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September 25, 2012 - Volume 34 - Issue 18 > HER2-Positive Breast Cancer: Subcutaneous Trastuzumab as Eff...
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Oncology Times:
25 September 2012 - Volume 34 - Issue 18 - p 8–10
doi: 10.1097/01.COT.0000421351.11905.a0
News
HER2-Positive Breast Cancer: Subcutaneous Trastuzumab as Effective as Intravenous
Carlson, Robert H.
A subcutaneous formulation of trastuzumab appears to be equivalent to the standard intravenous formulation in terms of producing pathologic complete response (pCR) as well as in safety and pharmacokinetics in the treatment of women with HER2-positive breast cancer, according to the results of a Phase III, multicenter, neoadjuvant trial published in
Lancet Oncology (2012;13:869–878).
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The shortened duration of subcutaneous administration has the potential to save time for patients, physicians, and nursing staff, the first author and co-principal investigator, Gustavo Ismael, MD, a medical oncologist and Medical Coordinator of Clinical Research at Hospital Amaral Carvalho, Miraglia in Jaú, Brazil, noted in a telephone interview. “The injection takes no more than five minutes, instead of 30 to 60 minutes for an infusion.”
The subcutaneous formulation of trastuzumab is possible with the development of recombinant human hyaluronidase PH-20 (rHuPH-20), an enzyme that temporarily degrades interstitial hyaluronic acid in the subcutaneous space, allowing injection of larger volumes—in this case, 5 ml of the drug injected into the thigh with a hand-held syringe.
The study's neoadjuvant setting made it possible to determine pCR, but Ismael said the potential convenience of a subcutaneous formulation could be in the adjuvant setting, when patients would typically return to the clinic every three weeks for IV treatment.
The researchers also point to other potential benefits including improved patient convenience, better compliance, reduced pharmacy preparation times, and optimization of medical resources.
GUSTAVO ISMAEL, MD, ...
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The randomized, open-label “HannaH” study (enHANced treatment with NeoAdjuvant Herceptin) enrolled women with newly diagnosed HER2-positive, operable, locally advanced, or inflammatory invasive adenocarcinoma of the breast, clinical stage I to IIIC, with primary tumors 1 cm or larger by ultrasound or 2 cm or larger by palpation. The patients' mean age was 50.
Patients were randomly assigned to receive eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every three weeks: 299 were assigned to be treated intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) and 297 to be treated subcutaneously (fixed dose of 600 mg, with no loading dose).
CHRISTIAN JACKISCH, ...
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Chemotherapy consisted of four cycles of docetaxel (75 mg/m2) followed by four cycles of the FEC regimen—fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2)—every three weeks. After surgery, patients continued trastuzumab for one year, continuing with SC or IV administration as assigned in the neoadjuvant portion of the trial.
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Non-Inferiority in Co-Primary Endpoints
The co-primary endpoint of pCR was achieved in 107 of 263 patients in the intravenous group (40.7%) and 118 of 260 (45.4%) in the subcutaneous group. Similarly, the “co-primary endpoint of geometric mean presurgery serum trough of trastuzumab concentration” 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.
“Thus, subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints,” the authors reported.
The safety profiles were also similar for the two routes of administration. The most common grade 3–5 adverse events were neutropenia, with an incidence of 33.2% among 298 patients in the intravenous group and 29.0% of 297 in the subcutaneous group; leucopenia in 5.7% vs. 4.0%; and febrile neutropenia, 3.4% vs. 5.7%.
However, more patients had serious adverse events in the subcutaneous group (21%) than in the intravenous group (12%). Ismael attributed the difference to more infections at the injection site in the SC group—8.1% vs. 4.4% in the intravenous group. The cardiac safety profile was comparable between both groups, with no severe symptomatic congestive heart failure reported. Two patients in the subcutaneous trastuzumab group developed congestive heart failure NYHA class II, but both had preexisting risk factors of obesity and hypertension.
Four adverse events led to death, one in the intravenous group and three in the subcutaneous group, all occurring in the neoadjuvant phase. Two of the deaths, both in the subcutaneous group, were considered treatment related. But Ismael noted that treatment included anthracycline chemotherapy and that one of those patients had a history of heart disease.
