FDA Approves Pertuzumab Regimen as Adjuvant Treatment for HER2+ Breast Cancer

The FDA has approved the combination of pertuzumab (Perjeta), trastuzumab (Herceptin) and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence. The approval is based on findings from the APHINITY trial.

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.

von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). J Clin Oncol. 2017;35(suppl; abstr LBA500).