Subcutaneous injection of trastuzumab by a healthcare provider at home was not associated with any new safety signals, according to results from the BELIS trial. The BELIS trial was conducted in Belgium and Israel and aimed to assess the safety and tolerability of trastuzumab subcutaneous in the at-home setting for HER2-positive early breast cancer patients (Abstract P4-21-17). The results were reported in a poster at the 2016 San Antonio Breast Cancer Symposium.
In Europe, the subcutaneous formulation of trastuzumab has been approved since 2013 for use among HER2-positive breast cancer patients but has yet to be approved in the U.S.; currently, only the IV formulation of trastuzumab is FDA-approved.
Typically, women who receive trastuzumab receive it every 3 weeks for 1 year as neoadjuvant therapy, then undergo surgery, and then receive it again every 3 weeks for 1 year as adjuvant therapy. Subcutaneous administration is much faster than IV, taking only 2-5 minutes to inject, and does not require a port-a-cath.
Lesley Fallowfield, DBE, BSc, DPhil, FMedSci, the Director of Sussex Health Outcomes Research & Education in Cancer at Brighton & Sussex Medical School in the U.K., told Oncology Times that a patient in Europe once described the experience in the hospital setting: “with [IV] it was like a visit to the dentist for tooth extraction, with [subcutaneous] it is like a quick check-up, in and out with no fuss.”
Administration of trastuzumab subcutaneous by a healthcare provider at home could further improve a patient's quality of life. It would benefit patients who cannot easily make the trip to the hospital, such as older patients who might have difficulty traveling, noted Noa Efrat Ben-Baruch, MD, one of the study's researchers and Head of the Department of Oncology at Kaplan Medical Center, Rehovot, Israel.
The European approval of trastuzumab subcutaneous was based on the results of the HannaH study, which concluded that the safety and efficacy profiles for subcutaneous and IV trastuzumab were comparable. Further exploring those findings, the PrefHer trial reported that patients prefer the subcutaneous formulation of trastuzumab over IV.
“The BELIS trial took these findings one step forward and studied the benefits of at-home administration of trastuzumab [subcutaneous],” Ben-Baruch said. “The BELIS study is the first study presenting results for the administration of trastuzumab subcutaneous in the home setting.”
BELIS Trial Specifics
The study enrolled 102 women with HER2-positive early breast cancer, of which 101 moved on to receive trastuzumab. Women eligible to enroll had to have completed 6 cycles of trastuzumab IV. Over the course of the study, participants would receive an additional 12 cycles: 3 cycles of trastuzumab IV in the hospital, 3 cycles of trastuzumab subcutaneous in the hospital, and 6 cycles of trastuzumab subcutaneous at home. All cycles were administered by a healthcare provider.
The most frequently reported adverse event was system organ class disorders and administration site conditions, which consisted of injection site pain, injection site swelling, and injection site erythema. This adverse event was reported by 41.6 percent of patients. The second most common was musculoskeletal and connective tissue disorders, reported by 11.9 percent of patients, and consisted of myalgia and muscle spasms.
The study reported eight serious adverse events for eight participants, two of which discontinued study treatment. Two of the events occurred during IV administration, two during subcutaneous administration in the hospital, and four during subcutaneous administration at home.
Nearly 99 percent of participants reported satisfaction with their treatment to a large or very large extent when treated in the hospital with trastuzumab IV or subcutaneous before home administration. At home, 100 percent of participants reported satisfaction with their treatment to a large or very large extent.
For duration of treatment, measured from the time the participant arrived to when she left, 66.7 percent of healthcare providers reported a duration of less than 2 hours and the remaining 33.3 percent reported between 2 and 3 hours. This was in contrast to 23.8 percent of healthcare providers reporting a duration of less than 2 hours, 52.4 percent a duration between 2 and 3 hours, 19 percent a duration between 3 and 4 hours, and 4.8 percent a duration of more than 4 hours.
Overall, the safety of at-home trastuzumab subcutaneous was consistent with that seen for administration of trastuzumab subcutaneous in a hospital setting in previous trials, and participants and healthcare providers considered at-home trastuzumab subcutaneous beneficial.
