Subcutaneous trastuzumab (not available in the United States) has been shown to have noninferior efficacy and similar pharmacokinetic and safety profiles compared with intravenous trastuzumab (Herceptin) in patients with early-stage HER2-positive breast cancer. In the PrefHer trial reported in Lancet Oncology, Xavier Pivot, MD, of CHU Jean Minjoz in Besançon, and colleagues found that such patients preferred subcutaneous trastuzumab over intravenous administration.1
In this international, open-label, crossover study, 248 patients aged 18 years or older with HER2-positive, histologically confirmed primary invasive breast adenocarcinoma were randomized to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a single-use injection device every 3 weeks followed by four cycles of standard intravenous trastuzumab every 3 weeks (SC/IV group, n = 124) or the reverse sequence (IV/SC group, n = 124).
Intravenous trastuzumab was administered as a loading dose of 8 mg/kg in patients receiving trastuzumab de novo (approximately 90 minutes) and a 6-mg/kg maintenance dose (approximately 60 minutes) thereafter. Subcutaneous trastuzumab was given at 600 mg/5 mL (including 10,000 U of recombinant human hyaluronidase, or rHuPH20) injected into the thigh over approximately 5 minutes.
Patients had to have no evidence of residual, locally recurrent, or metastatic disease after completion of surgery and neoadjuvant or adjuvant chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and baseline left-ventricular ejection fraction ≥ 55% before the first dose of trastuzumab. Radiotherapy and hormone therapy were permitted. Randomization was stratified by de novo vs non–de novo use of intravenous trastuzumab. The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous administration, as assessed by patient interviews conducted at baseline and after completion of the crossover period.
A total of 117 SC/IV patients and 119 IV/SC patients completed both interviews. At baseline, these SC/IV and IV/SC groups had a median age of 55 and 51 years, 81% of both had ECOG performance status of 0, 51% and 33% had T1 disease and 32% and 48% had T2 disease, 54% and 43% had node-negative disease, and 25% and 24% were de novo trastuzumab users. Furthermore, 100% of both had received chemotherapy, 62% and 60% had received radiotherapy, and 43% and 40% had received hormone therapy.
In total, 216 (91.5%) of 236 patients preferred subcutaneous trastuzumab (P < .0001), 16 (7%), preferred intravenous administration, and 4 (2%) had no preference. In the SC/IV group, 112 (96%) of 117 preferred subcutaneous administration and 5 (4%) preferred intravenous administration. In the IV/SC group, 104 (87%) of 119 preferred subcutaneous administration, 11 (9%) preferred intravenous administration, and 4 (3%) had no preference.
Preference for subcutaneous administration was found in 54 (95%) of 57 patients in the de novo trastuzumab group and in 162 (90.5%) of 179 who had previously received intravenous trastuzumab. Overall preference for subcutaneous trastuzumab was “very strong” in 67% of patents, “fairly strong” in 19%, and “not very strong” in 5%. Overall preference for intravenous administration was “very strong” in 3%, “fairly strong” in 1%, and “not very strong” in 2%.
Factors that significantly influenced preference were study group (odds ratio [OR] = 3.28, 95% confidence interval [CI] = 1.14–9.48) and venous access type (OR = 4.61, 95% CI = 1.48–14.37).
Preference for subcutaneous administration was 95% among patients receiving intravenous trastuzumab by cannula (122/129 patients) and 87% among those with a venous access device (90/113 patients). Hypothetical preference for subcutaneous administration was 46% at the baseline interview and did not affect final preference.
Among the 216 patients preferring subcutaneous administration, the main reasons cited were “time saving” (90%) and “less pain/discomfort” (41%). Subcutaneous administration was considered to be less painful than intravenous administration by 67% vs 14% of patients (with 19% reporting no difference), to cause less bother from bruising by 46% vs 14% (with 40% reporting no difference), and to cause less bother from irritation to the injection site by 36% vs 15% (with 50% reporting no difference).
Among 103 health-care personnel queried on preference, 74% vs 2% were more satisfied with subcutaneous administration, with 24% expressing no preference.
Clinician-reported adverse events occurred in 141 (58%) of 242 patients during the pooled subcutaneous periods, including grade 1 events in 51%, grade 2 in 22%, and grade 3 in 3%, and in 105 (44%) of 241 during the pooled intravenous periods, including grade 1 events in 32%, grade 2 in 19%, and grade 3 in 2%.
The most common grade 3 adverse event was influenza, which occurred in two patients (0.8%). The most common adverse events during subcutaneous administration periods were injection site reactions (19% vs 0% during intravenous periods) and administration-related reactions (9% vs 5%). The most common adverse event during intravenous periods was arthralgia (6% vs 4%). Study drug discontinuation due to adverse events occurred in two patients (0.8%) during subcutaneous periods and one patient (0.4%) during intravenous periods.
Data collection for PrefHer is ongoing, including data from a cohort using a handheld syringe for subcutaneous administration. A prospective, international, open-label, nonrandomized study (SafeHer study, NCT01566721) is assessing the safety and tolerability of adjuvant subcutaneous trastuzumab via handheld syringe injection and assisted or self-administered single-use injection device, with or without chemotherapy, in 2,500 patients with HER2-positive early breast cancer. The study will have a follow-up period of 5 years to permit long-term safety assessment.
The investigators concluded, “Patient preference and safety results from PrefHer, combined with the known non-inferior efficacy and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab administered [subcutaneously] every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients.” ■
Disclosure: The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com.
1. Pivot X, Gligorov J, Müller V, et al: Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): An open-label randomised study. Lancet Oncol 14:962-970, 2013.