T-DXd Emerges as Top Pick For HER2+ Breast Cancer

Nour Abuhadra, MD

Director, Rare Breast Cancer Program, Department of Medicine Co–Section Head, Triple Negative Breast Cancer Clinical Research Program, Department of Medicine Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine New York, NY

As a second-line option, trastuzumab deruxtecan (Enhertu; T-DXd) has become a preferred treatment choice in the management of HER2- positive metastatic breast cancer based on updates from the DESTINY-Breast03 trial (NCT03529110). Trial investigators reported that the median progression-free survival (PFS) was about 4 times longer using T-DXd (28.8 months; 95% CI, 22.4-37.9) when compared with trastuzumab emtansine (Kadcyla; T-DM1) (6.8 months; 95% CI, 5.6-8.2), Nour Abuhadra, MD, explained at the 41st Annual Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow® conference held from November 8 to 10, 2023, in New York.¹

“We observed a significant difference in PFS between T-DXd and T-DM1, with T-DXd demonstrating an PFS of 28 months compared with 6.8 months with T-DM1. This extended duration of PFS exceeded historical benchmarks, surpassing the CLEOPATRA trial [NCT00567190] findings in the first-line setting. Moreover, this PFS benefit was consistently evident across various subgroups,” Abuhadra, said. Abuhadra is the director of the Rare Breast Cancer Program in the Department of Medicine, co–section head of the Triple Negative Breast Cancer Clinical Research Program and in the Department of Medicine at Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine in New York, New York.

The multicentered phase 3 DESTINY-Breast03 trial, enrolled 524 patients who were randomly assigned 1:1 into 2 arms. Patients in the first arm (n=261) received 5.4 mg/kg of T-DXd every 3 weeks, and patients in the second arm (n=263) received 3.6 mg/kg of T-DM1 every 3 weeks. The primary end point was PFS, and the notable secondary end point was overall survival (OS). The median duration of study follow-up was 28.4 months (22.1-32.9) with T-DXd compared with 26.5 months (14.5-31.3) with T-DM1, and the median PFS by blinded independent central review was 28.8 months (95% CI, 22.4-37.9) with T-DXd and 6.8 months (5.6-8.2; HR, 0.33 [95% CI, 0.26-0.43] P =.0001) with T-DM1. Although the median OS was not reached (95% CI, 40.5 months-not reached), "the 24-month OS was 77% with T-DXd vs 69% with T-DM1, and this is statistically significant,” Abuhadra said.^1,2

Among the patients in the study, 100% received prior trastuzumab (Herceptin), 60% received prior pertuzumab (Perjeta), 16% received a HER2 tyrosine kinase inhibitor (TKI), and 50% received 1 line of unspecified therapy for metastatic breast cancer.1 PFS benefit was also observed across subgroups when receiving T-DXd, particularly for patients with brain metastases (n=114). For these patients (n=114), the median PFS was 15.0 months (95% CI, 12.6-22.2) with T-DXd vs 5.7 months (95% CI, 2.9-7.1) with T-DM1 showing an HR of 0.3796 (0.2267-0.6357).

Another trial Abuhadra mentioned was the HER2CLIMB trial (NCT02614794), which also included patients with brain metastasis in the second-line setting. This trial evaluated tucatinib (Tukysa), trastuzumab, and capecitabine (Xeloda) compared with placebo, trastuzumab, and capecitabine. Investigators showed that “the risk of progression in patients with brain metastases was reduced by 52%, and the risk of death in patients with brain metastases was reduced by 42%,” Abuhadra said. The median PFS for patients with brain metastases was 7.6 months (6.2-9.5) in the experimental arm vs 5.4 months (4.1-5.7) with placebo.^1,3

“In the second line, our favored agent is T-DXd, especially for patients with active central nervous system disease, while considering the HER2CLIMB regimen. Moving into the third and fourth lines of treatment, we consider utilizing T-DM1 if it hasn’t been previously used, or the HER2CLIMB regimen if not already administered. Additionally, we have TKIs such as margetuximab [Margenza] combined with chemotherapy and trastuzumab combined with chemotherapy, as other viable options,” Abuhadra said.

REFERENCES

1. Abuhadra N. Sequencing in HER2+ breast cancer. Presented at: 41st Annual CFS Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow; November 8-10, 2023; New York, NY.

2. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5

3. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005