A subcutaneous formulation of trastuzumab(Drug information on trastuzumab) (Herceptin) may soon be available. The results of the phase III, open-label, international, neoadjuvant HannaH trial, published in the Lancet, show early, promising data that the subcutaneous formulation of trastuzumab is as efficacious and safe as the intravenous (IV) version of the drug.
The study found the pathologic complete response of the subcutaneous dose to be comparable to the IV formulation. Of the patients who administered the subcutaneous formulation, 45.4% achieved a pathologic complete response compared to 40.7% of IV-administered patients. The median time to response was 6 weeks in both study arms.
The new subcutaneous injection could be administered by patients themselves in their home, after appropriate training and support. Roche highlights that the new formulation is another option for patients—less invasive, likely more convenient, and certainly more time efficient for both the patient and the medical staff, requiring 5 minutes of administration compared to the 30 to 90 minutes it takes for the IV drip version.
According to Roche, the manufacturer of trastuzumab, the subcutaneous formulation uses a novel carrier of the active ingredient in trastuzumab. The carrier, recombinant human hyaluronidase(Drug information on hyaluronidase) (rHuPH20), can reversibly break down hyaluronan, a gel-like material that forms a barrier between cells in the skin, allowing for relatively painless delivery under the skin, even of a large volume. The current subcutaneous dose of trastuzumab is 5 mL.
The largest neoadjuvant HER2-positive breast cancer trastuzumab trial to date, the NOAH trial, showed an improvement of the 3-year disease-free survival from 56% to 71% for the combination of trastuzumab plus chemotherapy.
Further follow-up of patients is still necessary to understand whether the comparable pathologic complete response rates will translate into similar survival and mortality reduction rates.
Adverse event rates were comparable between both study arms. Patients administering the subcutaneous formulation had slightly higher rates of serious infections—24 patients (8.1%) compared to 13 patients (4.1%) in the IV arm—but no infection was associated with the site of subcutaneous administration.
In an accompanying editorial, Javier Cortes and Jose Perez-Garcia of the Breast Cancer Program at the Vall d'Hebron Institute of Oncology, Barcelona, Spain, emphasize that the current study could lead to approval of the subcutaneous formulation of trastuzumab for the neoadjuvant, adjuvant, and metastatic breast cancer indications. The authors highlight the ongoing debate of whether pathologic complete response is a suitable surrogate marker for disease-free survival and overall survival, stating that the HannaH trial may help facilitate “a new route for accelerated drug approval in patients with breast cancer”—pending that the pathologic complete response translates into the more substantial endpoints of disease-free survival and overall survival.
Whether subcutaneous delivery of trastuzumab translates into a better quality of life for patients and whether medical professionals prefer the subcutaneous formulation is being addressed in the ongoing company-sponsored phase II PrefHer trial.
1. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-384.