 7.9 years (range: 0.0 to 12.2) in the AC→P arm; median duration of long-term follow-up for study BCIRG 006 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 10.4 years (range: 0.0 to 12.7) in the AC→DH arm. Early breast cancer (neoadjuvant and adjuvant treatment) To date, no results are available comparing the efficacy of trastuzumab administered with chemotherapy in the adjuvant setting with results obtained from neoadjuvant/adjuvant administration. Study MO16432, a multicentre randomised trial of neoadjuvant and adjuvant treatment, was designed to evaluate the clinical efficacy of concurrent administration of trastuzumab with neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant trastuzumab for a total treatment duration of up to 1 year. Patients with newly diagnosed locally advanced (stage III) or inflammatory early breast cancer were enrolled in the study. Patients with HER2+ tumours were randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant and adjuvant trastuzumab or neoadjuvant chemotherapy alone. In study MO16432, trastuzumab (initial loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg every 3 weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows: - Doxorubicin 60 mg/m² and paclitaxel 150 mg/m², administered every 3 weeks for 3 cycles, followed by - Paclitaxel 175 mg/m², administered every 3 weeks for 4 cycles, followed by - CMF on days 1 and 8, administered every 4 weeks for 3 cycles, and after surgery, followed by - further cycles of adjuvant trastuzumab (to complete 1 year of treatment). Efficacy results from study MO16432 are summarised in Table 12. The median follow-up in the trastuzumab arm was 3.8 years. Table 12: Efficacy results in study MO16432 Parameter | Chemotherapy + trastuzumab (n = 115) | Chemotherapy alone (n = 116) Event-free survival – Patients with event | 46 | 59 Hazard ratio (95% CI) 0.65 (0.44–0.96) p = 0.0275 Total pathological complete response* | 40% | 20.7% | p = 0.0014 (95% CI) | (31.0–49.6) | (13.7–29.2) Overall survival Hazard ratio (95% CI) Patients with event | 22 | 33 0.59 (0.35–1.02) p = 0.0555 * defined as the complete absence of any invasive tumour in both the breast and the axillary nodes. When evaluating the 3-year event-free survival rate, the estimated absolute benefit is 13 percentage points in favour of the trastuzumab arm (65% versus 52%). Metastatic gastric cancer Trastuzumab was evaluated in ToGA (BO18255), a randomised, open-label phase III study, in combination with chemotherapy versus chemotherapy alone. Chemotherapy was administered as follows: - capecitabine — 1,000 mg/m² orally twice daily for 14 days, administered every 3 weeks for 6 cycles (from the evening of day 1 to the morning of day 15 of each cycle) or - intravenous fluorouracil — 800 mg/m²/day as a continuous intravenous infusion over 5 days, administered every 3 weeks for 6 cycles (days 1 to 5 of each cycle) Each was given in combination with: - cisplatin — 80 mg/m² administered every 3 weeks for 6 cycles, on day 1 of each cycle. Efficacy results from study BO18225 are summarised in Table 13: Table 13: Efficacy results in study BO18225 Parameter | FP n = 290 | FP+H n = 294 | Hazard ratio (95% CI) | p-value Overall survival, median months | 11.1 | 13.8 | 0.74 (0.60–0.91) | 0.0046 Progression-free survival, median months | 5.5 | 6.7 | 0.71 (0.59–0.85) | 0.0002 Time to disease progression, median months | 5.6 | 7.1 | 0.70 (0.58–0.85) | 0.0003 Overall response rate, % | 34.5% | 47.3% | 1.70ª (1.22, 2.38) | 0.0017 Duration of response, median months | 4.8 | 6.9 | 0.54 (0.40–0.73) | < 0.0001 FP+H: fluoropyrimidine/cisplatin + trastuzumab; FP: fluoropyrimidine/cisplatin ª odds ratio Patients enrolled in the study had not been previously treated for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction and were not candidates for curative therapy. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. At the time of analysis, a total of 349 randomised patients had died: 182 (62.8%) patients in the control arm and 167 (56.8%) patients in the treatment arm. Most deaths were due to events related to the underlying malignancy. A post-hoc subgroup analysis indicates that the positive treatment effects are largely limited to tumours with higher levels of HER2 protein (IHC2+/FISH+ or IHC3+). Median overall survival in the high HER2 expression group was 11.8 months versus 16 months, hazard ratio (HR) 0.65 (95% CI 0.51–0.83), and median progression-free survival was 5.5 months versus 7.6 months, hazard ratio 0.64 (95% CI 0.51–0.79) for the FP arm versus the FP+H arm, respectively. For overall survival, the hazard ratio (HR) was 0.75 (95% CI 0.51–1.11) in the IHC 2+/FISH+ group, and 0.58 (95% CI 0.41–0.81) in the IHC 3+/FISH+ group. In an exploratory subgroup analysis from the ToGA trial (BO18255), the addition of trastuzumab provided no apparent overall survival benefit in patients with a baseline ECOG performance status of 2 [hazard ratio 0.96 (95% CI 0.51–1.79)], non-measurable disease [hazard ratio 1.78 (95% CI 0.87–3.66)] or locally advanced disease [hazard ratio 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 the reference medicinal product in all subsets of the paediatric population for breast cancer and gastric cancer (see section 4.2 for information on paediatric use).