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Authors Antoinette R Tan, Seock-Ah Im, Andre Mattar, Ramon Colomer, Daniil Stroyakovskii, Zbigniew Nowecki, Michelino De Laurentiis, Jean-Yves Pierga, Kyung Hae Jung, Christian Schem, Sarah Heeson, Mahesh Shivhare, Whitney P. Kirschbrown, Eleonora Restuccia, Tanja Badovinac Crnjevic and Christian Jackisch
Title 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
Journal Cancer Res
Vol 80
Issue 4 Suppl
Date
URL https://cancerres.aacrjournals.org/content/80/4_Supplement/PD4-07
Abstract Text Background: Intravenous pertuzumab (P IV) + trastuzumab (H IV) + chemotherapy (CT) improves outcomes in patients (pts) with HER2-positive breast cancer, compared with H + CT.A new subcutaneous (SC) formulation, for the first time combining two monoclonal antibodies, P + H, with recombinant human hyaluronidase in one vial, was developed. This ready-to-use fixed-dose combination (PH FDC) is administered subcutaneously into the thigh over 5-8 minutes. The dose of H SC was confirmed in the phase III HannaH trial (NCT00950300) and the dose of P SC was established in a phase Ib study (NCT02738970). We report the first results from FeDeriCa (NCT03493854), which was designed to assess the pharmacokinetics, efficacy, and safety of this novel SC PH FDC compared with H IV + P IV in pts with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting. Methods: Pts with centrally confirmed HER2-positive invasive breast cancer (tumor >2 cm, or node-positive disease; Stage II-IIIC) were randomized 1:1 to receive 8 cycles of CT in the neoadjuvant setting with H IV (loading dose 8 mg/kg, maintenance 6 mg/kg) + P IV (loading dose 840 mg, maintenance 420 mg) (Arm A) or CT per Arm A + PH FDC (loading dose 1200 mg P SC/600 mg H SC, maintenance 600 mg each; Arm B) administered q3w during cycles 5-8. CT was investigator’s choice of either 4 cycles of dose-dense doxorubicin + cyclophosphamide q2w → 4 cycles of weekly paclitaxel (total: 12 weeks), or 4 cycles of doxorubicin + cyclophosphamide q3w → 4 cycles of docetaxel q3w. Post-surgery, pts continued anti-HER2 treatment per randomization to complete 18 cycles. The primary objective was noninferiority (NI) of the pre-dose cycle 8 P serum trough concentration (Ctrough) within the PH FDC versus P IV (NI margin for the lower bound of the 90% confidence interval [CI] of the geometric mean ratio [GMR]: ≥0.8). Key secondary objectives were NI of pre-dose cycle 8 H Ctrough within the PH FDC versus H IV, total pathologic complete response in the breast and axilla (ypT0/is, ypN0; tpCR), and safety (primary cardiac events were defined as heart failure [New York Heart Association III + IV] with significant left ventricular ejection fraction [LVEF] decline; cardiac death. Secondary cardiac events were defined as LVEF decline ≥10% from baseline to below 50% and confirmed LVEF decline). Results: Five-hundred pts were randomized (252 to Arm A, 248 to Arm B - ITT and safety populations) from 06/14/18-12/24/18 at 122 sites. At clinical cutoff (07/04/19), 242 pts (96.0%) in Arm A and 234 (94.4%) in Arm B completed the neoadjuvant treatment phase. Baseline pt demographics and disease characteristics were well balanced between arms.The study met its primary endpoint: P GMR was 1.22 (90% CI 1.14-1.31) with the lower limit of the 90% CI being above the prespecified NI margin of 0.8. H GMR was 1.33 (90% CI 1.24-1.43), meeting the NI criteria. tpCR rates were comparable between arms (59.5%; 95% CI 53.2-65.6 in Arm A and 59.7%; 95% CI 53.3-65.8 in Arm B) and were similar to other P + H + CT trials. Overall safety, including cardiac safety, was comparable between arms (Table). Safety was as expected for P + H + CT trials. Conclusions: SC PH FDC demonstrated noninferior pre-dose cycle 8 P + H Ctrough to that of P IV + H IV, with comparable efficacy and safety. PH FDC offers a faster and simpler method of P + H administration for HER2-positive breast cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Pertuzumab/trastuzumab/hyaluronidase-zzxf Phesgo HER2 (ERBB2) Antibody 47 Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) is an injectable formulation consists of Perjeta (pertuzumab), Herceptin (trastuzumab), and hyaluronidase, which demonstrates anti-tumor activity against ERBB2 (HER2)-positive breast cancer (Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07). Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf injection) is FDA approved for use in combination with chemotherapy in ERBB2 (HER2)-positive early breast cancer, and in combination with Taxotere (docetaxel) in ERBB2 (HER2)-positive metastatic breast cancer that has not received prior anti-HER2 therapy (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 amp Her2-receptor positive breast cancer sensitive Pertuzumab/trastuzumab/hyaluronidase-zzxf FDA approved Actionable In a Phase III trial (FeDeriCa) that supported FDA approval, Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) treatment in combination with chemotherapy in the neoadjuvant-adjuvant setting demonstrated safety and total pathological complete response rate (59.7% vs 59.5%) comparable to intravenous Perjeta (pertuzumab) and Herceptin (trastuzumab) plus chemotherapy in patients with ERBB2 (HER2)-positive early breast cancer (Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07; NCT03493854). detail... detail...
ERBB2 over exp Her2-receptor positive breast cancer sensitive Pertuzumab/trastuzumab/hyaluronidase-zzxf FDA approved Actionable In a Phase III trial (FeDeriCa) that supported FDA approval, Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) treatment in combination with chemotherapy in the neoadjuvant-adjuvant setting demonstrated safety and total pathological complete response rate (59.7% vs 59.5%) comparable to intravenous Perjeta (pertuzumab) and Herceptin (trastuzumab) plus chemotherapy in patients with ERBB2 (HER2)-positive early breast cancer (Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07; NCT03493854). detail... detail...
ERBB2 over exp Her2-receptor positive breast cancer sensitive Docetaxel + Pertuzumab/trastuzumab/hyaluronidase-zzxf FDA approved Actionable In a Phase III trial (FeDeriCa) that supported FDA approval, Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) demonstrated pharmacokinetics, safety, and efficacy comparable to i.v. pertuzumab and trastuzumab (H+P) (Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07; NCT03493854), warranted the extrapolation of data from a Phase III trial supporting the approval of H+P plus docetaxel in Erbb2 (Her2)-positive metastatic breast cancer (PMID: 23602601; NCT00567190) for approval of Phesgo (FDA.gov). detail... detail... 23602601 detail...
ERBB2 amp Her2-receptor positive breast cancer sensitive Docetaxel + Pertuzumab/trastuzumab/hyaluronidase-zzxf FDA approved Actionable In a Phase III trial (FeDeriCa) that supported FDA approval, Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) demonstrated pharmacokinetics, safety, and efficacy comparable to i.v. pertuzumab and trastuzumab (H+P) (Cancer Res 2020;80(4 Suppl):Abstract nr PD4-07; NCT03493854), warranted the extrapolation of data from a Phase III trial supporting the approval of H+P plus docetaxel in Erbb2 (Her2)-positive metastatic breast cancer (PMID: 23602601; NCT00567190) for approval of Phesgo (FDA.gov). detail... 23602601 detail... detail...