Trastuzumab Deruxtecan Outperforms T-DM1 in Overall Survival for Patients With Metastatic Breast Cancer

Second-line treatment with trastuzumab deruxtecan (T-DXd) (Enhertu; Daiichi Sankyo, Inc and AstraZeneca) produced significantly longer overall survival (OS) than with trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer, according to updated results from the DESTINY-Breast03 (NCT0352911) phase 3 clinical trial presented at the San Antonio Breast Cancer Symposium (SABCS) in Texas on December 7.¹

In a press conference and later presentation at SABCS, Sara Hurvitz, MD, a professor of medicine at the David Geffen School of Medicine at the University of California Los Angeles and Jonsson Comprehensive Cancer Center, shared previously unreported OS data and updated progression-free survival (PFS) and safety data from the clinical trial.^2,3

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.¹

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, OS 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, OS rates were 77.4% and 69.9% for patients treated with T-DXd and T-DM1, respectively.¹

Meanwhile, the median PFS 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 those treated with T-DM1. In addition, 21.1% of patients treated with T-DXd had a complete response compared with 9.5% of those treated with T-DM1.¹

T-DXd and T-DM1 are antibody-drug conjugates approved as second-line treatment for patients with HER2-positive metastatic breast cancer. Both therapies use trastuzumab to seek HER2-expressing cells and deliver a cytotoxic drug.¹

“Almost all patients with HER2-positive metastatic breast cancer experience disease progression on first-line treatment, requiring transition to a second-line treatment,” Hurvitz said.¹

The DESTINY-Breast03 trial compared the efficacy and safety of T-DXd with those of T-DM1 in patients with HER2-positive metastatic breast cancer that progressed on or after first-line treatment. Previously published interim results from the trial showed that patients treated with T-DXd had significantly longer PFS than those who received T-DM1, which led to the approval of T-DXd as a second-line treatment for patients with HER2-positive metastatic breast cancer. However, OS data had not been reached in the first interim analysis.¹

“While PFS benefits are important, the gold standard measure of efficacy is [OS],” Hurvitz said.¹

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.¹

“What’s notable about this trial is the lack of deaths, the lack of grade 4 events,” Hurvitz said during the press conference.²

Drug-related interstitial lung disease(ILD)/pneumonitis occurred in 15.2% and 3.1% of patients in the T-DXd and T-DM1 arms, respectively.¹

“Much is to be learned about patients with ILD. So, we’re looking for clinical features, as well as demographic features to see who’s at higher risk,” Hurvitz said during the press conference.²

The new cases of ILD/pneumonitis were mild or moderate in severity, she said.¹

“The results of this analysis demonstrated remarkable [OS] and continued PFS 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. With this overall survival analysis, we can confirm that the previously demonstrated benefit from T-DXd in PFS improvement transforms into a statistically significant improvement in overall survival, a substantial advantage for our patients,” Hurvitz said.¹

“In addition, T-DXd continued to demonstrate a manageable and tolerable safety profile, with similar rates of treatment-related adverse events between treatment arms,” she said.¹

Future analyses of DESTINY-Breast03 may investigate the efficacy of T-DXd in patients with brain metastases and explore predictive markers of response, Hurvitz said.¹

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.¹

One limitation of the study was the disproportionate enrollment of Asian patients compared with European and North American patients. An additional limitation was that median OS was not reached at the time of the analysis.¹

References

1. T-DXd yields longer overall survival than T-DM1 in patients with HER2-positive metastatic breast cancer. American Association for Cancer Research. News release. December 7, 2022. Accessed December 7, 2022. https://www.aacr.org/about-the-aacr/newsroom/news-releases/t-dxd-yields-longer-overall-survival-than-t-dm1-in-patients-with-her2-positive-metastatic-breast-cancer/

2. Press conference II. San Antonio Breast Cancer Symposium. December 6, 2022.

3. Hurvitz S. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: San Antonio Breast Cancer Symposium; Henry B. Gonzalez Convention Center in Texas: December 7, 2022.