FDA Approves Fixed-Dose Pertuzumab/Trastuzumab Combo in HER2+ Breast Cancer

In Clinical Studies News by Barbara Jacoby

By: Kristi Rosa

From: onclive.com

The FDA has approved a fixed-dose combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) with hyaluronidase, administered via subcutaneous injection in combination with intravenous chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer.

The FDA has approved a fixed-dose combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) with hyaluronidase-zzxf (Phesgo) for administration via subcutaneous injection in combination with intravenous (IV) chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer.1

This marks the first time that Genentech, the drug developer, has paired 2 monoclonal antibodies that can be administered via a single subcutaneous injection. Patients should be selected for this combination based on an FDA-approved companion diagnostic test.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“As part of the FDA’s ongoing commitment to address the novel coronavirus pandemic, we continue to keep a strong focus on patients with cancer who constitute a vulnerable population at risk of contracting the disease,” Pazdur added. “At this critical time, we continue to expedite oncology product development. This application was approved about 4 months ahead of the FDA goal date.”

The combination is available in 1 single-dose vial. The initial loading dose is estimated to take approximately 6 minutes to administer with each subsequent maintenance dose taking approximately 5 minutes. Typically, infusion of a loading dose of the standard IV formulations of pertuzumab and trastuzumab take approximately 150 minutes; subsequent maintenance infusions of the 2 agents can take anywhere from 60 to 150 minutes. Notably, the newly approved combination allows for administration by a healthcare professional in either a treatment center or at home.

The regulatory decision was based on the results from the phase 3 FeDeriCa trial, in which the combination demonstrated noninferiority to IV formulations of the 2 drugs with regard to pharmacokinetics, clinical efficacy, and safety.2

The study enrolled a total of 500 patients and was reported to have met its primary end point after showing noninferiority on the basis of predose cycle 8 serum Ctrough for the pertuzumab component of the fixed-dose combination; the mean value was 93.7 versus 78.5 µg/mL for IV pertuzumab. Geometric means were 88.7 and 72.4 µg/mL, respectively (geometric mean ratio [GMR], 1.22; 90% CI, 1.14-1.31).

Additionally, results from the trial showed noninferiority for the predose cycle 8 serum Ctrough for the trastuzumab component of the fixed-dose combination versus with IV trastuzumab, at 62.9 versus 48.1 µg/mL, respectively. Additionally, geometric means were 58.7 µg/mL for the subcutaneous formulation and 44.1 µg/mL for the IV formulation of trastuzumab (GMR 1.33; 90% CI, 1.24-1.43).

Notably, total pathologic complete response (tpCR) in the breast and axilla, as well as safety, was found to be comparable between the 2 treatment regimens.

The combination of IV pertuzumab, IV trastuzumab, and chemotherapy has been shown to lead to improved outcomes in patients with HER2-positive breast cancer versus IV trastuzumab plus chemotherapy alone.

In the phase 1b dose-finding HannaH trial, investigators were able to establish the appropriate dose of trastuzumab and hyluronidase-oysk (Herceptin Hylecta).3 The appropriate dose of subcutaneous pertuzumab was identified in a phase 1b dose-finding trial.4

To compare the new combination (SC FDC) with conventional IV treatment, patients with newly diagnosed stage II-IIIC HER2-positive breast cancer were enrolled at 122 sites onto the trial of neoadjuvant therapy. Participants were randomized to receive 4 cycles of doxorubicin and cyclophosphamide chemotherapy followed by 4 cycles of docetaxel administered with randomized therapy: IV pertuzumab and trastuzumab or the SC FDC.

Following surgery, patients received adjuvant therapy with the same pertuzumab/trastuzumab formulation that they had been given in the neoadjuvant setting. The primary analysis for the trial occurred prior to the start of adjuvant therapy.

The median age of participants was 50 years, 80% had stage II-IIIA disease, and 61% had hormone receptor–positive disease.

The comparison of predose cycle 8 Ctrough values for IV pertuzumab and trastuzumab compared with the individual components of the FDC led to GMRs that fell within the 90% confidence intervals for noninferiority.

The 2 treatment arms showcased almost identical rates of tpCR, which was defined as ypT0/Tis, ypN0. Specifically, the tpCR was 59.5% with the IV agents versus 59.7% with the SC FDC.

With regard to safety, the most common adverse events observed with the combination include alopecia, nausea, diarrhea, anemia, and asthenia. The combination can also lead to the worsening of chemotherapy-induced neutropenia, according to the FDA.

Notably, prescribing information for the combination includes a boxed warning to warn both healthcare professionals and patients about the risk of potential heart failure, fetal harm, and lung events. Providers should use similar monitoring parameters as those used with IV pertuzumab and IV trastuzumab.


  1. FDA approves breast cancer treatment that can be administered at home by health care professional. News release. FDA. June 29, 2020. Accessed June 29, 2020. bit.ly/2ZjoQzI.
  2. Tan AR, Im S-A, Mattar A, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Presented at: 2019 San Antonio Breast Cancer Symposium. Poster PD4-07.
  3. Ismael G, Hegg R, Muehlbauer S, et al. 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. Lancet Oncol. 2012;13(9):869-78. doi: 10.1016/S1470-2045(12)70329-7.
  4. Kirschbrown WP, Wynne C, Kagedal M, et al. Development of a subcutaneous fixed-dose combination of pertuzumab and trastuzumab: results from the phase Ib dose-finding study. J Clin Pharmacol. 2019;59(5):702-716. doi: 10.1002/jcph.1362.