Adjuvant Pertuzumab Plus Trastuzumab and Chemotherapy Leads to OS Benefit in Early-Stage HER2+ Breast Cancer

HER2+ Breast Cancer | Image Credit:

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The addition of adjuvant pertuzumab (Perjeta) to trastuzumab (Herceptin) and chemotherapy led to a significant improvement in overall survival (OS) vs placebo plus trastuzumab and chemotherapy in patients with early-stage, HER2-positive operable breast cancer, according to data from the final analysis of the phase 3 APHINITY trial (NCT01358877) presented during the 2025 ESMO Breast Cancer Congress.1

At a median follow-up of 11.3 years, patients who received pertuzumab (n = 2400) experienced a 17% reduction in the risk of death compared with those who received placebo (n = 2404; adjusted HR, 0.83; 95% CI, 0.69-1.00; P = .0441). The 10-year OS rates were 91.6% and 89.8%, respectively, representing a 1.8% difference (95% CI, 0.03%-3.47%).

“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,” Sibylle Loibl, MD, said during a presentation of the data. “These final results with long-term follow-up further support the benefit of pertuzumab in [the] early breast cancer setting.”

Loibl is the chair of the German Breast Group and the chief executive officer of the GBG Forschungs GmbH. She is also an associate professor of obstetrics and gynecology at the Goethe University of Frankfurt in Germany.

In December 2017, the FDA approved pertuzumab for use in combination with trastuzumab and chemotherapy as adjuvant treatment for patients with HER2-positive early breast cancer at high risk of recurrence.2 The regulatory decision was supported by prior findings from APHINITY.

Dissecting the Study Design

APHINITY was a double-blind study that enrolled patients with nonmetastatic operable primary invasive HER2-positive breast cancer that was adequately excised.3 Patients also needed to have an ECOG performance status of 0 or 1, a baseline left ventricular ejection fraction (LVEF) greater than or equal to 55%, and have an interval between definitive surgery for breast cancer and the first dose of chemotherapy of no more than 8 weeks. Additionally, the first dose of chemotherapy must have been administered within 7 days of random assignment or on day 56, whichever came first.

Patients were randomly assigned to receive intravenous (IV) pertuzumab at an 840-mg loading dose followed by 420 mg every 3 weeks for 1 year or matching placebo. Patients in both arms also received an 8-mg/kg loading dose of IV trastuzumab followed by 6 mg/kg every 3 weeks for 1 year and investigator’s choice of chemotherapy.

The primary end point was invasive disease-free survival (iDFS).1,3 Secondary end points included iDFS with second primary non-breast primary cancers included, OS, disease-free survival, relapse-free interval, distant relapse-free survival, safety, and health-related quality of life.

At baseline, 25% of patients in both the pertuzumab and placebo arms had at least 4 positive nodes.1 One to 3 positive nodes were reported in 38% and 37% of patients, respectively. Thirty-four percent of patients in both arms had 0 positive nodes and a tumor diameter above 1 cm. No positive nodes and a tumor diameter measuring less than 1 cm were observed in 4% and 3% of patients, respectively.

Patients in both arms received adjuvant chemotherapy with a non-anthracycline at a rate of 22% and with an anthracycline at a rate of 78%. In terms of central hormone receptor status, patients in both arms were estrogen receptor (ER) and/or progesterone receptor (PR) positive at a rate of 64%. Thirty-six percent of patients in both arms had ER- and PR-negative disease.

Further Efficacy Data and Safety Results

Loibl noted that the iDFS benefit with pertuzumab vs placebo was maintained at the time of the final analysis (adjusted HR, 0.79; 95% CI, 0.68-0.92). The 10-year iDFS rates were 87.2% and 83.8%, respectively, representing a difference of 3.4% (95% CI, 1.27%-5.42%). iDFS events were reported in both arms (12.6% vs 15.8%) and consisted of distant recurrence (6.3% vs 8.8%), including central nervous system metastases (2.1% vs 2.2%), locoregional breast cancer recurrence (1.5% vs 2.5%), contralateral invasive breast cancer recurrence (1.8% vs 1.2%), and death without a prior event (3.1% vs 3.2%).

Data from a subgroup analysis showed that the iDFS benefit in the investigational vs placebo arm was present, except in patients with node-negative disease (HR, 1.01; 95% CI, 0.74-1.38) and node-negative, hormone receptor–positive disease (HR, 1.03; 95% CI, 0.70-1.51).

Among patients with node-positive disease, those in the pertuzumab arm (n = 1503) experienced a 21% reduction in the risk of death compared with those in the placebo arm (n = 1502; unadjusted HR, 0.79; 95% CI, 0.64-0.97). The 10-year OS rates were 89.6% and 86.9%, respectively, representing a 2.7% difference (95% CI, 0.27%-5.09%).

Notably, the OS benefit among node-negative patients in the pertuzumab arm (n = 897) was small compared with those in the placebo arm (n = 902; unadjusted HR, 0.99; 95% CI, 0.66-1.49). The 10-year OS rates were 94.9% and 94.6%, respectively, for a difference of 0.2% (95% CI, –1.92%-2.40%).

Patients in the safety population who received pertuzumab (n = 2364) experienced a primary cardiac event at a rate of 0.9% compared with 0.5% in the placebo arm (n = 2405). New York Heart Association class III or IV heart failure coupled with a LVEF drop occurred at rates of 0.8% and 0.3%, respectively. Patients in both arms experienced cardiac death at low rates (0.1% vs 0.2%).

“Cardiac deaths were rare, [with] 3 and 4 cases [in the investigational and control arms], respectively,” Loibl said in conclusion. “No new cardiac safety issues emerged from this analysis. The main drivers of cardiac events were anthracycline-containing therapy.”

Disclosures: Loibl reports receiving grants and/or honoraria for advisory boards and/or contracts with AstraZeneca, AbbVie, Agendia, Amgen, BioNTech, Celgene/BMS, Celcuity, DSI, Exact Science, Gilead, GSK, Incyte, Lilly, Medscape, Molecular Health, MSD, Novartis, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemline/Menarini, Olema, Bayer, Bicycle, JAZZ Pharma, and BeiGene. She also reports support for attending meetings and/or travel from DSI, ESMO, SGBCC, ASCO, and AGO Komission Mamma, as well as royalties from VM Scope.

Reference

1. Loibl S, Piccart M, Clark E, et al. Adjuvant pertuzumab or placebo + trastuzumab + chemotherapy (P or Pla + T + CT) in patients (pts) with early HER2-positive operable breast cancer in APHINITY: final analysis at 11.3 years’ median follow-up. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract LBA1.
2. FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer. FDA. Updated December 21, 2017. Accessed May 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pertuzumab-adjuvant-treatment-her2-positive-breast-cancer
3. A study of pertuzumab in addition to chemotherapy and trastuzumab as adjuvant therapy in participants with human epidermal growth receptor 2 (HER2)-positive primary breast cancer (APHINITY). ClinicalTrials.gov. Updated January 13, 2025. Accessed May 15, 2025. https://clinicaltrials.gov/study/NCT01358877