On June 29, 2020, a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) for subcutaneous injection was approved for the following indications1,2:
Use in combination with chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (tumors either > 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer; and as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence
Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Supporting Efficacy Data
Approval was based on findings in the open-label, multicenter FeDeriCa trial (ClinicalTrials.gov identifier NCT03493854).2 In the trial, 500 patients with operable or locally advanced HER2-positive breast cancer were randomly assigned to receive either 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase-zzxf /15 mL, followed every 3 weeks by a maintenance dose of 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase-zzxf/10 mL (n = 248), or the recommended dosages for intravenous (IV) pertuzumab and IV trastuzumab (n = 252).
Patients were randomly assigned to receive eight cycles of neoadjuvant chemotherapy with concurrent administration of four cycles of either PHESGO or IV pertuzumab and trastuzumab during cycles 5 to 8, followed by surgery. After surgery, patients continued therapy with pertuzumab/trastuzumab/hyaluronidase-zzxf or IV pertuzumab and IV or subcutaneous trastuzumab as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles.
The primary endpoint of the FeDeriCa trial was noninferiority of cycle 7 pertuzumab serum trough concentration comparing the triplet regimen with IV pertuzumab. Secondary endpoints included cycle 7 trastuzumab serum trough concentration and pathologic complete response rate.
The pertuzumab cycle 7 trough concentration showed noninferiority of pertuzumab within the triplet regimen (88.7 µg/mL) to IV pertuzumab (72.4 µg/mL), with a geometric mean ratio of 1.22 (90% confidence interval [CI] = 1.14–1.31). The trastuzumab cycle 7 trough concentration showed noninferiority of trastuzumab within the triplet regimen (58.7 µg/mL) to IV trastuzumab (44.1 µg/mL), with a geometric mean ratio of 1.33 (90% CI = 1.24–1.43). The pathologic complete response rate was 59.7% (95% CI = 53.3%–65.8%) with the triplet and 59.5% (95% CI = 53.2%–65.6%) with IV pertuzumab and trastuzumab (difference = 0.15%, 95% CI = –8.7% to 9.0%).
How It Is Used
The triplet regimen of pertuzumab/trastuzumab/hyaluronidase-zzxf is for subcutaneous use in the thigh only. The recommended initial dose is 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase-zzxf administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase-zzxf administered subcutaneously over approximately 5 minutes.
For neoadjuvant treatment of breast cancer, the triplet regimen should be given every 3 weeks for three to six cycles as part of a treatment regimen for early breast cancer. Following surgery, patients should continue to receive the three-drug regimen to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity as a part of a complete regimen for early breast cancer.
For adjuvant treatment of breast cancer, the triplet regimen should be given every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity as part of a complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. The triplet regimen of pertuzumab, trastuzumab, and hyaluronidase-zzxf should be started on day 1 of the first taxane-containing cycle.
In treatment of metastatic breast cancer, when given with the triplet regimen, the recommended initial dose of docetaxel is 75 mg/m2, administered as an IV infusion. The dose may be escalated to 100 mg/m2 every 3 weeks if the initial dose is well tolerated. The triplet regimen should be given until disease progression or unmanageable toxicity.
The median duration of treatment for the triplet regimen in the FeDeriCa trial was 24 weeks (range = 0–42 weeks). The most common adverse events of any grade (> 30%) in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf were alopecia (77% vs 71% in pertuzumab/trastuzumab control group), nausea (60% vs 61%), diarrhea (60% vs 57%), anemia (36% vs 43%), and asthenia (31% vs 32%). The most common grade 3 or 4 adverse events included neutropenia (14% vs 14%) and diarrhea (7% vs 5%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (37% vs 36%), decreased neutrophils (30% vs 33%), and decreased leukocytes (25% vs 25%).
Serious adverse events occurred in 16% of patients in the triplet-regimen group. Adverse events led to dosage interruption in 40% of patients, with the most common causes being neutropenia (8%), diarrhea (7%), and decreased neutrophil count (4%).
Cardiac function should be monitored prior to and during treatment. The three-drug regimen should be discontinued in the event of cardiomyopathy.
Women of reproductive potential must be advised of the risk of embryofetal death and birth defects and advised to use effective contraception. The pregnancy status of female patients must be assessed prior to initiation of therapy. The triplet regimen should be discontinued for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. There are warnings/precautions for exacerbation of chemotherapy-induced neutropenia and hypersensitivity and administration-related reactions. Patients should be monitored for systemic hypersensitivity reactions.
1. U.S. Food and Drug Administration: FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf for HER2-positive breast cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-combination-pertuzumab-trastuzumab-and-hyaluronidase-zzxf-her2-positive-breast-cancer. Accessed on July 7, 2020.
2. PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection, for subcutaneous use, prescribing information, Genentech, Inc, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf. Accessed on July 7, 2020.