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

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

References

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. https://www.aacr.org/about-the-aacr/newsroom/news-releases/t-dxd-yields-superior-outcomes-over-chemotherapy-based-regimens-in-patients-previously-treated-with-t-dm1/

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.