Adjuvant Pertuzumab Shows OS Benefit in Breast Cancer
The benefit was driven only by those with node-positive cancer, according to findings presented by Sibylle Loibl, MD, PhD, on May 15 at ESMO Breast Cancer 2025.
The results, from 11.3 years of follow-up in the final analysis from the APHINITY trial, are the first analysis to show an overall survival benefit.
'The [invasive disease-free survival] benefit was maintained, remaining clinically meaningful in the node-positive subgroup, while no benefit was observed in the node-negative subgroup,' Loibl, an associate professor of obstetrics and gynecology at the Goethe University of Frankfurt, Frankfurt, Germany, said during her presentation.
In the original trial of 4805 patients with HER2-positive operable breast cancer, 2400 patients received adjuvant pertuzumab (840 mg, then 420 mg), and 2405 received placebo, both in addition to standard adjuvant chemotherapy and 1 year of treatment with trastuzumab. The patient groups were similarly balanced in terms of nodal status, adjuvant chemotherapy regimen (with or without anthracyclines), and hormone receptor status.
In the 2017 analysis published in The New England Journal of Medicine , patients receiving pertuzumab had improved invasive disease-free survival (IDFS), but the benefit compared with placebo was seen only in those with node-positive disease. The third analysis with 8 years of follow-up in 2022 showed similar findings without any overall survival benefit seen in those receiving pertuzumab.
In this analysis, conducted 34 months after the third previously reported analysis, there were 62 additional deaths and 73 additional IDFS events, for a total of 452 deaths and 682 IDFS events since the trial's start. Total deaths in the pertuzumab arm were 205 (8.5%) compared with 247 (10.3%) in the placebo arm, for a 1.8% absolute difference in death rate (adjusted hazard ratio [aHR], 0.83; 95% CI, 0.69-1.00; P = .441).
Stratification by nodal status revealed the difference in overall survival benefit for node-positive vs node-negative disease. In node-positive patients, those receiving pertuzumab had an 89.6% survival rate compared with 86.9% in the placebo group, an absolute difference of 2.7% (unadjusted HR, 0.79; 95% CI, 0.64-0.97). In node-negative patients, however, those receiving pertuzumab had a survival rate of 94.9% compared with 94.6% with placebo (unadjusted HR, 0.99; 95% CI, 0.66-1.49).
An IDFS event occurred in 12.6% of patients receiving pertuzumab vs 15.8% receiving placebo. Distant recurrence was seen in 6.3% with pertuzumab and 8.8% with placebo, and locoregional recurrence in 1.5% with pertuzumab and 2.5% with placebo. In the pertuzumab group, IDFS was 87.2% vs 83.8% with placebo (aHR, 0.79; 95% CI, 0.68-0.92), an absolute difference of 3.4%. Again, the benefit only occurred in those with node-positive disease (HR, 0.74; 95% CI, 0.62-0.88), while patients with node-negative disease saw no benefit with pertuzumab vs placebo (HR, 1.01; 95% CI, 0.74-1.38).
IDFS events did not differ by hormone receptor (HR) status, with both node-positive HR+ (HR, 0.68) and node-positive HR− (HR, 0.83) patients seeing benefits. In the node-negative patients, neither those with HR+ (HR, 1.03) nor HR− (0.98) saw benefit with pertuzumab.
Cardiac events were similar in the pertuzumab (0.9%) and placebo (0.5%) groups, with similar rates of cardiac death in both groups (0.1% and 0.2%, respectively) and no new cardiac safety signals. An analysis of those only receiving anthracyclines similarly showed no significant differences in cardiac events or deaths.
The data from 3 years ago showing an IDFS benefit without an overall survival benefit were 'good enough to consider pertuzumab for the node-positive population,' said invited discussant Javier Cortés, MD, PhD, of the International Breast Cancer Center at Pangaea Oncology in Barcelona, the Universidad Europea de Madrid and Hospital Beata Maria Ana in Madrid, and the Medica Scientia Innovation Research, Barcelona, Spain, with Oncoclínicas & Co in Jersey City, New Jersey, and São Paulo, Brazil.
The overall survival benefit seen with pertuzumab is comparable to the 2.7% absolute benefit seen with aromatase inhibitors compared with tamoxifen, he noted. Cortés said he does not think it's necessary to wait to see an overall survival benefit to give the green light to a therapy with a clear IDFS benefit.
'The question we have to ask ourselves, in my opinion, is, should we wait to see overall survival improvements when we have significant, distant, disease-free survival improvements?' Cortés told attendees.
'You maybe are not going to see the overall survival, but you may prevent metastasis, and that's something, in my opinion, that we have to consider in the early breast cancer setting,' he said. 'In early breast cancer studies, the primary point, in my opinion, should not be invasive disease-free survival.'
Instead, the primary endpoint should be distant disease-free survival, and 'we should not wait for overall survival data to mature before making drug approval decisions,' he said.
'Delaying approval may result in patients progressing to metastatic disease and dying as a consequence,' he emphasized. 'Many patients will die if we are unable to use a drug because we are waiting for the approval based on the overall survival data.'
Cortés also addressed the cost-effectiveness of the therapy on the basis of analysis from the United States and Spain. 'If we select the patients carefully, if we go for the highest risk group of patients, maybe the addition of pertuzumab is likely to be cost-effective,' he said.
The research was funded by F. Hoffmann-La Roche Ltd in collaboration with the Breast International Group. Loibl reported royalties from VMscope and grants or honoraria from AstraZeneca, AbbVie, Agendia, Amgen, BioNTech, Celgene/BMS, Celcuity, DSI, Exact Sciences, Gilead Sciences, GSK, Incyte, Eli Lilly and Company, Molecular Health, MSD, Novartis, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemline Therapeutics/Menarini, Olema, Bayer, Bicycle, Jazz Pharmaceuticals, and BeiGene, plus three planned, issued, or pending patents.
Co-lead author Martine Piccart, MD, PhD, reported receiving consulting fees, advisory roles, scientific board service, or research funding from AstraZeneca, Eli Lilly and Company, MSD, Novartis, Pfizer, Menarini, Seagen, Roche/Genentech, NBE Therapeutics, Frame Therapeutics, Gilead Sciences, Radius Health, Synthon, Servier, Immunomedics/Gilead Sciences, and Oncolytics.
Cortés reported stock with MAJ3 Capital and a relative's stock in Leuko and disclosures with Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, Biolnvent, GEMoaB, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, ExpreS2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, BridgeBio, BioNTech, Biocon, Novartis, Eisai, Pfizer, Stemline Therapeutics, ARIAD Pharmaceuticals, Baxalta GmbH/Servier Affaires, Bayer, Guardant Health, PIQUR Therapeutics, and IQVIA. He holds a patent for a pharmaceutical combination of a PI3K inhibitor and a microtubule-destabilizing agent and for an HER2 predictor of response.
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