Second-line treatment with fam-trastuzumab deruxtecan-nxki (T-DXd) led to significantly longer overall survival compared with ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, according to updated results from the DESTINY-Breast03 phase III clinical trial presented by Sara Hurvitz, MD, and colleagues at the 2022 San Antonio Breast Cancer Symposium (Abstract GS2-02).

Sara Hurvitz, MD

“Almost all patients with HER2-positive metastatic breast cancer experience disease progression on first-line treatment, requiring transition to a second-line treatment,” said Dr. Hurvitz, Medical Director of the Clinical Research Unit at Jonsson Comprehensive Cancer Center and Professor of Medicine in the Division of Hematology/Oncology at the University of California, Los Angeles. 

Two antibody-drug conjugates, T-DXd and T-DM1, are approved as second-line treatment for this patient population. Both therapies utilize trastuzumab to seek HER2-expressing cells and deliver a cytotoxic drug. In the case of T-DXd, the cytotoxic payload induces cell death by inhibiting topoisomerase; the conjugated drug of T-DM1 kills cells by disrupting microtubule assembly.

DESTINY-Breast03

The DESTINY-Breast03 trial compared the efficacy and safety of T-DXd vs T-DM1 in patients with HER2-positive metastatic breast cancer and disease progression on or after first-line treatment. Previously published interim results from the trial demonstrated that patients treated with T-DXd had significantly longer progression-free survival compared with patients who received T-DM1. These results led to the approval of T-DXd as a second-line treatment for this patient population. However, overall survival data had not been reached in the first interim analysis.

“While progression-free survival benefits are important, the gold standard measure of efficacy is overall survival,” said Dr. Hurvitz.

Overall Survival Data

In her presentation, Dr. Hurvitz shared previously unreported overall survival data from the trial, as well as updated progression-free survival and safety data. Among the 524 patients enrolled in the trial, 261 received T-DXd and 263 received T-DM1. The median study follow-up was 28.4 months for the T-DXd arm and 26.5 months for the T-DM1 arm.

New data showed that patients treated with T-DXd had a 36% lower risk of death than those treated with T-DM1, a statistically significant improvement. In addition, overall survival rates were significantly higher for patients treated with T-DXd: after 12 months, 94.1% of patients in the T-DXd arm were alive compared with 86% of those in the T-DM1 arm. After 24 months, overall survival rates were 77.4% and 69.9% for patients treated with T-DXd and T-DM1, respectively.

Updated progression-free survival data continued to favor T-DXd, and Dr. Hurvitz reported median values for the first time. The median progression-free survival in patients treated with T-DXd was 28.8 months compared with 6.8 months for patients treated with T-DM1. Objective responses were observed in 78.5% of patients who received T-DXd and 35% of patients treated with T-DM1. Furthermore, 21.1% of patients treated with T-DXd had a complete response compared with 9.5% of patients treated with T-DM1.

Grade 3 or higher treatment-related adverse events were observed in 56.4% and 51.7% of patients in the T-DXd and T-DM1 arms, respectively. Drug-related interstitial lung disease/pneumonitis was observed in 15.2% and 3.1% of patients in the T-DXd and T-DM1 arms, respectively. Dr. Hurvitz noted that new cases of interstitial lung disease/pneumonitis were mild or moderate in severity.

“The results of this analysis demonstrated remarkable overall survival and continued progression-free survival benefit with T-DXd in patients with HER2-positive metastatic breast cancer who progressed on prior therapy, further supporting the use of T-DXd over T-DM1 in the second-line setting,” said Dr. Hurvitz. “With this overall survival analysis, we can confirm that the previously demonstrated benefit from T-DXd in progression-free survival improvement transforms into a statistically significant improvement in overall survival—a substantial advantage for our patients.” She added: “T-DXd continued to demonstrate a manageable and tolerable safety profile, with similar rates of treatment-related adverse events between treatment arms.”

Future analyses of DESTINY-Breast03 may investigate the efficacy of T-DXd in patients with brain metastases and explore predictive markers of response, Dr. Hurvitz noted. Ongoing studies aim to determine the efficacy and safety of T-DXd as a first-line treatment for patients with HER2-positive metastatic breast cancer.

A limitation of the study was the disproportionate enrollment of Asian patients as compared with North American and European patients. An additional limitation was that median overall survival was not reached at the time of this analysis.

Disclosure: The study was supported by Daiichi Sankyo and AstraZeneca. Dr. Hurvitz is married to a shareholder/stockholder in Ideal Implant; has received honoraria from Daiichi Sankyo; and has received funding to her institution from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Daiichi Sankyo, CytomX Therapeutics, Dantari, Dignitana, G1 Therapeutics, Genentech/Roche, Gilead Sciences, GSK, Immunomedics, Eli Lilly and Company, MacroGenics, Novartis, Pfizer, OBI Pharma, Phoenix Molecular Designs, Orinoco Pharmaceuticals, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Samumed, Sanofi, Seattle Genetics, and Zymeworks.