Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study

Background: HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations [subcutaneous (s. c.) and intravenous (i. v.)] in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s. c. versus i. v. trastuzumab in terms of serum concentration (Ctrough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months. Patients and methods: Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s. c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i. v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out. Results: s. c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s. c. treatment {64 [21.5%; 95% confidence interval (CI) 17.0%-26.7%] versus 42 (14.1%; 95% CI 10.4%-18.6%) in the i. v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure. Conclusions: Overall, the safety profile of s. c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i. v. trastuzumab. EFS rates were comparable between the i. v. and s. c. groups.