Antoinette R. Tan, MD, discusses the FDA approval of the fixed-dose combination of SC pertuzumab and trastuzumab with hyaluronidase, in combination with IV chemotherapy in HER2-positive breast cancer.
Subcutaneous (SC) pertuzumab (Perjeta) and trastuzumab (Herceptin), in combination with hyaluronidase-zzxf (Phesgo) and intravenous (IV) chemotherapy offers an outpatient option for patients, according to Antoinette R. Tan, MD, who added that developing an at home administration protocol for the SC formulation is an important area of future research.
Results from the phase 3 FeDeriCa trial showed that the combination demonstrated noninferiority to IV formulations of the 2 drugs with regard to pharmacokinetics, clinical efficacy, and safety.1 These findings led to the June 2020 FDA approval of the fixed-dose pertuzumab/trastuzumab combination with hyaluronidase for SC administration in combination with IV chemotherapy in patients with early and metastatic HER2-positive breast cancer.
The global, multicenter, 2-arm, open-label, randomized phase 3 trial, which enrolled 500 patients, met its primary end point after demonstrating noninferiority on the basis of predose cycle 8 serum Ctrough for the pertuzumab component of the fixed-dose combination. Moreover, noninferiority for the predose cycle 8 serum Ctrough was also demonstrated for the trastuzumab component of the SC combination compared with IV trastuzumab.
Notably, the total pathologic complete response in the breast and axilla, along with the safety profile, was found to be comparable between the 2 treatment regimens.
Regarding safety, common adverse effects (AEs) observed with the SC combination included alopecia, nausea, diarrhea, anemia, and asthenia. The combination can also lead to the worsening of chemotherapy-induced neutropenia, according to the FDA.2
“The fixed-dose combination of SC petuzumab and trastuzumab offers a faster and more convenient treatment option for patients with HER2-positive breast cancer compared with intravenous infusions,” Tan emphasized. “Several benefits are associated with this SC administered product, such as less time spent in treatment chairs and infusion centers, which is a critical quality-of-life factor.”
In a special episode of OncLive On Air™,we passed the mic to Tan, who is chief of Breast Medical Oncology and co-director of the Phase I Program at the Levine Cancer Institute of Atrium Health. In our interview, she spotlighted the FDA approval of the fixed-dose combination of SC pertuzumab and trastuzumab with hyaluronidase, in combination with IV chemotherapy, along with the significance of the approval in the HER2-positive treatment paradigm .
OncLive: In June 2020, the FDA approved the fixed-dose combination of SC pertuzumab and trastuzumab with hyaluronidase. Could you discuss the need to establish a combination such as this in this patient population? What are the benefits of this approach versus the standard regimen?
Tan: The treatment of patients with HER2-positive breast cancer with intravenous (IV) pertuzumab in combination with trastuzumab and chemotherapy has been considered a standard of care in the neoadjuvant and adjuvant settings, as well as in the first-line setting, in advanced HER2-positive breast cancer.
However, for many patients, the long infusion times, along with the need for repeated invasive IV access, are inconvenient aspects of the treatment experience. Additionally, increasing usage of IV-administered agents in oncology has placed a strain on medical centers with respect to the time and resources required to prepare and administer such infusions. As such, the switch to the subcutaneous route of administration for monoclonal antibodies such as trastuzumab, has been demonstrated to reduce the treatment burden for patients while improving time and resource utilization at a treatment facility.
The new SC formulation, which combined the 2 monoclonal antibodies trastuzumab and pertuzumab with the recombinant human hyaluronidase in 1 vial, was developed. Unlike the IV formulation of trastuzumab, dosing with this SC fixed-dose formulation is not dependent on the patient’s body weight. Also, the fixed-dose combination of pertuzumab and trastuzumab is administered in about 5-8 minutes as opposed to the 150 minutes it would take for an IV infusion of the loading dose of each of the 2 medicines given sequentially, followed by 30 to 90 minutes for each IV administration of the maintenance doses. With this being said, this new SC formulation improves the treatment experience by lessening the time associated with administration.
Could you speak to the design of the phase 3 FeDeriCa trial that resulted in this regulatory decision?
FeDeriCa was a randomized, open-label, international, multicenter, 2-arm, phase 3 noninferiority study. A total of 500 patients were randomized. Eligible patients included those who had HER2-positive invasive breast cancer with a tumor that was greater than 2 cm or who had node-positive disease. Mostly patients with stage II/III breast cancer were included.
