Trastuzumab Deruxtecan Bests Chemotherapy-Based Regimens in Those Previously Treated With T-DM1


DESTINY-Breast02 clinical trial results show trastuzumab deruxtecan demonstrated a clinically meaningful and statistically significant improvement in progression-free and overall survival.

Treatment with trastuzumab deruxtecan (T-DXd) (Enhertu; Daiichi Sankyo, Inc) led to higher response rates and longer survival in the third-line setting for patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1) compared with capecitabine-based regimens, according to the results of the phase 3 DESTINY-Breast02 (NCT03523585) trial presented at the San Antonio Breast Cancer Symposium in Texas on December 7, 2022.1

T-DXd is an antibody-drug conjugate that uses the HER2-targeted antibody trastuzumab to deliver a cytotoxic payload selectively to HER2-expressing cells. In the single-arm DESTINY-Breast01 phase 2 clinical trial, T-DXd showed clinical activity in the third-line setting for patients with HER2-positive metastatic breast cancer who were previously treated with T-DM1, another HER2-targeted antibody-drug conjugate.

This led to the accelerated approval of T-DXd in 2019 as a third-line therapy for patients with metastatic or unresectable breast cancer who had received 2 or more prior HER2-targeted therapies.1

“While DESTINY-Breast01 established T-DXd as a new treatment for this population, it was a modestly sized, single-arm phase 2 trial,” Ian Krop, MD, PhD, associate cancer center director for clinical research and the chief clinical research officer at the Yale Cancer Center in New Haven, Connecticut, said in a statement.1

The DESTINY-Breast02 trial was designed as a confirmatory study for DESTINY-Breast01 (NCT03248492) to evaluate T-DXd versus treatment of physician’s choice (TPC) in patients previously treated with T-DM1, he said.1

“In addition to confirming the favorable benefit-to-risk profile of T-DXd in this population, this research was also important to evaluate the efficacy of one antibody-drug conjugate, T-DXd, in patients whose cancer has already progressed on another antibody-drug conjugate, T-DM1,” Krop said. “This is the first randomized trial to ask this important question.”1

The DESTINY-Breast02 trial enrolled 608 patients whose metastatic breast cancers had progressed on or after T-DM1 treatment. Patients were randomly assigned 2:1 to receive either T-DXd or TPC, a combination of capecitabine with either lapatinib or trastuzumab.1

Among the patients treated with T-DXd, 69.7% experienced an objective response compared with 29.2% of those treated with TPC. Those treated with T-DXd were also 64% less likely to experience disease progression than patients receiving TPC, with a median progression-free survival of 17.8 months and 6.9 months for patients in the T-DXd and TPC arms, respectively. Overall survival was also significantly longer for patients treated with T-DXd, at 39.2 months compared with 26.5 months with TPC.1

“The results of DESTINY-Breast02 confirm the findings of DESTINY-Breast01, demonstrating high levels of efficacy of T-DXd in patients with HER2-positive metastatic breast cancer previously treated with T-DM1,” Krop said. “Furthermore, they extend these findings, demonstrating that T-DXd is not only highly active but also superior to conventional chemotherapy-based regimens in this patient population.”1

Adverse events (AEs) in patients who received T-DXd were consistent with prior studies, Krop said.1

T-DXd-related interstitial lung disease (ILD) was observed in 10.4% of patients who received the therapy. Most of these cases were grade 1 or 2, but 2 cases of death, or grade 5 ILD, were reported.1

“ILD remains a serious adverse event associated with T-DXd and needs to be monitored," Krop said during a SABCS presentation of the study results.2

Follow-up analyses may assess patient-reported outcomes from this trial, and additional studies may examine AEs, efficacy, and safety of the treatment in patients with metastases to the central nervous system (CNS), Krop said.1

Ongoing studies are also evaluating T-DXd as a first-line therapy for patients with early-stage disease and with HER2-positive metastatic breast cancer.1

One limitation of this study was that the control arm was limited to therapies based on capecitabine, precluding direct comparison of T-DXd to treatment regimens containing other chemotherapeutic agents. An additional limitation was that patients with progressive metastases to the CNS were not eligible for the trial.1


1. T-DXd yields superior outcomes over chemotherapy-based regimens in patients previously treated with T-DM1. American Association for Cancer Research. News release. December 7, 2022. Accessed December 7, 2022.

2. Krop I. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized phase 3 study DESTINY-Breast02. Presented at: San Antonio Breast Cancer Symposium; Henry B. Gonzalez Convention Center in Texas: December 7, 2022.

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