“I think it's really interesting” and “the study met the endpoint,” said Jame Abraham, MD, FACP, Medical Director of the Breast Oncology Program at Cleveland Clinic. However, he would have liked to see the study evaluate efficacy, too. “It's a really good first step.”
At-home administration by a healthcare provider, at least in the U.S., does not seem cost-effective, Julie Gralow, MD, medical oncologist and Director of Breast Medical Oncology at Seattle Cancer Care Alliance, explained. “That would be very expensive to have a group of nurses who would be traveling around to people's homes.”
One possible benefit could be the ability to send the drug to a remote clinic, possibly saving a patient an hour or two drive, suggested Gralow.
Geeta Sandhu, BPharm(Hons), BSc, GDipClinPharm, cancer pharmacist at the Princess Alexandra Hospital in Australia, noted the subcutaneous formulation currently has some downsides that need to be addressed. For starters, she said the subcutaneous injection has a short expiry time of about 24 hours once it's been reconstituted; IV can last for 37 days. The short shelf life can lead to wastage if a patient doesn't show up for treatment and the drug has been prepared for their appointment.
She also mentioned there's the possibility of underexposure of the drug when subcutaneously injected for obese patients, and clinicians currently “don't know the significance of reduced exposure in obese patients.”
In regard to the subcutaneous approval of trastuzumab in Europe, Gralow said, “We've been watching that and wondering whether we might have that opportunity [in the U.S.] at some point.”
Teri Pollastro, a patient of Gralow, said, “I would be very interested in receiving [trastuzumab] subcutaneously.” Pollastro has metastatic breast cancer, and unlike patients with early breast cancer, she receives trastuzumab intravenously every 3 weeks long-term. “In a perfect world, I could do it myself and not have to go in [to a hospital], but I don't think that's going to happen.”
When Pollastro started trastuzumab IV, she was on it for 7 years but then went off the drug for 5 years, and when the disease came back, she started trastuzumab again. She has now been back on trastuzumab for about 2 years.
“I just felt like I didn't have a life, and it was dominated by my infusion every 3 weeks,” she recalled in regard to her reason for temporarily stopping. She said, “A 30-minute infusion can easily be 2 hours.”
Despite the appeal for subcutaneous use in the U.S., there are no clear plans to approve this formulation.
“We've known since trastuzumab first got approved back in the 90s that there was data that it could be given subcutaneously,” Gralow said. “At this point, trastuzumab is about to go off patent. I don't think this [approval] would get any more drug sold, so it's not clear to me what would be the incentive of the pharmaceutical company to invest money in a trial.”
Gralow said FDA approval may not be absolutely necessarily, considering that “there's plenty of safety data.” She explained that, if the subcutaneous administration is incorporated into treatment guidelines, it would be possible to “have uptake in the U.S. without having to get it added to the label.”
One such example of this is the use of trastuzumab for leptomeningeal carcinoma. “We're giving trastuzumab into the spinal fluid now; that's not an FDA-approved way of giving it, but there's safety data supporting it,” Gralow explained.
Abraham and Gralow each said that one aspect of trastuzumab subcutaneous that would need clarification is reimbursement. “If a clinic is reimbursed differently for an intravenous versus a subcutaneous [administration], that could be a barrier,” Gralow emphasized.
In countries where trastuzumab subcutaneous is approved, reimbursement in the hospital setting has been a barrier and could also be a barrier for the at-home setting, whether administered by a healthcare provider or a patient.
“Some clinicians do not like subcutaneous trastuzumab, as they and their institutions are reimbursed more for [IV]; likewise, there is some reluctance regarding self-administration for financial reasons,” Fallowfield explained about her experience in Europe. She said these reasons are “often dressed up as patient safety issues.”
“Funding for subcutaneous administration is not covered in Victorian public hospitals or by private health care. Therefore, [there's] less incentive for prescribers to offer it up front,” Sandhu added regarding her experience in Australia.
One barrier specific to self-administration could be compliance. “If the patient doesn't take it, we won't know,” Abraham said.
“Administering trastuzumab subcutaneous at home will allow greater independence for patients and may lead to an improved quality of life for a selection of patients,” Ben-Baruch concluded. “It should be considered as a new option for patients to be offered, of course taking into account the local legislations about home administration.”
Christina Bennett is a contributing writer.