This article is more than 5 years old. Information may no longer be current.
Two new therapies offer options for treatment of HER-2–positive breast cancer
Click Here to Manage Email Alerts
HER-2–positive breast cancer is an aggressive form of the disease, with the potential to carry a poor prognosis and decreased OS.
With the advent of trastuzumab-based therapy, treatment of HER-2–positive breast cancer has changed dramatically for the better. However, treatment of HER-2–positive metastatic breast cancer (mBC) still remains a challenge.
Until recently, trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) were the only options available for treatment of HER-2–positive mBC. Within the past year, the FDA approved two new therapies. Pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech), each of which has a unique mechanism of action and indication for use, are welcomed additions to the treatment vault.
Mechanisms of action
The FDA approved pertuzumab in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER-2–positive mBC who have not received prior anti-HER–2 therapy or chemotherapy for metastatic disease.
Pertuzumab is an anti-HER–2 humanized monoclonal antibody that inhibits receptor dimerization, a mechanism of action that is complementary to that of trastuzumab. It binds at a different epitope of the HER-2 extracellular domain (subdomain II) than that of trastuzumab (subdomain IV). Pertuzumab thereby blocks ligand-dependent heterodimerization of HER-2 with other HER family members.
The FDA approved ado-trastuzumab emtansine, formerly known as T-DM1, in February for the treatment of patients with HER-2–positive mBC who previously received trastuzumab and a taxane, separately or in combination. Patients should have received either prior therapy for mBC or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Ado-trastuzumab emtansine is an antibody-drug conjugate that incorporates the HER-2–targeted antitumor properties of trastuzumab with the cytotoxic activity of microtubule-inhibitory agent DM1. The antibody and cytotoxic agent are conjugated by a stable linker. Upon binding to subdomain IV of the HER-2 receptor, it undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM-1–containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.
Clinical activity
The phase 3 trial that led to approval of pertuzumab was a randomized, double blind, multicenter, placebo-controlled trial that included 808 patients with HER-2–positive mBC who had not received chemotherapy or biologic therapy. Researchers randomly assigned patients in a 1:1 ratio to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until time of disease progression or the development of adverse effects that could not be effectively managed.
Median PFS was significantly improved with the addition of pertuzumab (18.5 months vs. 12.4 months; P<.001).
Median OS at the time of trial publication showed a strong trend in favor of the pertuzumab group. The subsequent secondary interim OS analysis showed a statistically significant improvement of OS in favor of the pertuzumab group (HR=0.66; 95% CI, 0.52-0.84) and is considered the confirmatory OS analysis. Median OS was 37.6 months in the control arm and has not yet been reached in the pertuzumab arm. Given this benefit, patients in the control arm have been offered treatment with pertuzumab.
The phase 3 trial that led to approval of ado-trastuzumab emtansine was a randomized, open-label, multicenter trial that included 991 patients with HER-2–positive, unresectable, locally advanced or mBC who were previously treated with a taxane and trastuzumab.
Patients were eligible if progression during or after most recent treatment for locally advanced or mBC was documented or if patients had recurrence within 6 months of treatment for early-stage breast cancer. Study participants were randomly assigned in a 1:1 ratio to receive ado-trastuzumab emtansine 3.6 mg/kg by IV infusion every 21 days or lapatinib 1,250 mg orally daily plus capecitabine 1,000 mg/m2 orally every 12 hours on days 1 through 14 of a 21-day cycle.
Ado-trastuzumab emtansine significantly improved PFS compared with the control arm (9.6 months vs. 6.4 months; P<.001). Patients in the study group also demonstrated significantly longer OS (30.9 months vs. 25.1 months, P<.001) and a significantly higher objective response rate (43.6% vs. 30.8%, P<.001).
Toxicities
Febrile neutropenia and diarrhea were the most commonly reported grade 3/4 toxicities in the pertuzumab group. Grade 3/4 febrile neutropenia occurred in 13.8% of patients and grade 3/4 diarrhea occurred in 7.6% of patients.
The most common adverse events associated with pertuzumab in combination with trastuzumab and docetaxel were diarrhea (66.8%), alopecia (60.9%), neutropenia (52.8%), nausea (42.3%), fatigue (37.6%) and rash (33.7%).
Per the prescriber’s information, peripheral neuropathy (32.4%) also was common. Rates of infusion-related reactions were 13% when pertuzumab was administered alone on day 1 of cycle 1 and 9.8% in the control group. Less than 1% was grade 3/4.
The overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the pertuzumab group and 9.1% in the control group.
Left ventricular systolic dysfunction (LVSD) occurred more in the control group than in the pertuzumab group (8.3% vs. 4.4%), as did symptomatic LVSD (1.8% vs. 1%).
