Adjuvant pertuzumab delivers survival gain in HER2+ EBC

The APHINITY trial of adding pertuzumab to adjuvant therapy for early HER2+ breast cancer turns in a significant overall survival (OS) improvement, with results presented at ESMO Breast Cancer 2025 concluding a phase III trial spanning over a decade.

“In this prespecified final OS analysis with a median follow-up of 11.3 years, a statistically significant OS improvement was observed by adding pertuzumab to trastuzumab and chemotherapy,” said Professor Sibylle Loibl from the German Breast Group Forschungs GmbH, Neu-Isenburg in Hesse, Germany. “These final results with long-term follow-up further support the benefit of pertuzumab in the early breast cancer (EBC) setting.”

This final analysis of OS, one of the secondary endpoints, culminated after continuing through three interim OS analyses, with data covering an additional median follow-up of 7.5 years since the primary report. [ESMO Breast Cancer 2025, abstract LBA1]

“At 10 years, the OS rate was 91.6 percent in the pertuzumab arm vs 89.8 percent in the placebo arm, with an absolute difference of 1.8 percentage points (95 percent confidence interval [CI], 0.03–3.47),” said Loibl.

In relative terms, receiving pertuzumab instead of placebo for 1 year alongside adjuvant trastuzumab and chemotherapy after excision reduced the risk of death by 17 percent (adjusted hazard ratio [HR], 0.83, 95 percent CI, 0.69–1.00; p=0.0441 vs p≤0.0496 required for statistical significance).

Node-positive disease

APHINITY was a multinational, two-arm, randomized, double-blind, placebo-controlled trial (n=4,805) of patients with HER2+ operable breast cancer, either with node-positive (N+) disease or high-risk node-negative (N−) disease. Participants (mean age 51.5 years, 99.8 percent female, 64.2 percent HR+) were randomized to receive either chemotherapy and 1-year treatment with trastuzumab plus pertuzumab or chemotherapy and 1-year treatment with trastuzumab plus placebo. The primary endpoint was invasive disease-free survival (iDFS) at 3 years. [N Engl J Med 2017;377:122-131]

The overall OS benefit was mainly driven by that for N+ participants (62.6 percent across both arms). In the N+ subgroup, the 10-year OS rate was 89.6 percent with the pertuzumab combination vs 86.9 percent with the placebo combination. The absolute benefit of 2.7 percentage points (95 percent CI, 0.27–5.09) corresponded to a 21-percent lower risk of death (unadjusted HR, 0.79, 95 percent CI, 0.64–0.97).

On the other hand, the addition of pertuzumab did not impact overall survival (OS) in N− participants, as few deaths occurred in both treatment arms up to the final analysis, limited to around 5 percent (10-year OS rate, 94.9 percent vs 94.6 percent; absolute difference, 0.2 percentage points, 95 percent CI, −1.92 to 2.40).

This was not unexpected, as earlier iDFS results also showed a favouring of pertuzumab over placebo in the N+ cohort but not in the N− cohort, which remained consistent with the current updated descriptive iDFS analysis.

Overall, the risk of an iDFS event was lower with pertuzumab vs placebo by 21 percent (adjusted HR, 0.79, 95 percent CI, 0.68–0.92) and absolutely by 3.4 percentage points at 10 years (95 percent CI, 1.27–5.42). When separating the population by nodal status, only the N+ cohort observed an iDFS benefit (HR, 0.74, 95 percent CI, 0.62–0.88), while the N− cohort did not (HR, 1.01, 95 percent CI, 0.74–1.38).

“The iDFS benefit was maintained and remained clinically meaningful in the N+ subgroup, while no benefit was observed in the N− subgroup; the same was true for the OS analysis,” said Loibl.

Importantly, within the N+ subgroup, HR+ patients derived “the same, if not greater” iDFS benefit from pertuzumab relative to HR− patients (HR, 0.68 and 0.83, respectively), as Loibl emphasized, which justifies dual HER2 blockade in the adjuvant setting for HR+/HER2+ EBC if it is N+.

Should we wait to see OS improvements?

These “landmark results”, as moderator Professor Nicholas Turner from the Institute of Cancer Research and The Royal Marsden in London, UK, described, spurred a discussion about another important issue that medical oncologists caring for breast cancer patients are facing.

“We should not wait for OS data from adjuvant trials to mature before making drug approval decisions,” said discussant Dr Javier Cortés from the International Breast Cancer Center in Barcelona, Catalonia, Spain. “Delaying approval may result in patients progressing to metastatic disease, and many patients will die if we are unable to use a drug because we're waiting for approval based on OS data.”

Indeed, prior research had evaluated whether DFS with adjuvant treatment can serve as a surrogate for OS in HER2+ EBC. The “strong” association between the two in patient-level modelling (correlation coefficient, 0.90, 95 percent CI, 0.89–0.90) warrants the continued use of DFS as a surrogate for OS in clinical trials. [Lancet Oncol 2019;20:361-370]

“I think there is something in between. If we wait for OS to mature, we must always keep in mind that patients may die from other competing causes rather than from breast cancer itself,” commented Loibl. “I think distant DFS is the compromise because patients with distant metastasis usually die from the disease. With iDFS as the primary endpoint like APHINITY, I think we need to wait longer to see it as surrogacy for OS.”