In the phase III APHINITY trial, pertuzumab with trastuzumab plus chemotherapy demonstrated a 0.9% improvement in overall survival and continued to reduce the risk of disease recurrence in patients with HER2-positive early breast cancer in the adjuvant setting, according to a 6-year analysis of the phase III APHINITY trial presented at the 2019 San Antonio Breast Cancer Symposium.
Martine Piccart, MD, PhD
In the phase III APHINITY trial, 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 in the adjuvant setting, 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.2
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 = .045).3The 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-anthracyclinecontaining 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.
In the intent-to-treat population, results from the updated descriptive analysis showed that the iDFS rate at 6 years was 90.6% with trastuzumab/chemotherapy plus pertuzumab and 87.8% with placebo (HR, 0.76; 95% CI, 0.64-0.91). The absolute benefit rate was 2.8% (1.0-4.6).
The total number of patients with an iDFS event was 221 (9.2%) in the pertuzumab arm and 287 (11.9%) in the placebo arm. A total 5.9% and 7.7% of patients experienced distant recurrence in the pertuzumab and placebo arms, respectively, and 2.0% of patients in each arm had central nervous system metastases. Locoregional breast cancer recurrence was reported in 1.2% of those on pertuzumab and 2.0% of those on placebo. Moreover, contralateral invasive breast cancer recurrence was reported in 0.5% and 0.6% of patients, respectively, and death without a prior event occurred in 1.6% of those on both arms.
When stratified by nodal status, a clinical benefit was observed with the addition of pertuzumab in the iDFS analysis. Here, the 6-year IDFS rate was 87.9% in the pertuzumab arm and 83.4% in the placebo arm (unstratified HR, 0.72; 95% CI, 0.59-0.87), and there was an absolute benefit rate of 4.5% (95% CI, 1.9-7.1). For those with node-negative disease, the 6-year iDFS results were comparable at 95.0% and 94.9%, respectively (unstratified HR, 1.02; 95% CI, 0.69-1.53). The absolute benefit rate was 0.1% (95% CI, 2.0-2.2).
“I think we can say that the clinical benefit of pertuzumab in HER2-positive early breast cancer is triumphed in early breast cancer patients, but no benefit can be claimed to the node-negative population,” noted Piccart.
Additionally, an iDFS benefit was also observed with pertuzumab, regardless of HR status. For patients with HR-positive disease, the 6-year iDFS was 91.2% with the pertuzumab regimen and 88.2% with placebo (unstratified HR, 0.73; 95% CI, 0.59-0.92), with an absolute benefit rate of 3.0% (95% CI, 0.8-5.2). For those with HR-negative disease, these rates were 89.5% and 87.0%, respectively (unstratified HR, 0.83; 95% CI, 0.63-1.10) and the absolute benefit rate was 2.5% (95% CI, -0.7-5.6).
Regarding safety, no new cardiac issues emerged. Primary cardiac events occurred in 18 patients (0.8%) on the pertuzumab arm and 8 patients (0.3%) in the placebo group. Two cardiac deaths were reported on each arm.
“One additional cardiac event was reported in the pertuzumab arm, and 1 additional patient in each arm had a secondary cardiac event,” Piccart said. “What is important to remember is that the rate of the severe cardiac events is below 1% in the 2 groups.”
Secondary cardiac events, which were asymptomatic or mildly symptomatic (NYHA class II) ejection fraction drop ≥10% from baseline <50%, were similar between the 2 arms, occurring in 65 (2.7%) and 68 (2.8%) patients, respectively.
The third interim OS analysis will occur in 2.5 years, and a definitive OS analysis will occur after 640 deaths, Piccart concluded.