FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase–zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer

Abstract

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

“…These concepts drive several studies towards strategies that target ECM compartments to develop therapeutic agents that facilitate drug perfusion and delivery by tumor cells. For instance, the use of hyaluronidase (HYAL) that degrades HA in breast cancer therapy has been approved by the FDA, demonstrating that HA has a critical role in cancer [ 36 ]. In addition, HA has also been considered a prognostic biomarker associated with a poor prognosis in patients with various types of cancers, such as breast, pancreatic, and ovarian, rendering HA an ECM macromolecule with a key role in cancer [ 6 , 37 , 38 ].…”

Clinical implications of plasma ctDNA features and dynamics in gastric cancer treated with HER2‐targeted therapies

“…5 To date, a variety of HER2-targeted drugs has been developed and evaluated by clinical trials separately and combined, including HER2 antibody and its derivatives (Trastuzumab and Pertuzumab), tyrosine kinase inhibitor (Lapatinib, Neratinib, and Afatinib), and antibody-drug conjugates (ADCs) (DS-8201a, TDM1, and RC48). [6][7][8][9][10][11][12][13] Monoclonal antibody Trastuzumab is the only HER2-targeted agent currently approved for first-line practice of GC. 14 DS-8201a, also known as Trastuzumab deruxtecan, is an ADC conjugated with humanized anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload.…”

“…Due to its tight regulation to crucial downstream signaling nodes such as RAS/RAF/MYC and PI3K‐Akt, HER2 remains to be the prior choice of targeted drug development for patients with advanced GC 5 . To date, a variety of HER2‐targeted drugs has been developed and evaluated by clinical trials separately and combined, including HER2 antibody and its derivatives (Trastuzumab and Pertuzumab), tyrosine kinase inhibitor (Lapatinib, Neratinib, and Afatinib), and antibody‐drug conjugates (ADCs) (DS‐8201a, TDM1, and RC48) 6–13 . Monoclonal antibody Trastuzumab is the only HER2‐targeted agent currently approved for first‐line practice of GC 14 .…”

Patient‐Reported Outcomes: Listening for What Is Most Important in Clinical Care and Patient‐Focused Drug Development

“…In clinical development of a breast cancer regimen alternative to intravenous administration, the early design of a separate patient preference study afforded patientcentered information and complemented pharmacokinetic, efficacy and safety data in the US labeling of a fixed-dose combination product given subcutaneously. 6 While most patients placed greatest value on the time savings of a brief subcutaneous administration, 14% of patients preferred the intravenous product due to greater comfort experienced during the approximately hour-long infusion. This treatment preference study illustrates that reports directly from patients may be heterogeneous, revealing insights into different patients' perceptions, priorities, and values.…”

“…Patient preference studies that compare relative satisfaction with alternate therapeutic regimens provide insights regarding what different patients value. In clinical development of a breast cancer regimen alternative to intravenous administration, the early design of a separate patient preference study afforded patient‐centered information and complemented pharmacokinetic, efficacy and safety data in the US labeling of a fixed‐dose combination product given subcutaneously 6 . While most patients placed greatest value on the time savings of a brief subcutaneous administration, 14% of patients preferred the intravenous product due to greater comfort experienced during the approximately hour‐long infusion.…”