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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 | ||||||||||||
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| 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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Pertuzumab/trastuzumab/hyaluronidase-zzxf | Pertuzumab/trastuzumab/hyaluronidase-zzxf | 0 | 5 |
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| Pertuzumab/trastuzumab/hyaluronidase-zzxf | Phesgo | HER2 (ERBB2) Antibody 72 | 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 |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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