The adjuvant combination of pertuzumab (Perjeta) with trastuzumab (Herceptin) plus chemotherapy demonstrated a modest 0.9% improvement in overall survival (OS) 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.
At the 6-year mark, 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 (HR, 0.85; 95% CI, 0.67-1.07; P = .170). This difference did not reach statistical significance based on the pre-determined P value threshold of .0012. The survival data remain immature, with only 42.5% of the target events needed for definitive analysis.
"We have seen fewer deaths in the pertuzumab arm compared with the placebo arm," said Dr. Martine Piccart, cofounder of Breast International Group and Scientific Director at the Institut Jules Bordet in Brussels, Belgium. "Further follow-up will be very important to determine whether there is a survival benefit after treatment with pertuzumab in these patients."
Significant Improvement in Disease-Free Survival
The updated analysis showed more compelling benefits in invasive disease-free survival (iDFS). At 6 years, the iDFS rate was 90.6% with the pertuzumab regimen versus 87.8% with placebo (HR, 0.76; 95% CI, 0.64-0.91), representing an absolute benefit of 2.8%.
The FDA approved the pertuzumab combination for adjuvant treatment in December 2017 based on earlier APHINITY trial results, which showed an 18% reduction in the risk of developing invasive disease or death at a median follow-up of 45.4 months.
Node Status Determines Benefit
The most significant clinical benefit was observed in patients with node-positive disease. For these higher-risk patients, the 6-year iDFS rate was 87.9% with pertuzumab versus 83.4% with placebo (unstratified HR, 0.72; 95% CI, 0.59-0.87), yielding an absolute benefit of 4.5%.
In contrast, patients with node-negative disease showed no meaningful difference between treatment arms, with 6-year iDFS rates of 95.0% and 94.9% for pertuzumab and placebo, respectively (unstratified HR, 1.02; 95% CI, 0.69-1.53).
"The clinical benefit of pertuzumab in HER2-positive early breast cancer is pronounced in node-positive breast cancer patients, but no benefit can be claimed for the node-negative population," Dr. Piccart emphasized.
Benefits Across Hormone Receptor Status
The analysis also demonstrated iDFS benefits with pertuzumab regardless of hormone receptor (HR) status:
- For HR-positive disease: 91.2% with pertuzumab versus 88.2% with placebo (unstratified HR, 0.73; 95% CI, 0.59-0.92)
- For HR-negative disease: 89.5% versus 87.0%, respectively (unstratified HR, 0.83; 95% CI, 0.63-1.10)
Trial Design and Patient Population
The phase III double-blind, placebo-controlled APHINITY trial randomized 4,805 patients with operable HER2-positive early (T1-3) breast cancer in a 1:1 ratio to receive adjuvant treatment with trastuzumab plus chemotherapy with either pertuzumab (n = 2400) or placebo (n = 2405).
All patients had undergone mastectomy or lumpectomy prior to enrollment. The study population included 63% with node-positive disease and 36% with HR-negative disease.
Treatment consisted of 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.
Detailed Recurrence Patterns
The updated analysis provided detailed information on recurrence patterns. In the pertuzumab arm, 221 patients (9.2%) experienced an iDFS event compared to 287 (11.9%) in the placebo arm. Distant recurrence occurred in 5.9% and 7.7% of patients in the pertuzumab and placebo arms, respectively.
Central nervous system metastases were reported in 2.0% of patients in each arm. Locoregional breast cancer recurrence was observed in 1.2% of those on pertuzumab and 2.0% of those on placebo. Contralateral invasive breast cancer recurrence was reported in 0.5% and 0.6% of patients, respectively.
Cardiac Safety Profile
The cardiac safety profile remained favorable with no new concerns emerging in the updated analysis. 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 in each arm.
Secondary cardiac events, defined as asymptomatic or mildly symptomatic ejection fraction drops of ≥10% from baseline to below 50%, were similar between the two arms, occurring in 65 (2.7%) and 68 (2.8%) patients, respectively.
"What is important to remember is that the rate of severe cardiac events is below 1% in both groups," Dr. Piccart noted.
Future Analyses
A third interim OS analysis is planned for 2.5 years from now, with a definitive OS analysis to occur after 640 deaths have been reported. These future analyses will provide more conclusive evidence regarding the survival benefit of adding pertuzumab to standard adjuvant therapy.
The current findings reinforce the value of pertuzumab in the adjuvant setting for patients with node-positive, HER2-positive early breast cancer, while suggesting limited benefit for those with node-negative disease. This differentiation may help clinicians better select patients who are most likely to benefit from this treatment approach.
