Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study

Tan, Antoinette R.; Im, Seock‐Ah; Mattar, André; Colomer, Ramón; Stroyakovskii, Daniil; Nowecki, Zbigniew; Laurentiis, Michelino De; Pierga, Jean‐Yves; Jung, Kyung Hae; Schem, Christian; Hogea, Alexandra; Črnjević, Tanja Badovinac; Heeson, Sarah; Shivhare, Mahesh; Kirschbrown, Whitney P.; Restuccia, Eleonora; Jackisch, Christian

doi:10.1016/s1470-2045(20)30536-2

Cited by 84 publications

(79 citation statements)

References 32 publications

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“…Five hundred patients were randomized [ 30 ], and 5656 pertuzumab serum PK samples were collected from 489 patients. A summary of baseline demographics and clinical characteristics is shown in Online Resource 1.…”

Section: Resultsmentioning

confidence: 99%

“…FeDeriCa was conducted in conformance with Good Clinical Practice guidelines and the Declaration of Helsinki [ 30 ]. The protocol was reviewed and approved by the institutional review board or ethics committee at each study site; all patients provided written informed consent [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…As such, the PH FDC SC is given as a loading dose of 1200 mg pertuzumab and 600 mg trastuzumab in 15 mL, and 600 mg pertuzumab and trastuzumab maintenance doses in 10 mL, along with 2000 U/mL rHuPH20 every 3 weeks. This dose was assessed clinically in the FeDeriCa study (NCT03493854), which showed that PH FDC SC was non-inferior to P + H IV, based on cycle 7 pertuzumab serum C trough concentrations, and that PH FDC SC and P + H IV demonstrated comparable efficacy (total pathologic complete response) and safety profiles [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Wang¹,

Deng²,

Hennig

et al. 2021

Cancer Chemother Pharmacol

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Purpose To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen. Methods Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression. Results SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest. Conclusion 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 every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Wang¹,

Deng²,

Hennig

et al. 2021

Cancer Chemother Pharmacol

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“…The results of this study were presented at the San Antonio Breast Cancer Symposium in 2019 and subsequently published in the Lancet Oncology. 71 , 72 …”

Section: New Formulation Of Dual Her2 Targeting Therapymentioning

confidence: 99%

“…The results of this study were presented at the San Antonio Breast Cancer Symposium in 2019 and subsequently published in the Lancet Oncology. 71,72 PH FDC SC is injected into the thigh over 8 minutes for the loading dose and over 5 minutes for the maintenance dose. Dosing is not weight-based.…”

Section: New Formulation Of Dual Her2 Targeting Therapymentioning

confidence: 99%

Combination of Pertuzumab and Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer: A Review of the Emerging Clinical Data

Jagosky¹,

Tan²

2021

BCTT

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Human epidermal growth factor receptor type 2 (HER2) is a relevant and effective target in breast cancer. The development of monoclonal antibodies against HER2 has revolutionized the treatment of HER2-positive breast cancer. The humanized monoclonal antibody, trastuzumab, was the first in its class to be widely adopted. It was initially studied in the metastatic setting and then in the treatment of early-stage disease, demonstrating significant improvement in overall survival in both settings. The addition of pertuzumab further improved upon results achieved with trastuzumab and chemotherapy, specifically extending overall survival in patients with metastatic disease, lessening the risk of recurrence when used in the adjuvant setting, and improving pathologic complete response rate when utilized in the neoadjuvant setting. In this article, we review the studies that support the use of HER2-directed monoclonal antibodies in early-stage breast cancer both in the adjuvant and neoadjuvant settings and focus on the success of dual HER2-targeted therapy achieved with the combination of trastuzumab and pertuzumab. A newer way to administer these agents, specifically the subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase, will also be discussed.

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Subcutaneous Administration of a Zwitterionic Chitosan‐Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies

Gréa,

Jacquot,

Durand

et al. 2023

Advanced Materials

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Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA‐/EMA‐approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two‐component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.

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Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study

Cited by 84 publications

References 32 publications

Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Combination of Pertuzumab and Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer: A Review of the Emerging Clinical Data

Subcutaneous Administration of a Zwitterionic Chitosan‐Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies

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