Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up

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Abstract

PURPOSE

APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease–free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)–negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up.

METHODS

After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab.

RESULTS

This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance ( P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen.

CONCLUSION

This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

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Most cited references 29

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Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

Dennis J Slamon, Brian Leyland-Jones, Steven Shak … (2001)

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

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Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

Gunter von Minckwitz, Chiun-Sheng Huang, Max S Mano … (2018)

Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.

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Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

Luca Gianni, Tadeusz Pienkowski, Young-Hyuck Im … (2012)

Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. F Hoffmann-La Roche. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Title: Journal of Clinical Oncology

Abbreviated Title: JCO

Publisher: American Society of Clinical Oncology (ASCO)

ISSN (Print): 0732-183X

ISSN (Electronic): 1527-7755

Publication date (Electronic): February 04 2021

Page: JCO.20.01204

Affiliations

[1 ]Institut Jules Bordet and L'Université Libre de Bruxelles (ULB), Brussels, Belgium

[2 ]Frontier Science Scotland Ltd, Kincraig, Kingussie, United Kingdom

[3 ]Breast International Group (BIG), Brussels, Belgium

[4 ]Roche Products Limited, Welwyn Garden City, United Kingdom

[5 ]University of Texas, MD Anderson Cancer Center, Huston, TX

[6 ]Hoffmann-La Roche Ltd, Basel, Switzerland

[7 ]CHU Liege and Liege University, Liege, Belgium

[8 ]Duke Cancer Institute, Duke University, Durham, NC

[9 ]Inaugural Chair—Consumer Advisory Panel, Breast Cancer Trials Group, Newcastle, Australia

[10 ]Consumer Advisor to Breast Researchers, Garvan Institute of Research, Sydney, Australia

[11 ]Institute Bergonié, UNICANCER, University of Bordeaux, Bordeaux, France

[12 ]Dana-Farber Cancer Institute, Boston, MA

[13 ]National Health Research Institutes, Taipei, Taiwan

[14 ]Oncological Department, Postgraduate Medical Education Center, Warsaw, Poland

[15 ]Breast Cancer Unit, Kyoto University Hospital, Kyoto, Japan

[16 ]Director of Medical Oncology, Westmead Hospital, Sydney

[17 ]Associate Professor of Medicine, University of Sydney, Sydney, Australia

[18 ]Department of Oncology, Rigshospitalet, University Hospital, Copenhagen, Denmark

[19 ]Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

[20 ]Comprehensive Breast Health Center, Experimental Surgery, Department of Surgery, Taipei-Veterans General Hospital, Taipei, Taiwan

[21 ]Gynäkologisch-Onkologische Praxis Hannover, Hannover, Germany

[22 ]Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy

[23 ]Instituto Nacional de Câncer, Rio de Janeiro, Brazil

[24 ]Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health, Frontier Science Foundation, Boston, MA

[25 ]University of Milan, IEO, European Institute of Oncology, IRCCS, Milan, Italy

[26 ]Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

Article

DOI: 10.1200/JCO.20.01204

PubMed ID: 33539215

SO-VID: 9eba1758-08d9-499b-b178-513d0d73566d

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