In the phase III trial, adjuvant treatment with pertuzumab, trastuzumab, and chemotherapy demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo. This represented an 18% reduction in the risk of developing invasive disease or death (HR, 0.82, 95% CI, 0.67-1.00, P = .047). The 4-year iDFS rates were 92.3% versus 90.6%, respectively.
The FDA's decision also transitioned an accelerated approval granted to pertuzumab in September 2013 to a full regulatory approval for use of the agent in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early breast cancer. Those receiving the pertuzumab regimen in the neoadjuvant space can effectively continue both HER2-blocking agents following surgery for a full year of treatment.
“The goal of treating breast cancer early is to provide people with the best chance for a cure. While we come closer to this goal with each advance, many people still have a recurrence and progress to the metastatic stage,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, said in a statement. “Today’s approval of Perjeta means people with HER2-positive early breast cancer at high risk of recurrence have a new, clinically meaningful treatment option to reduce the chances of their disease returning.”
The phase III double-blind, placebo-controlled APHINITY trial randomized 4805 patients with operable HER2+ early (T1-3) breast cancer in a 1:1 ratio to adjuvant treatment with trastuzumab plus chemotherapy (anthracycline or non-anthracycline-containing regimen) with pertuzumab (n = 2400) or placebo (n = 2404). Patients had undergone mastectomy or lumpectomy. Overall, 63% of the participants had node-positive disease and 36% had HR-negative disease.
The pertuzumab arm received 6 to 8 cycles of chemotherapy with pertuzumab and trastuzumab, followed by pertuzumab and trastuzumab alone every 3 weeks for a total of 1 year of therapy. The control arm received the same treatment schedule, with placebo replacing pertuzumab.
At the end of adjuvant chemotherapy, patients could start receiving radiotherapy and/or endocrine therapy. The primary endpoint was iDFS, with secondary endpoints including cardiac and overall safety, overall survival, disease-free survival, and health-related quality of life.
The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. At 3 years, the iDFS rate for patients with node-positive disease was 92.0% with pertuzumab versus 90.2% with standard therapy (HR, 0.77; 95% CI, 0.62-0.96; P = .019). At 4 years, the rates were 89.9% and 86.7%, respectively.
For participants with hormone receptor (HR)–negative disease, the 3-year iDFS rate with pertuzumab was 92.8% compared with 91.2% in the control group (HR, 0.76; 95% CI, 0.56-1.04; P = .085). At 4 years, the rates were 91.0% and 88.7%, respectively.
The number of patients needed to treat to achieve benefit was 112 for the study overall, 63 in the HR-negative subgroup, and 56 in the node-positive subgroup.
The addition of pertuzumab did not significantly increase cardiotoxicity. The primary cardiac endpoint was heart failure, defined as New York Heart Association class III/IV failure plus a drop in left ventricular ejection fraction (≥10% from baseline and to <50%), or cardiac death. Primary cardiac events were reported in 17 patients (0.7%) in the pertuzumab-containing arm versus 8 participants in the standard therapy group (0.3%). The primary cardiac endpoint also included cardiac death, and the 17 and 8 primary events includes the two cardiac deaths in each arm.
Diarrhea of grade ≥3 severity was more common with the pertuzumab-containing therapy, affecting 9.8% of patients in the safety analysis versus 3.7% of those who received standard therapy. The incidence of diarrhea occurred predominantly during chemotherapy and more frequently among patients who were administered TCH.