The evidence supporting this protocol is provided by a phase 3, open label, multicentre, randomised trial (HannaH study) comparing subcutaneous trastuzumab with intravenous trastuzumab in patients with HER-2 positive, clinical stage I-III breast cancer.rr
Between October 2009 and December 2010, 596 patients were randomised in a 1:1 ratio to receive eight cycles of neoadjuvant chemotherapy administered concurrently with either trastuzumab administered intravenously every 3 weeks (8 mg/kg loading dose, 6 mg/kg maintenance dose) or trastuzumab administered subcutaneously every 3 weeks (fixed dose of 600 mg). Chemotherapy consisted of four cycles of docetaxel (75 mg/m2) followed by four cycles of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment with the same formulation as presurgery. 299 patients were randomised to the intravenous trastuzumab group and 297 patients to the subcutaneous trastuzumab group.
The co-primary endpoints were serum trough concentration at pre-dose cycle 8 (end of cycle 7) and pathological complete response (pCR). The secondary end points were pharmacokinetic profile, total complete pathological response, overall response, time to response, event free survival, overall survival, safety and tolerability, and immunogenicity.rr
Subcutaneous trastuzumab has a similar safety profile to intravenous trastuzumab and is non-inferior in terms of pharmacokinetic profile and efficacy and therefore is a valid alternative route of administration compared to standard intravenous trastuzumab.rr
Efficacy
HannaH study
After a median follow-up of 12 months, the geometric mean pre-surgery Ctrough was 51.8 microgram/mL in the group with intravenous administration and 69.0 microgram/mL in the group with subcutaneous administration. The geometric mean ratio of Ctrough subcutaneous to Ctrough intravenous was 1·33 (90% CI 1·24–1·44), well above the previously defined non-inferiority limit of 0.80. 40.7% patients in the intravenous group and 45.4% in the subcutaneous group achieved a pCR.r Subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both co-primary endpoints.
© Lancet Oncology 2012
PrefHer Study
PrefHer was a two cohort, cross over trial assessing patient and practitioner preference and satisfaction for subcutaneous or intravenous trastuzumab in 488 patients with HER2-positive early breast cancer. Patients were randomised to receive 4 cycles of 600 mg subcutaneous trastuzumab every three weeks followed by 4 cycles of standard intravenous trastuzumab 6mg/kg every three weeks, or vice versa. 88.9 % of patients preferred subcutaneous administration to intravenous administration (95 % CI: 85.7–91.6 %; p < 0.0001). 181 of 235 surveyed healthcare professionals reported greater satisfaction with subcutaneous administration compared to intravenous administration (77 %, 95 % CI: 71.1–82.2 %).r
© Annals of Oncology 2014
Toxicity
In the HannaH study, the incidence of grade 3–5 adverse events was similar between groups. However, more patients had serious adverse events in the subcutaneous group (21.5%) than in the intravenous group (14.1%); the difference was mainly attributable to serious infections and infestations with 8·1% in the subcutaneous group vs 4.4% in the intravenous group.r No infection was associated with a subcutaneous trastuzumab injection site.r The cardiac safety profile was comparable between both study groups. No cases of symptomatic congestive heart failure NYHA class III or IV were reported. Two patients in the subcutaneous group developed congestive heart failure NYHA class II compared with none in the intravenous group.r
Six adverse events led to death (two in the intravenous group and four in the subcutaneous group), four of which occurred during the neoadjuvant phase and two in the treatment-free follow up period.r
Table 1: Summary of grade > 3 adverse eventsr
| Adverse events grade > 3 |
Intravenous trastuzumab (n=298) |
Subcutaneous trastuzumab (n=297) |
| Neutropenia |
33.2% |
29.3% |
| Leucopenia |
6.0% |
4.0% |
| Febrile neutropenia |
4.4% |
5.7% |
| Anaemia |
1.0% |
0.3% |
| Diarrhoea |
2.7% |
2.7% |
| Nausea |
1.3% |
1.3% |
| Vomiting |
1.7% |
1.0% |
| Infections and infestations |
5.0% |
7.1% |
| Irregular menstruation |
2.0% |
1.7% |
| Amenorrhoea |
1.7% |
1.0% |
| Fatigue |
1.3% |
0.3% |
| Asthenia |
1.0% |
0.3% |
| Alopecia |
1.7% |
1.3% |
| Hypertension |
0.3% |
2.0% |
Table 2: Overview of serious and grade > 3 infection events by treatment groupr
| |
Intravenous trastuzumab (n=298)
|
Subcutaneous trastuzumab (n=297)
|
|
Serious AE infection events
Neoadjuvant phase
Adjuvant phase
|
13 (4.4%, 95% CI 2.3 - 7.3)
8 (2.7%; 95% CI 1.2 - 5.2)
5 (1.7%; 95% CI 0.5 - 3.9)
|
24 (8.1%; 95% CI 5.2 - 11.8)
10 (3.4%; 95% CI 1.6 - 6.1)
13 (4.4%; 95% CI 2.4 - 7.4)
|
|
Grade > 3 AE infection events
Neoadjuvant phase
Adjuvant phase
|
15 (5.0%; 95% CI 2.8 - 8.2)
9 (3.0%; 95% CI 1.4 - 5.7)
6 (2.0%; 95% CI 0.7 - 4.3)
|
21 (7.1%; 95% CI 4.4 - 10.6)
10 (3.4%; 95% CI 1.6 - 6.1)
11 (3.7%; 95% CI 1.9 - 6.5)
|
In the PrefHer study, no new safety signals were identified with subcutaneous trastuzumab compared with intravenous trastuzumab but there were more grade 1/2 events reported in the SC group related to administration-related reactions. There were no differences in serious adverse events (0.8%) between the groups.r
The safety profile of the subcutaneous formulation will be further investigated in the large, international phase IIIb SafeHer study.r