Subcutaneous administration of trastuzumab might offer improvements in patient convenience and resource use compared with conventional intravenous administration (Herceptin). A new subcutaneous trastuzumab formulation containing a fixed dose of 600 mg and recombinant human hyaluronidase PH-20 (rHuPH-20) as excipient has been evaluated in the recently reported phase III, open-label, multicenter HannaH trial.1 The trial showed that subcutaneous trastuzumab given in the neoadjuvant and adjuvant settings resulted in noninferior trough drug levels and pathologic complete response rates compared with intravenous trastuzumab and had a similar safety profile.
Study Design
In HannaH, 596 patients with HER2-positive stage I to III locally advanced or inflammatory breast cancer were randomly assigned to subcutaneous trastuzumab (n = 297) or intravenous trastuzumab (n = 299) every 3 weeks as neoadjuvant treatment in combination with chemotherapy consisting of four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide. The subcutaneous dose of 600 mg was given over approximately 5 minutes; the intravenous dose was an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose.
After surgery, trastuzumab was continued to complete 1 year of treatment. The primary endpoints of the study were trough serum trastuzumab concentration prior to dosing in cycle 8 before surgery, with a noninferiority margin of 0.80 for the ratio between the two groups, and pathologic complete response rate, with a noninferiority margin for difference between the two groups of –12.5%.
Locoregional radiation therapy was given to 71.0% of patients in the subcutaneous arm and 68.8% of patients in the intravenous arm after surgery. Hormonal therapy after surgery consisted of tamoxifen in 30.3%, anastrozole in 5.7%, and letrozole in 4.4% of patients in the subcutaenous group compared with 25.5%, 6.7%, and 7.0%, respectively, in the intravenous group.
Noninferior Trough Drug Levels, Complete Response Rates
The geometric mean presurgery trastuzumab trough concentration was 69.0 µg/mL in the subcutaneous group and 51.8 µg/mL in the intravenous group; the geometric mean ratio of subcutaneous trough level to intravenous trough level of 1.3 (90% confidence interval [CI] = 1.24–1.44) met the noninferiority requirement. Presurgery trough drug levels exceeded the target therapeutic level of 20 µg/mL in 97.0% of patients in the subcutaneous group and in 98.7% of those in the intravenous group.
Although the trough drug level was approximately 30% higher in the subcutaneous group, overall exposure as indicated by the geometric mean area under the concentration-time curve from 0 to 21 days (AUC0-21d) was very similar in the two groups (2,108 µg/mL day for the subcutaneous group vs 1,978 µg/mL day for the intravenous group, geometric mean ratio = 1.07). The similarity in AUC despite the higher trough level in the subcutaneous group was related to a higher maximum concentration in the intravenous group (mean at cycle 7 before surgery of 149 µg/mL in the subcutaneous group vs 221 µg/mL in the intravenous group, geometric mean ratio = 0.67).
Pathologic complete response was observed in 118 (45.4%) of 260 evaluable patients in the subcutaneous group and in 107 (40.7%) of 263 evaluable patients in the intravenous group; the difference between groups was 4.7% (95% CI = –4.0 to 13.4%), thus satisfying the noninferiority requirement. No association between body weight and pathologic complete response was observed. Overall response rates were similar in the subcutaneous and intravenous groups (87.2% and 88.8%), as were median times to response (6 weeks in both groups). Study patients continue to be followed to substantiate the study’s efficacy findings.
More Serious Adverse Events?
The safety profile of the subcutaneous formulation was consistent with the known profile of intravenous trastuzumab. The incidence of adverse events of grades 3 to 5 in the subcutaneous group was similar to that in the intravenous group (51.9% vs 52.0%), with the most common being neutropenia (29.0% vs 33.2%), leukopenia (4.0% vs 5.7%), and febrile neutropenia (5.7% vs 3.4%). Serious adverse events were more common in the subcutaneous group (20.9% vs 12.4%), with the difference being mainly attributable to a higher incidence of infection/infestation adverse events in subcutaneous patients (8.1% vs 4.4%).
No specific clinical explanation for the imbalance in serious adverse events was identified; multiple regression analysis did not show any association between trastuzumab AUC or body weight and rates of serious adverse events. It was noted, however, that the proportion of both grade 3 (18.1% vs 7.7%) and grade 2 (1.5% vs 0.5%) adverse events classified as serious was higher in the subcutaneous group; the authors speculated that this imbalance may reflect a more conservative attitude on the part of investigators toward adverse events in the subcutaneous group in this open-label trial.
Adverse events led to three deaths in the subcutaneous group and one in the intravenous group, with all deaths occurring during neoadjuvant treatment; two deaths in the subcutaneous group, due to myocardial infarction and septic shock, were considered treatment-related. The authors stated that these deaths did not appear to be causally related to trastuzumab per se. Causality assessment in one intravenous patient dying from pneumonia and the subcutaneous patient dying from septic shock were confounded by underlying pulmonary fibrosis and febrile neutropenia, respectively, and deaths attributed to myocardial infarction and sudden death in the subcutaneous group occurred in patients with recognized concurrent cardiovascular risk factors.
Cardiac safety profiles were similar in the two groups. No cases of New York Heart Association (NYHA) class III or IV congestive heart failure were observed. Two patients in the subcutaneous group (both obese with a history of hypertension) and none in the intravenous group had class II heart failure. Reductions in left-ventricular ejection fraction of 10% or more to below 50% occurred in 2.4% of subcutaneous patients and 2.1% of intravenous patients.
Injection-site reactions, most commonly pain, occurred in 11.1% of the subcutaneous group, with almost all being grade 1. Irrespective of baseline antibody status, antidrug antibody was found in 6.8% of subcutaneous patients and 3.4% of intravenous patients, and anti-rHuPH-20 antibodies were found in 11.5% of subcutaneous patients. No neutralizing antibodies to either protein were detected, and the presence of antibodies had no effect on trastuzumab trough concentrations, pathologic complete response rate, or infusion-related reactions.
The authors concluded, “[Subcutaneous] trastuzumab at a fixed dose of 600 mg administered every 3 weeks in about 5 minutes could … provide an alternative to the [intravenous] regimen given every 3 weeks for HER2-positive breast cancer. The shortened duration of administration … suggests the potential for substantial time-saving for patients, physicians, and nursing staff.”
The PrefHer trial (NCT01344863) is examining patient convenience, patient preference for route of administration, and medical resource use with the subcutaneous formulation. ■
Disclosure: TheHannaH study was funded by Hoffman-La Roche. Among the HannaH investigators, Dr. Gustavo Ismael has received honoraria from F Hoffmann-La Roche for participation in conferences. Dr. Tadeusz Pienkowski has received travel grants from Hoffmann-La Roche. Dr. Bohuslav Melichar has received speakers honoraria and honoraria from Hoffman-La Roche for participation in advisory board meetings. Dr. Christian Jackisch has received speakers honoraria from Hoffmann-La Roche. Dr. Bert Lum is an employee of Genentech and a stockholder in Roche Holding AG. Drs. Susanne Muehlbauer and Dominik Heinzmann are employees of and have stock ownership in Hoffmann-La Roche. Drs. Roberto Hegg, Sung-Bae Kim, Mikhail Lichinitser, and Vladimir Semiglazov reported no potential conflicts of interest.
Reference
1. Ismael G, Hegg R, Muehlbauer S, et al: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): A phase 3, open-label, multicentre, randomized trial. Lancet Oncol 13:869-878, 2012.
