Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer

Author(s): Sara M. Tolaney, M.D.¹; Zefei Jiang, M.D.²; Qingyuan Zhang, M.D.³; Romualdo Barroso-Sousa, M.D.⁴; Yeon Hee Park, M.D.⁵; Mothaffar F. Rimawi, M.D.⁶; Cristina Saura, M.D.⁷; Andreas Schneeweiss, M.D.⁸; Masakazu Toi, M.D.⁹; Yee Soo Chae, M.D.¹⁰; Yasemin Kemal, M.D.¹¹; Mukesh Chaudhari, M.D.¹²; Mehmet A.N. Şendur, M.D.¹³; Toshinari Yamashita, M.D.¹⁴; Monica Casalnuovo, M.D.¹⁵; Michael A. Danso, M.D.^16,17; Jie Liu, Ph.D.¹⁸; Jagdish Shetty, M.D.¹⁹; Pia Herbolsheimer, M.D.¹⁹; Sibylle Loibl, M.D.^20,21; the DESTINY-Breast09 Trial Investigators*;

Source: DOI: 10.1056/NEJMoa2508668

Dr. Maen Hussein's Thoughts

Median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab vs 26.9 months with a hazard ratio (HR) of 0.56. This is impressive. However, there is no reported placebo trastuzumab deruxtecan arm, so this is not truly a “no chemotherapy” regimen. It is important to remember that deruxtecan is itself a chemotherapy agent. So, this is really comparing deruxtecan vs taxol or more accurately, a comparison of chemotherapy delivery systems. The advantage of trastuzumab deruxtecan plus pertuzumab versus THP may lie in the fact that the chemotherapy is conjugated to a monoclonal antibody. Possibly. It will be interesting to see whether the monotherapy arm is equally or less efficient.

BACKGROUND

Trastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)–positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear.

METHODS

We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety. Research Summary Trastuzumab Deruxtecan for HER2-Positive Metastatic Breast Cancer

RESULTS

For this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P

CONCLUSIONS

Trastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast09 ClinicalTrials.gov number, NCT04784715.)

Author Affiliations

¹Dana–Farber Cancer Institute, Harvard Medical School, Boston; ²Department of Breast Cancer, Fifth Medical Center of People’s Liberation Army General Hospital, Beijing; ³Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China; ⁴Brasilia Hospital, Rede Américas, Brasilia, Brazil; ⁵Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ⁶Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston; ⁷Vall d’Hebron University Hospital, Barcelona; ⁸National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany; ⁹Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo; ¹⁰Department of Oncology and Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, South Korea; ¹¹Department of Medical Oncology, Faculty of Medicine, Altınbas University, Istanbul, Turkey; ¹²Department of Medical Oncology, HCG Manavata Cancer Center, Mumbai Naka, Nashik, India; ¹³Department of Medical Oncology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara Bilkent City Hospital, Ankara, Turkey; ¹⁴Department of Breast Surgery and Oncology, Kanagawa Cancer Center, Yokohama, Japan; ¹⁵Clinical Oncology Unit, LUCEN, Buenos Aires; ¹⁶Department of Medical Oncology, Brock Cancer Center, Virginia Oncology Associates, Norfolk; ¹⁷Department of Medical Oncology, Brock Cancer Center, Sarah Cannon Research Institute, Norfolk, VA; ¹⁸Biometrics Oncology, Late-Stage Development, Oncology Research and Development, AstraZeneca, San Francisco; ¹⁹Late Development Oncology, Clinical Development, Oncology Research and Development, AstraZeneca, Gaithersburg, MD; ²⁰Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany; ²¹German Breast Group, Frankfurt am Main, Germany

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