Most deaths in both groups were attributed to disease progression. Among deaths due to adverse events, infections were the most common cause.
Thrombocytopenia and elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were the most commonly reported grade 3/4 toxicities with ado-trastuzumab emtansine.
Grade 3/4 thrombocytopenia occurred in 12.9% of patients treated with ado-trastuzumab emtansine. Grade 3/4 AST occurred in 4.3% of patients and ALT elevations occurred in 2.9% of patients. Overall incidence of bleeding was higher in the ado-trastuzumab emtansine group (29.8% vs. 15.8%). Monitoring of AST/ALT and bilirubin is recommended before each cycle.
The most common adverse reactions (all grades) observed were nausea (39.8%), fatigue (36.3%), musculoskeletal pain (36.1%), thrombocytopenia (31.2%), increased transaminases (28.8%), headache (28.2%), constipation (26.5%), diarrhea (24.1%), epistaxis (22.5%) and peripheral neuropathy (21.2%).
Source: Kadcyla [package insert]. South San Francisco, CA: Genentech Inc.; May 2013.
Three patients in the phase 3 study had left ventricular ejection fraction decreases to <40% from baseline. Dose adjustments for specific toxicities are listed in Table 1. Ado-trastuzumab emtansine should be held permanently for patients diagnosed with interstitial lung disease or pneumonitis.
Incidence of peripheral neuropathy was not reported in the phase 3 trial, but this is a concern due to the antimicrotubule activity of DM1. Per the prescriber’s information, the incidence of peripheral neuropathy was 21.2% (all grades); however, grade 3 peripheral neuropathy was reported in 2.2% of patients. If a patient experiences grade 3/4 neuropathy, the drug should be held until resolution to grade ≤2.
Dosing and administration
Pertuzumab requires a flat loading dose of 840 mg, followed by 420 mg every 3 weeks administered IV. The first dose should be administered over 60 minutes, and subsequent doses administered over 30 minutes if the first infusion is well tolerated. The dose should be diluted into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. The infusion solution may be stored in the refrigerator for up to 24 hours.
Pertuzumab should not be diluted in or administered through a line containing dextrose. For delayed or missed doses, if the time between two sequential infusions is 6 weeks or more, the loading dose of 840 mg should be re-administered as a 60-minute infusion, followed by the 420-mg dose every 3 weeks. Dose reductions are not recommended for pertuzumab; however, pertuzumab should be withheld if trastuzumab is withheld or discontinued.
When administered with pertuzumab, trastuzumab and docetaxel should be given IV every 3 weeks. The recommended trastuzumab dose is 8 mg/kg, followed by 6 mg/kg, and the recommended docetaxel dose is 75 mg/m2. The docetaxel dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.
The recommended dose of ado-trastuzumab emtansine is 3.6 mg/kg administered intravenously every 21 days. The first dose should be administered over 90 minutes, with subsequent doses administered over 30 minutes if the first infusion is well tolerated. The dose should be diluted in 250 mL of 0.9% sodium chloride and infused with a 0.22-micron in-line polyethersulfone filter. The infusion solution may be stored in the refrigerator for up to 24 hours.
It is important to note that trastuzumab and ado-trastuzumab emtansine are not interchangeable, and the drug name should be clearly indicated on the label, as well as in the patient’s chart, to avoid confusion. If a dose reduction is made, the dose of ado-trastuzumab emtansine should not be re-escalated (see Table 2).
Conclusion
Pertuzumab and ado-trastuzumab emtansine are the newest anti-HER–2 medications for the treatment of HER-2–positive mBC. These drugs have different indications, dosing strategies and toxicity profiles.
Pertuzumab is a monoclonal antibody currently approved in combination with trastuzumab and docetaxel for first-line treatment of HER-2–positive mBC, whereas ado-trastuzumab emtansine is an antibody-drug conjugate most recently approved for treatment of HER-2–positive mBC after treatment with a taxane and trastuzumab.
The costs associated with treatment are significant (see Table 3). Patient assistance is available through the manufacturer and may aid in offsetting some of the cost to the patient.
References:
Baselga J. N Engl J Med. 2012;366:109-119.
Kadcyla [package insert]. South San Francisco, CA: Genentech Inc.; May 2013.
Perjeta [package insert]. South San Francisco, CA: Genentech Inc.; June 2012.
Swain SM. Abstract # P5-18-26. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio.
Verma S. N Engl J Med. 2012;367:1783-1791.
For more information:
Neelam K. Patel, PharmD, and Bonnie Lin Boster, PharmD, BCOP, are clinical pharmacy specialists at The University of Texas MD Anderson Cancer Center. They can be reached at Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030-4009; email: nkpatel2@mdanderson.org or bboster@mdanderson.org.
Disclosure: Patel and Boster report no relevant financial disclosures.