Martine Piccart, MD, PhD
The adjuvant combination of pertuzumab (Perjeta) with trastuzumab (Herceptin) plus chemotherapy demonstrated a 0.9% improvement in overall survival (OS) and continued to reduce the risk of disease recurrence in patients with HER2-positive early breast cancer, according to a 6-year analysis of the phase III APHINITY trial presented at the 2019 San Antonio Breast Cancer Symposium.1
At 6 years, the OS rate was 94.8% with the pertuzumab regimen compared with 93.9% with placebo, translating to a 15% reduction in the risk of death; this was not found to be statistically significant as per a pre-determined P
value of .0012 (HR, 0.85; 95% CI, 0.67-1.07; P
= .170). The survival data currently remain immature, said Martine Piccart, MD, PhD, cofounder of Breast International Group and Scientific Director at the Institut Jules Bordet in Brussels, Belgium.
“We have seen fewer deaths in the pertuzumab arm compared with the placebo arm,” Piccart said in a press briefing during the conference. “The difference of 0.9% is not statistically significant, and further follow-up will be very important to determine whether there is a survival benefit after treatment with pertuzumab in these patients with early HER2-positive breast cancer. A third interim OS analysis that is also time-driven is planned for 2.5 years from now.”
In December 2017, the FDA approved pertuzumab in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence, based on invasive disease-free survival (iDFS) findings from the APHINITY trial.
The primary results, which were at a median follow-up of 45.4 months, showed that adjuvant treatment with pertuzumab, trastuzumab, and chemotherapy demonstrated a 3-year iDFS rate of 94.1% versus 93.2% in those who received trastuzumab plus chemotherapy and placebo, leading to an 18% reduction in the risk of developing invasive disease or death (HR, 0.81; 95% CI, 0.66-1.00, P
The 4-year iDFS rates were 92.3% versus 90.6%, respectively.
In the phase III double-blind, placebo-controlled APHINITY trial, investigators randomized patients with operable HER2-positive 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 = 2405). All patients had undergone mastectomy or lumpectomy.
Patients were stratified by nodal status, hormone receptor (HR) status, chemotherapy regimen, geographic region, and Protocol version (A vs B). 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 begin receiving radiotherapy and/or endocrine therapy.
The primary end point of the trial was iDFS, with secondary endpoints including iDFS with second primary non-breast primary cancers included, disease-free survival, OS, recurrence-free survival (RFI), distant recurrence-free interval (DRFI), cardiac and overall safety, and health-related quality of life.
Results of the primary analysis also showed that iDFS benefits were more pronounced among higher-risk subgroups. 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. Patients with node-negative disease had 3-year iDFS rates of 97.5% and 98.4% in the pertuzumab and placebo groups, respectively (HR, 1.13; 95% CI, 0.68-1.86).
For those with HR-negative disease, the 3-year iDFS rate with pertuzumab was 92.8% versus 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. In the HR-positive subgroup, the iDFS rate was 94.8% with pertuzumab and 94.4% with placebo (HR, 0.86; 95% CI, 0.66-1.13).
The second interim OS analysis, which was pre-planned and time-driven, occurred 2.5 years from the primary analysis in which 50% of target events were anticipated. A P
value of .0012 was required for statistical significance for this analysis.
At a median follow-up of 74.1 months, 272 deaths were reported, which was 103 more than what had been reported at the primary analysis; this is 42.5% of the 640 deaths that are needed for a definitive OS analysis. There were 125 events in the pertuzumab arm and 147 in the placebo group.
Updated descriptive analyses were also performed and focused on iDFS, which now comprises 508 patients with an iDFS event, as well as cardiac safety.