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Survival Not Addressed
Survival data will take years to accumulate, but in a telephone interview, the study's other co-principal investigator, Christian Jackisch, MD, Professor and Director of the Department of OB/GYN at Klinikum Offenbach in Germany, stressed that survival was not a study endpoint: “Everyone is asking about survival data, but that was not the question of this trial, which was simply whether the C-trough concentration was the same, and secondarily, was efficacy the same in terms of pCR.”
He said previous studies have correlated pCR rates with survival times and reduced mortality. “And since it is the same drug and the same disease, what should be the difference—that is my opinion.”
Study sites were located around the world including Europe, Canada, South America, South Africa and Korea, but none were in the U.S.
The drug's manufacturer, Roche, which funded the study and was involved in the design and the interpretation of the data, is now testing subcutaneous trastuzumab in two other studies, a news release notes:
* SafeHer is a Phase III prospective, non-randomized, open-label study currently recruiting patients to assess the safety of assisted- and self-administered SC trastuzumab as adjuvant therapy in patients with operable HER2-positive early breast cancer. The study allows the use of both vial administration and administration via the ready-to-use device with the option of self-administration.
EDITH A. PEREZ, MD: ...
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CHARLES L. SHAPIRO, ...
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* And PrefHer (Preferences for Herceptin SC or IV administration) will use pre- and post-treatment questionnaires to determine patients' and health care professionals' satisfaction with the two methods.
And, the company noted, as a result of the HannaH data, a Line Extension Application for Herceptin SC has been submitted to the European Medicines Agency for the treatment of HER2-positive breast cancer.
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Faster Delivery, Accelerated Approval?
In an accompanying editorial (
Lancet Oncology 2012;13:850–861), Jose Perez-Garcia, MD, and Javier Cortes, MD, both of Vall d'Hebron Institute of Oncology in Barcelona, listed the obvious advantages of rapid, subcutaneous delivery including convenience for staff and patients and a psychological benefit for patients.
This might be moot, however, if a treatment regimen includes IV agents as well as trastuzumab, they noted.
In the larger picture, though, Perez-Garcia and Cortes said HannahH may be the first example of a neoadjuvant trial leading to accelerated approval of a drug for breast cancer, if pCR is indeed predictive of overall and disease-free survival.
Using neoadjuvant outcomes for drug approval has some major limitations, they continued:
* First, it is unknown what improvement in pCR would be necessary to translate into a benefit for disease-free or overall survival;
* Second, it is also unknown what proportion of patients achieving a pCR would be needed to establish noninferiority between two drugs or between two methods of administering the same drug; and
* Third, the method of categorizing long-term adverse effects “might be insufficient, because many adverse events might appear after pCR, so if pCR is enough for regulatory purposes, the consequences of these long-term events might not be taken into account.”
The editorial also advised trialists to take into account the higher immunogenicity of subcutaneous administration of a monoclonal antibody.
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Ease Clinic Congestion
Also asked to comment on the study for this article, Edith A. Perez, MD, Professor of Medicine and Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, FL, said the subcutaneous formulation could be a very important improvement for the quality of life of breast cancer patients.
The time savings could also potentially relieve the congestion that sometimes exists in oncology practices, she noted. In practice, she explained, patients are usually not managed with trastuzumab (Herceptin) alone, and it would typically be given in the adjuvant setting.
“But in the setting in which we traditionally use intravenous Herceptin, this seems to be a good alternative to consider,” Perez said.
Also asked for his opinion, Charles L. Shapiro, MD, Professor of Medicine at the Wexner Medical Center and Section Chief of Breast Cancer at Ohio State University Comprehensive Cancer Center, noted that a subcutaneous version of trastuzumab could be important to women in less developed areas of the world with limited access to a cancer clinic. On the other hand, compliance might be an issue in home administration.
In terms of efficacy, Shapiro said it is still not certain whether complete response is an adequate surrogate for long-term survival, and that he would want to see larger trials confirm the efficacy outcomes.
© 2012 Lippincott Williams & Wilkins, Inc.
http://journals.lww.com/oncology-tim...taneous.2.aspx