subcutaneous herceptin-- getting closer to reality!

[Lani]

Wouldn't it be nice not to have to travel for an infusion, rather to administer herceptin yourself, in the privacy of your own home and without having to have an IV, sit 30-60 minutes, and receive and be charged for salt solution not otherwise needed?

This one may happen relatively quickly, as it is a way for Roche/Genentech to keep its exclusivity longer on herceptin ( I would think that a new formulation would start a new clock ticking on their exclusivity of drug production)

It seemed in this trial anyway to have even a higher rate of pcr, perhaps because of the hyaluronase in it. The purpose of the hyaloronase here is to increase absorption under the skin, but it may even serve to improve tumor killing as well (they may have to look into that)

Only downside may be a slightly increased risk of infection NOT at the injection site--this seems also to be the case with many subcutaneous drugs used against rhematoid arthritis, so I am sure they will be looking into this to try t determine if it is consistent across trials, why it occurs and if anything might be done to remedy it. Again it was a small trial so that may turn out to be a spurious finding.


RESEARCH REPORT
Subcutaneous Trastuzumab (Herceptin) Injection Shows Promise
Could patients administer drug in the comfort of their home?
By Anna Azvolinsky, PhD1 | August 8, 2012


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.
If disease-free survival and overall survival rates equal those of trastuzumab given intravenously, patients could find themselves administering the subcutaneous 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.[1]

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.
Reference

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.

[Lani]

Lancet Oncol. 2012 Aug 8. [Epub ahead of print]
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, randomised trial.
Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C.
Source
Hospital Amaral Carvalho, Jaú, Brazil.
Abstract
BACKGROUND:
A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer.
METHODS:
The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300.
FINDINGS:
299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 μg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 μg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two-both in the subcutaneous group-were deemed to be treatment related.
INTERPRETATION:
Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.
FUNDING:
F Hoffmann-La Roche.
Copyright © 2012 Elsevier Ltd.

[Ellie F]

Wonder how long before its approved? I guess it will be quicker in the States then hopefully sometime in the not to distant future in Europe.
Ellie