Pertuzumab in Adjuvant Treatment of HER2-Positive Breast Cancer


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AT THE END OF 2017, pertuzumab (Perjeta) was granted regular approval for use in combination with trastuzumab (Herceptin) and chemotherapy as adjuvant treatment of patients with HER2- positive early breast cancer at high risk of recurrence.1,2

Supporting Efficacy Data

APPROVAL WAS BASED on findings from the double-blind phase III APHINITY trial, in which 4,804 patients with HER2-positive early breast cancer with excision of their primary tumor were randomized to receive pertuzumab (n = 2,400) or placebo (n = 2,404) in combination with adjuvant trastuzumab and investigator-selected chemotherapy.2,3 Chemotherapy consisted of one of the following anthracycline-based or non–anthracycline-based regimens for individual patients: FEC (fluorouracil [5-FU], epirubicin, cyclophosphamide) or FAC (5-FU, doxorubicin, cyclophosphamide) followed by docetaxel or paclitaxel; AC (doxorubicin, cyclophosphamide) or EC (epirubicin, cyclophosphamide) either every 3 weeks or every 2 weeks with growth factor support followed by docetaxel or paclitaxel; or docetaxel in combination with carboplatin. Pertuzumab and trastuzumab were given every 3 weeks starting on day 1 of the first taxane-containing cycle for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity. The main efficacy outcome was invasive disease-free survival. Stratification factors included chemotherapy regimen, hormone receptor status, and nodal status.

OF NOTE

Pertuzumab carries a boxed warning for left-ventricular dysfunction and embryofetal toxicity.

The median age of patients was 51 years (13% ≥ 65 years), more than 99% were female, 63% had node-positive disease, 64% had hormone receptor– positive disease, 71% were white, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 78% received an anthracycline-containing regimen.

After a median follow-up of 45.4 months, the proportion of invasive disease–free survival events in the intent-to-treat population was 7.1% in the pertuzumab group and 8.7% in the placebo group (hazard ratio [HR] = 0.82, P = .047). High-risk patients included patients such as those with hormone receptor–negative or node-positive breast cancer. The proportion of events in patients with hormone receptor–negative disease was 8.2% vs 10.6% (HR = 0.76, 95% confidence interval [CI]: 0.56–1.04). The proportion of events among patients with node-positive disease was 9.2% vs 12.1% (HR = 0.77, 95% CI: 0.62–0.96). Overall survival data were not mature at the time of analysis.

How It Works

PERTUZUMAB IS a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of HER2 and thus blocks ligand-dependent heterodimerization of HER2 with other HER family members, including epidermal growth factor receptor (EGFR), HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways: mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity. Pertuzumab alone inhibits the proliferation of human tumor cells; the combination of pertuzumab and trastuzumab augmented antitumor activity in HER2-overexpressing xenograft models.

How It Is Used

PATIENTS SHOULD be selected for treatment based on HER2 protein overexpression or HER2 gene amplification in tumor specimens detected by U.S. Food and Drug Administration–approved tests specific for breast cancer.

The initial dose of pertuzumab is 840 mg via a 60-minute infusion followed every 3 weeks by a dose of 420 mg via a 30- to 60-minute infusion. When given with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg via a 90-minute infusion followed every 3 weeks by a dose of 6 mg/kg via an infusion over 30 to 90 minutes. Pertuzumab should be administered in combination with trastuzumab 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 as given in the APHINITY trial; details of these regimens are provided in the product labeling. Pertuzumab and trastuzumab should start on day 1 of the first taxane-containing cycle.

For delayed or missed doses, the 420-mg dose should be administered if the time between two sequential infusions is less than 6 weeks; if the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg should be readministered and followed every 3 weeks by a dose of 420 mg. Pertuzumab should be discontinued if trastuzumab is discontinued. Dose reductions are not recommended for pertuzumab. Relevant prescribing information should be consulted for chemotherapy dose modifications.

Among patients receiving anthracycline-based chemotherapy, a left-ventricular ejection fraction (LVEF) of at least 50% is required after completion of anthracyclines before starting pertuzumab and trastuzumab. Pertuzumab and trastuzumab should be withheld for at least 3 weeks for LVEF < 50% with a fall of ≥ 10% points below the pretreatment value. Treatment may be resumed if LVEF has increased to ≥ 50% or < 10% points below the pretreatment value. Treatment should be discontinued for confirmed clinically significant decrease in left-ventricular function.

The infusion rate of pertuzumab should be slowed or interrupted in patients developing an infusion-related reaction. The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction.

Safety Profile

IN THE APHINITY trial, the most common adverse events of any grade in the pertuzumab group were diarrhea (71% vs 45% in placebo group), nausea (69% vs 65%), alopecia (67% vs 67%), fatigue (49% vs 44%), peripheral neuropathy (33% vs 32%), and vomiting (32% vs 30%). The most common grade 3 or 4 adverse events in the pertuzumab group were neutropenia (16% vs 16%), febrile neutropenia (12% vs 11%), diarrhea (10% vs 4%), neutrophil count decreased (10% vs 10%), and anemia (7% vs 5%).

The incidence of diarrhea of any grade was higher when chemotherapy was administered with targeted therapy (61% in the pertuzumab group vs 34% in the placebo group) and was higher when administered with non–anthracycline-based therapy (85% vs 62%) than with anthracycline-based therapy (67% vs 41%). The incidence of diarrhea during the period that targeted therapy was administered without chemotherapy was 18% in the pertuzumab group vs 9% in the placebo group. The median duration of any-grade diarrhea was 8 days in the pertuzumab group vs 6 days in the placebo group. The median duration of grade ≥ 3 diarrhea was 20 days vs 8 days. Hospitalization for diarrhea was required in 2.4% vs 0.7% of patients.

Adverse events led to discontinuation of any study drug in 13% vs 12% of patients, with pertuzumab and placebo being discontinued in 7% vs 6%. The most common adverse events (> 0.5%) resulting in discontinuation of any study drug were decreased ejection fraction, peripheral neuropathy, diarrhea, and cardiac failure.

Pertuzumab carries a boxed warning for left-ventricular dysfunction and embryofetal toxicity. Pertuzumab can result in subclinical and clinical cardiac failure, manifesting as decreased LVEF and congestive heart failure. Cardiac function must be monitored prior to and during pertuzumab treatment. Patients should be advised of embryofetal risk and the need for effective contraception prior to starting pertuzumab.

Pertuzumab also has warnings/precautions for infusion-related reactions and hypersensitivity reactions/anaphylaxis. The agent is contraindicated in patients with known hypersensitivity to pertuzumab or any of its excipients. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm. Accessed July 6, 2018.

2. Perjeta (pertuzumab) injection prescribing information, Genentech, Inc, December, 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/ label/2017/125409s113s118lbl.pdf. Accessed July 6, 2018.

3. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.


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