These patients were randomized 1:1 to receive IV pertuzumab and trastuzumab or the fixed-dose SC combination injection. Both were administered every 3 weeks with neoadjuvant chemotherapy.
Following surgery, the patients continued adjuvant HER2-targeted treatment per their randomization. The chemotherapy backbone was either dose-dense doxorubicin and cyclophosphamide for 4 cycles, followed by weekly paclitaxel for 12 weeks, or doxorubicin and cyclophosphamide every 3 weeks for 4 cycles, followed by docetaxel every 3 weeks for 4 cycles. The choice between the chemotherapy regimen options [was based on the] investigator’s discretion prior to randomization.
I want to highlight the efficacy observed in terms of the pathologic complete response rate, meaning no tumor in the breast and lymph nodes; these rates were nearly identical in both arms at about 60% and proved to be comparable to [what has been seen in] other neoadjuvant trials with HER2-targeted therapy.
The SC injection, in combination with chemotherapy, also demonstrated noninferior trough concentrations of pertuzumab, when compared with IV trastuzumab and pertuzumab, in combination with chemotherapy, in early-stage HER2-positive breast cancer. Moreover, we also saw comparable safety profiles [between the 2 approaches].
What safety signals were observed with the SC combination?
No new or unexpected toxicities were observed. The most common grade 3/4 AEs with the fixed-dose combination included neutropenia, low white blood cell count, and diarrhea, but these toxicities were expected. The incidence rates of primary and secondary cardiac AEs were low in both arms and were pretty consistent with rates reported in previous studies with similar treatment regimens.
As with any SC product, there can be injection site reactions; however, in the SC arm, [the rates of these reactions] was low. About 13% of patients experienced low-grade symptoms such as pain, burning, or redness at the injection site.
What were the clinical implications of these findings?
Other than spending less time in treatment chairs, another benefit [of the SC administration] is the increased capacity of infusion chairs [in cancer centers]. This will create greater availability for patients who can only receive IV therapy. Furthermore, there's shorter administration time, which helps patients spend less time in infusion centers and allows for greater flexibility.
There's also the potential to reduce drug delivery, healthcare costs, as well as pharmacy and nursing resource use. A SC-administered product would involve shorter preparation time and shorter administration time. From a patient perspective, aside from spending less time in an infusion center, there could potentially be less pain and discomfort because they wouldn't need IV access. This [approach] will also help preserve their veins.
Especially in light of the coronavirus disease 2019 (COVID-19) pandemic, how could this regimen minimize the risk of contracting the virus?
Shorter administration time would certainly translate to less time spent in an infusion center, thereby decreasing risk of exposure.
Additionally, when you consider the current state of the COVID-19 pandemic, having a SC medication [that can potentially be] administered by a healthcare worker, such as a home health nurse, is very appealing because this could save patients a trip to the cancer center.
Where should future efforts be focused with regard to this approach?
Developing an at-home administration protocol for the SC formulation is an important area of future research. It could provide many advantages to both patients and infusion centers alike—especially during the COVID-19 pandemic. However, we must proceed cautiously. Specific protocols are required to ensure the setup is safe and it must be rigorously evaluated prior to implementation.
This strategy is actually being evaluated in a single-arm, multicenter, expanded-access study [that is being done in an attempt] to provide at-home SC administration of pertuzumab and trastuzumab fixed-dose combination (NCT04395508).
This study will enroll approximately 400 patients with HER2-positive breast cancer who are currently receiving IV pertuzumab and trastuzumab. An at-home health nursing provider will administer the fixed-dose of SC pertuzumab and trastuzumab from the patient’s homes. This is an important clinical trial effort that will assess whether this approach is feasible and safe.
Are any emerging agents under exploration that you’re excited about?
Several compounds are currently under clinical development, including novel antibody-drug conjugates (ADCs) that look promising. One agent it SYD985, which is an ADC composed of trastuzumab, linked to duocarmazine. The other emerging HER2-targeting ADCs, XMT-1522 and ARX788, are still in early-phase research. XMT-1522 is a human IgG1 anti-HER2 monoclonal antibody with a cytotoxic payload called auristatin F-hydroxypropylamide. ARX788 is another HER2-targeted antibody site, specifically conjugated to a different cytotoxic moiety called Amberstatin269, which is a tubulin inhibitor. It’s very exciting to see the development of this class of drugs.