Follow-Up Data From Second OS Analysis of APHINITY Reveal Growing Impact of Pertuzumab Within Patient Subgroups

Overall survival was shown to be greater but insignificant in patients administered pertuzumab compared with placebo, while subgroups of lymph node–positive and hormone receptor–negative patients were distinguished as major beneficiaries, according to the results of the second interim analysis of APHINITY presented at the San Antonio Breast Cancer Symposium in San Antonio, Texas.

Lead study author Martine Piccart, MD, PhD, director of the Medicine Department at Jules Bordet Institute, discussed the results of the second interim overall survival (OS) analysis of APHINITY, a randomized multi-center, double-blind, placebo-controlled trial. The trial compared the effectiveness of pertuzumab and placebo, in addition to chemotherapy plus trastuzumab, as adjuvant therapy in patients with operable HER2-positive early breast cancer.

Study results presented Wednesday at the 2019 San Antonio Breast Cancer Symposium (SABCS) expanded on the results of the first interim OS analysis. This initial OS study showed that for the 4805 patients included in the trial, a modest difference in benefit of adjuvant pertuzumab was found compared to placebo (stratified hazard ratio (HR) = 0.81; 95% CI, 0.66-1.00; P = .045), where 171 (7.1%) events of relapse occurred in 2400 patients administered pertuzumab and 210 (8.7%) events occurred for those administered placebo (n=2404) after a follow-up of 45.4 months.

The primary endpoint of invasive disease-free survival (IDFS) accounted for the statistics derived from the analyses.

These results were similarly shown in higher risk patients as well, in which the node-positive subgroup of patients administered pertuzumab compared to placebo exhibited an unstratified HR of 0.77 (95% CI, 0.62-0.96; P = .019) and the hormone receptor-negative subgroup of patients with HER2-positive early breast cancer showed an unstratified HR of 0.76 (95% CI, 0.56-1.04; P = .085).

The second interim OS analysis was conducted 2.5 years after the first, with a median follow-up time of 74.1 months:

  • P-value of .0012 required for statistical significance of this interim OS analysis
  • 272 deaths occurred (103 more than at the first analysis) which attributed to 42.5% of the 640 deaths needed for definitive OS analysis
  • Updated descriptive analyses of IDFS and cardiac safety performed, with 508 patients reporting an IDFS event (127 more than at the first analysis)

Results from the analysis showed insignificant OS statistics between pertuzumab and placebo in addition to adjuvant therapy. However, analyses on IDFS represented a 2.8% difference in event free survival (EFS) rate from pertuzumab after 6 years, with further benefit found in patients within the node-positive subgroup (difference in EFS rate = 4.5%). These benefits were not seen in the node-negative cohort.

For patients within the negative and positive hormone receptor cohorts, clinical benefits were found in both groups (hormone receptor-negative HR = 0.83; 95% CI, 0.63-1.10; hormone receptor-positive HR = 0.73; 95% CI, 0.59-0.92), which was unexpected considering the first analysis suggested that patients with hormone receptor-negative disease were the major beneficiary.

The benefits of pertuzumab in addition to adjuvant therapy are not to be taken at face value, however, as Piccart emphasized the importance of balancing these benefits against potential harm. “The great news is that no new cardiac safety issues have emerged with 2.5 more years of follow-up,” said Piccart.

Conclusions from the study showed that fewer deaths were seen in pertuzumab compared to placebo after follow-up, but 6-year OS statistics of 94.8% for pertuzumab versus 93.9% for placebo had an insignificant 0.9% difference. “A main limitation of APHINITY is that although we have seen fewer deaths among the patients who received treatment with pertuzumab, our data is still immature and have not shown definitive improvement in overall survival. A longer follow-up is needed to see any significant survival benefit,” said Piccart

In addressing the lack of substantial difference seen in the statistics, Piccart stressed the importance of understanding pertuzumab’s focus as a medication seeking to cure patients. In fact, Piccart highlighted that the ESMO Magnitude of Clinical Benefit scale would rate the benefit derived from pertuzumab (4.5%) as highly significant in the curative setting.

“We have documented reversibility of severe cardiac events already in 50% of patients, but we need to follow them longer to find out if they are all going to recover,” said Piccart. A third interim OS analysis was suggested, which will allow further surveillance of clinical benefits derived from pertuzumab.

“Ongoing research using the biological specimens and clinical data collected from this very large

study would help in refining the characteristics of the patients who will most benefit from

pertuzumab, particularly among those considered to be at lower risk of recurrence only on the basis of absence of lymph node disease,” said Piccart


Piccart M, Procter M, Fumagalli D, et al. Interim overall survival analysis of APHINITY: a randomized multi-center, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Presented at the San Antonio Breast Cancer Symposium, San Antonio, Texas; December 10-14.