The combination of PERJETA + Herceptin (pertuzumab and trastuzumab) together in 1 vial for subcutaneous (SC) administration was recently developed as a ready-to-use formulation to reduce the treatment burden on patients while improving healthcare efficiency. Furthermore, patients overwhelmingly prefer a SC option vs. traditional IV administration when treating their HER2+ breast cancer. Bridging from the IV to SC route of administration relies on pharmacokinetics and MIDD. The pertuzumab + Herceptin Ph 1 dose-finding study was a novel design which used health male volunteers, female early breast cancer patients, and a SC surrogate material while the Ph 3 and launch material was being finalized. This study aimed to identify an SC pertuzumab dose given with recombinant human hyaluronidase that results in comparable exposure to that of the intravenous (IV) pertuzumab dose, based on pertuzumab serum trough concentration and area under the serum concentration–time curve. Pharmacokinetics (PK), safety, and tolerability of a single dose of SC pertuzumab given alone or in a fixed-dose combination (comixed or coformulated) with trastuzumab were also assessed. A maintenance dose of 600 mg for SC pertuzumab resulted in an equivalent exposure to that of IV pertuzumab, and no new safety signals were identified for SC pertuzumab or trastuzumab. A loading dose of 1200 mg for SC pertuzumab was selected based on approximate dose proportionality. The PK and safety results supported further development of a fixed-dose coformulation combination of pertuzumab and trastuzumab for SC administration, which was investigated in the phase III trial FeDeriCa. FeDeriCa enrolled approximately 500 patients with HER2-positive early breast cancer, randomized 1:1 to receive pertuzumab and trastuzumab IV or the pertuzumab and trastuzumab SC fixed-dose combination (FDC). The FDC of pertuzumab and trastuzumab for subcutaneous injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf [PH FDC SC]) showed non-inferior serum trough concentrations to intravenous pertuzumab plus trastuzumab, the primary endpoint of the FeDeriCa trial. PH FDC SC, known as PHESGO was approved by the US FDA in June 2020, and rest of world filings are currently underway. The approved PH FDC SC dose (loading: 1200/600 mg pertuzumab/trastuzumab [15 mL]; maintenance: 600 mg pertuzumab/trastuzumab [10 mL] and 2000 U/mL recombinant human hyaluronidase) provides a positive benefit-risk profile with comparable efficacy and safety to P + H IV. This example highlights the successful use of selecting a SC dose in Ph 1 based on PK and safety data, and then demonstrating PK non-inferiority (Ctrough) between the IV and SC formulations in Ph 3 to ensure comparable efficacy. The FeDeriCa trial collected safety and efficacy data to show that there is consistency between the 2 routes of administration, however, the Ph 3 bridging study was not powered for efficacy, and the primary study endpoint was PK.
Understand the development strategy and clinical development program for switching from IV to SC administration of monoclonal antibodies.
Describe the impact that clinical pharmacology and model-informed drug development can have in subcutaneous drug product development.
Discuss the clinical development experience of PHESGO (Perjeta + Herceptin subcutaneous fixed-dose combination).