A supplemental biologics license application for pertuzumab (Perjeta) for use in combination with trastuzumab (Herceptin) and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer has been granted a priority review by the FDA.
Sandra Horning, MD
A supplemental biologics license application (sBLA) for pertuzumab (Perjeta) for use in combination with trastuzumab (Herceptin) and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer has been granted a priority review by the FDA. The sBLA is based on data from the phase III APHINITY trial.
Results from the trial demonstrated that patients who received adjuvant pertuzumab along with trastuzumab plus chemotherapy had an invasive disease-free survival (iDFS) rate of 94.1% after 3 years’ follow-up versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.81; 95% CI, 0.66-1.00). At 4 years’ follow-up, the rates were 92.3% versus 90.6%, respectively.
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.
APHINITY is also the confirmatory trial for the September 2013 accelerated approval of pertuzumab for use in combination with trastuzumab and docetaxel as a neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer. With the sBLA, Genentech, the manufacturer of pertuzumab, is also seeking to convert the accelerated neoadjuvant approval into a full approval.
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 or without pertuzumab. 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 study met its primary endpoint by exceeding a preset threshold for reducing the risk of an iDFS event. The pertuzumab-containing regimen reduced the risk of developing invasive breast cancer by 19%. After a median follow-up of 45.4 months, 7.1% (n = 171) in the pertuzumab group had developed invasive breast cancer, compared with 8.7% (n = 210) in the standard therapy group (HR, 0.81; 95% CI, 0.66-1.00;P= .045).
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%). Heart failure was reported in 17 patients (0.7%) in the pertuzumab-containing arm versus 8 participants in the standard therapy group (0.3%). Approximately half of the patients in each group recovered, and there were 2 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.
The priority review is based on data from the JAVELIN international development program of avelumab. In the JAVELIN solid tumor phase Ib trial, avelumab had a response rate of 16% in a cohort of patients with mUC, including 1 complete response and 6 partial responses. Under the Prescription Drug User Fee Act, the FDA will make a final approval decision on the BLA on or before August 27, 2017.
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).
“We are pleased to receive priority review for the Perjeta-based regimen for the adjuvant treatment of HER2-positive early breast cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. “The goal of treating breast cancer early is to provide people with the best chance for a cure. Despite advances in the treatment of this disease, many people treated with the current standard of care still see their cancer return.”