In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
In June 2012, pertuzumab (Perjeta) was approved for use in combination with trastuzumab (Herceptin) and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.1,2
Approval was based on a multicenter, double-blind trial in which 808 patients with HER2-positive metastatic breast cancer were randomly assigned to receive docetaxel and trastuzumab plus either pertuzumab (n = 402) or placebo (n = 406) as first-line treatment for metastatic disease.2,3 Pertuzumab was given via IV infusion at an initial dose of 840 mg followed by 420 mg every 3 weeks. Docetaxel was given at 75 mg/m2 every 3 weeks for six cycles, and the dose could be increased to 100 mg/m2 if the initial dose level was tolerated. Trastuzumab was given at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. No dose adjustments were permitted for pertuzumab or trastuzumab.
Patients who had received prior neoadjuvant or adjuvant therapy had to have a disease-free interval of more than 1 year prior to starting the study. HER2 overexpression was defined as 3+ on immunohistochemistry or a fluorescence in situ hybridization amplification ratio ≥ 2.0 on FDA-approved tests performed at a central laboratory. Treatment was continued until disease progression or unacceptable toxicity.
Patients had a median age of 54 years; 59% were white, and 78% had visceral disease. Most patients were from Europe (38%) or Asia (31%). Forty-eight percent of patients were hormone receptor–positive, 47% had received adjuvant or neoadjuvant chemotherapy, 11% had received hormonal therapy for metastatic disease, and 11% had received adjuvant or neoadjuvant trastuzumab. Among hormone receptor–positive patients, 45% had received adjuvant hormonal therapy.
Median durations of treatment were 18.1 months in the pertuzumab group and 11.8 months in the placebo group. Independently assessed progression-free survival, the primary endpoint, was significantly increased with pertuzumab, which reduced risk of progression by 38% (HR = 0.62, 95% CI = 0.51–0.75, P < .0001). Results for investigator-assessed progression-free survival were similar. Pertuzumab treatment increased median progression-free survival by 6.1 months (18.5 vs 12.4 months). A planned overall survival interim analysis performed at the time of the progression-free survival analysis showed a strong trend for improvement with pertuzumab treatment (HR = 0.64, 95% CI = 0.47– 0.88, P = .0053), but the HR and P value for this analysis did not meet the predefined stopping boundary (HR ≤ 0.603, P ≤ .0012).
How It Works
Pertuzumab blocks the extracellular dimerization domain (subdomain II) of HER2, inhibiting ligand-dependent heterodimerization of HER2 with other HER family members (eg, EGFR, HER3, and HER4) and thus inhibiting ligand-initiated intracellular signaling through the MAPK and PI3K pathways. Inhibition of these pathways can result in cell growth arrest and apoptosis, respectively. Pertuzumab also mediates antibody-dependent cell-mediated cytotoxicity. Pertuzumab alone inhibits proliferation of human tumor cells, but the combination of pertuzumab and trastuzumab has been shown to significantly increase antitumor activity in HER2-overexpressing xenografts.
How It Is Given
The initial dose of pertuzumab is 840 mg given as a 60-minute IV infusion, followed every 3 weeks by a dose of 420 mg given as a 30- to 60-minute infusion. When administered with pertuzumab, trastuzumab should be given at an initial dose of 8 mg/kg via 90-minute infusion followed by 6 mg/kg via 30- to 90-minute infusion every 3 weeks, and docetaxel should be given at 75 mg/m2 every 3 weeks. The docetaxel dose can be increased to 100 mg/m2 if the initial dose is tolerated. Pertuzumab infusion should be reduced in rate or interrupted for infusion-related reactions and discontinued immediately for severe hypersensitivity reactions.
Pertuzumab and trastuzumab should be withheld for 3 weeks in patients with a reduction in left-ventricular ejection fraction to < 40% or a ≥ 10% absolute reduction in left-ventricular ejection fraction to 40% to 45%. Pertuzumab can be resumed if left-ventricular ejection fraction recovers to > 45% or to 40% to 45% in patients with an absolute reduction of < 10%. Discontinuation of pertuzumab and trastuzumab should be strongly considered if such recovery does not occur within 3 weeks. Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued. Dose reductions of pertuzumab are not recommended.
In the pivotal clinical trial,2,3 adverse events led to discontinuation of all study treatment in 6.1% of pertuzumab patients and 5.3% of placebo patients, with docetaxel alone being discontinued in 23.6% and 23.2%, respectively. The most common adverse events (> 30%) in pertuzumab patients were neutropenia (53% vs 50% in placebo group), nausea (42% in both groups), fatigue (38% vs 37%), rash (34% vs 24%), and peripheral neuropathy (32% vs 34%).
The most common grade 3 or 4 adverse events (> 2%) were neutropenia (49% vs 46%), febrile neutropenia (13% vs 7%), leukopenia (12% vs 15%), diarrhea (8% vs 5%), peripheral neuropathy (3.2% vs 2.0%), anemia (2.5% vs 3.5%), asthenia (2.5% vs 1.5%), and fatigue (2.2% vs 3.3%). Asian patients in both treatment groups had a higher incidence of febrile neutropenia compared with patients of other races, with the incidence among Asian patients being higher in pertuzumab recipients (26% vs 12%).
Pertuzumab was not associated with an increase in the incidence of symptomatic left-ventricular systolic dysfunction or reductions in left-ventricular ejection fraction compared with placebo. The incidence of left-ventricular dysfunction was 4.4% in the pertuzumab group vs 8.3% in the placebo group.
Other significant adverse events observed in pertuzumab patients included infusion-associated reactions, hypersensitivity reactions (10.1% vs 8.6%), and anaphylaxis (4 vs 2 patients). Pertuzumab infusion-related reactions were assessed by administering the initial pertuzumab dose the day before trastuzumab/paclitaxel. Reactions occurred in 13.0% of pertuzumab patients vs 9.8% of placebo patients, with the most common reactions being pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. Grade 3 or 4 infusion reactions occurred in < 1% of patients.
Pertuzumab carries a boxed warning for embryo-fetal toxicity and birth defects, based on observations of oligohydramnios, delayed renal development, and embryo-fetal death in animal studies. Patients should be advised of these risks and the need for effective contraception prior to starting pertuzumab. Pertuzumab carries additional warnings/precautions for left-ventricular toxicity, infusion-related reactions, and HER2 testing. HER2 testing should be performed using FDA-approved tests by laboratories with demonstrated proficiency in testing. ■
1. U.S. Food and Drug Administration: Pertuzumab. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm307592.htm. Accessed June 25, 2012.
2. PERJETATM (pertuzumab) injection prescribing information, Genentech, Inc, June, 2012. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/125409lbl.pdf. Accessed June 25, 2012.
3. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.