FDA Accepts Roche's BLA for Subcutaneous Fixed-Dose Combination of Perjeta and Herceptin in HER2-Positive Breast Cancer

February 26, 2020 News /BioValleyBIOON/ -- Roche recently announced that the U.S. Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) submitted by it, which seeks approval for the subcutaneous formulation of the fixed-dose combination (FDC) of Perjeta and Herceptin, in combination with intravenous chemotherapy, for the treatment of eligible HER2-positiveBreast CancerPatient. This subcutaneous fixed-dose combination (FDC) formulation is developed using Halozyme’s Enhanze drug delivery technology, which is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20). This enzyme temporarily degrades hyaluronic acid in the body, facilitating faster dispersion and absorption of the injected medication, thereby enabling subcutaneous administration.

Compared with intravenous administration, subcutaneous injection of this fixed-dose combination can be completed within minutes, significantly reducing the time patients spend receiving treatment. Specifically, the subcutaneous (SC) formulation of the Perjeta + Herceptin fixed-dose combination (FDC) requires approximately 8 minutes for the initial loading dose and about 5 minutes for subsequent maintenance doses. In contrast, standard intravenous (IV) formulations of Perjeta and Herceptin, administered via intravenous infusion, require approximately 150 minutes for the loading dose, while subsequent maintenance infusions for the two drugs take 60–150 minutes.

Notably, this marks the first time two HER2-targeted antibodies have been combined into a single subcutaneous formulation, enabling administration in just a few minutes. This fixed-dose combination subcutaneous formulation offers a rapid and minimally invasive delivery option for patients with HER2-positive breast cancer who are currently receiving intravenous infusions of Perjeta and Herceptin.

Levi Garraway, M.D., Chief Medical Officer and Global Head of Product Development at Roche, stated, “For more than 20 years, our medicines have redefined the standard of care for patients with HER2-positive breast cancer. Today’s acceptance of the BLA builds on our commitment to provide patients with faster access to treatment with Perjeta and Herceptin. We are working withFDAcollaborate to provide this treatment regimen to patients as soon as possible.”

This BLA is based on data fromData from the Phase III FeDeriCa study. The results of this study were presented at the 42nd San Antonio Breast Cancer Symposium (SABCS) held in December 2019. The study demonstrated that, in eligible patients with HER2-positive early breast cancer (eBC), a new fixed-dose combination (FDC) subcutaneous (SC) injection of Perjeta (pertuzumab) plus Herceptin (trastuzumab) combined with intravenous (IV) chemotherapy showed non-inferiority in terms of Perjeta blood levels (pharmacokinetics), as well as comparable efficacy and safety, compared to the standard regimen of IV Perjeta (pertuzumab) + Herceptin (trastuzumab) + chemotherapy.

The FeDeriCa study met its primary endpoint: subcutaneous (SC) administration of the fixed-dose combination (FDC) demonstrated non-inferiority in Perjeta trough concentrations (Ctrough) during the dosing interval compared with intravenous infusion of Perjeta. The geometric mean ratio (GMR; a type of average used in pharmacokinetic assessments) for the primary endpoint was 1.22 (90% CI: 1.14–1.31), with the lower bound of the 90% CI for the GMR being ≥0.80 (the prespecified non-inferiority margin). The secondary endpoint of Herceptin non-inferior Ctrough was also met, with Herceptin trough concentrations in patients receiving the FDC being non-inferior to those in patients receiving intravenous Herceptin (GMR=1.33 [90% CI: 1.24–1.43]; the lower bound of the 90% CI for the GMR was ≥0.80). A non-inferiority endpoint was selected for this study to ensure that patients received adequate doses of Perjeta and Herceptin within the same treatment interval compared with the established intravenous dosing regimen. Furthermore, the total pathological complete response (pCR) rate, as a secondary endpoint, was comparable between the two treatment groups. Total pCR was achieved in 59.7% of patients receiving the FDC and 59.5% of patients receiving intravenous Perjeta and Herceptin, with a difference of 0.15% (95% CI: -8.67 to 8.97).

The safety profile of the FDC combination regimen was comparable to that of intravenous Perjeta plus Herceptin in combination with chemotherapy, with no new safety signals identified, including no significant difference in cardiotoxicity. The most commonAdverse Reactionshair loss, nausea, diarrhea, andAnemia。

In previous studies, compared with intravenous administration of the same drug, most patients preferred subcutaneous (SC) injection, with the most common reason being the shorter time required for clinical administration. Roche is currently investigating patient preference for SC-administered fixed-dose combination (FDC) versus standard IV-administered Perjeta + Herceptin in HER2-positive early breast cancer (eBC) patients in the Phase II PHranceSCa study. The interim results of this study will be presented at future medicalMeetingpublished above.

Breast cancer is the most common type of cancer in women, with over 2 million new cases diagnosed globally each year. HER2-positive breast cancer is a particularly aggressive subtype, accounting for approximately 15–20% of all breast cancer cases. Among patients with HER2-positive early breast cancer (eBC) treated with Herceptin plus chemotherapy, approximately one-quarter experience disease recurrence or death within 10–11 years, with even higher rates of recurrence or death observed in those with high-risk eBC.

Perjeta is a novel anti-HER2 agent that exerts its anti-HER2 effects by inhibiting both heterodimerization and homodimerization of HER2. Perjeta and Herceptin share the same mechanism of action, as both target and bind to the HER2 receptor; however, they bind to distinct epitopes. The combination of these two agents provides more comprehensive blockade of the HER2 signaling pathway, thereby inhibiting cancer cell growth and survival.

In the United States and the European Union, the Perjeta + Herceptin + chemotherapy regimen has been approved for: (1) neoadjuvant treatment of HER2-positive early breast cancer (eBC); (2) adjuvant treatment of HER2-positive eBC with a high risk of recurrence; (3) treatment of HER2-positive advanced breast cancer (aBC), where it significantly prolongs patient survival compared to Herceptin + chemotherapy.

In China, the Perjeta + Herceptin + chemotherapy regimen was approved in December 2018 for the adjuvant treatment of patients with HER2-positive early breast cancer (eBC) at high risk of recurrence. This approval marks the dawn of a new era in breast cancer treatment in China! Data from the global pivotal Phase III adjuvant therapy study demonstrated that, compared with the current standard of care (Herceptin + chemotherapy), adjuvant treatment with the Perjeta + Herceptin + chemotherapy regimen significantly prolonged invasive disease-free survival in patients with HER2-positive eBC at high risk of recurrence.Adverse ReactionsControllable, with a clear clinical benefit/risk advantage. (Bioon.com)

Original Source:FDA accepts Roche’s Biologics License Application for fixed-dose subcutaneous combination of Perjeta and Herceptin for HER2-positive breast cancer