Trastuzumab deruxtecan is revolutionizing the treatment paradigm. Compared with capecitabine-based regimens, trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca) 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; Kadcyla®; Genentech/Roche).
This is the conclusion based on results from the phase III DESTINY-Breast02 trial, which was designed and funded by Daiichi Sankyo in collaboration with AstraZeneca. The study results were presented at the San Antonio Breast Cancer Symposium, held December 6-10, 2022 in San Antonio, Tx. 
Trastuzumab deruxtecan is an antibody-drug conjugate or ADC that uses the HER2-targeted antibody trastuzumab to deliver a cytotoxic payload selectively to HER2-expressing cells. The drug links a humanized anti-HER-2 monoclonal antibody and topoisomerase inhibitor payload (deruxtecan) which are covalently attached through a tetra peptide-based cleavable linker. Once bound to the HER-2 receptor on tumor cells, cell internalizes the antibody along with the bounded deruxtecan and linker cleavage occurs through lysosomal enzymes which release deruxtecan. After its release, it impairs the replicating ability of cell at the time of cell division, causing DNA damage and leading to apoptotic cell death.
In the single-arm DESTINY-Breast01 phase II clinical trial, trastuzumab deruxtecan showed clinical activity in the third-line setting for patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab emtansine, another HER2-targeted antibody-drug conjugate.
These results led to the accelerated approval of trastuzumab deruxtecan in 2019 as a third-line therapy for patients with metastatic or unresectable breast cancer who have received two or more prior HER2-targeted therapies.
“While DESTINY-Breast01 established trastuzumab deruxtecan as a new treatment for this population, it was a modestly sized, single-arm phase II trial,” said Ian Krop, MD, PhD, associate cancer center director for Clinical Research and the chief clinical research officer at the Yale Cancer Center.
The DESTINY-Breast02 trial was designed as a confirmatory study for DESTINY-Breast01 to evaluate trastuzumab deruxtecan versus treatment of physician’s choice (TPC) in patients previously treated with trastuzumab emtansine, he explained.
“In addition to confirming the favorable benefit-to-risk profile of trastuzumab deruxtecan in this population, this research was also important to evaluate the efficacy of one antibody-drug conjugate, trastuzumab deruxtecan, in patients whose cancer has already progressed on another antibody-drug conjugate, trastuzumab emtansine,” Krop noted.
“This is the first randomized trial to ask this important question.”
The DESTINY-Breast02 trial enrolled 608 patients whose metastatic breast cancers had progressed on or after trastuzumab deruxtecan treatment. Patients were randomly assigned 2:1 to receive either trastuzumab deruxtecan or TPC (a combination of capecitabine (Xeloda®; Genentech/Roche) with either trastuzumab (Herceptin®; Genentech/Roche) or lapatinib (Tykerb®; Novartis).
Among the patients treated with trastuzumab deruxtecan, 69.7 percent experienced an objective response, as compared with 29.2 percent of patients treated with TPC. Those treated with trastuzumab deruxtecan were also 64 percent 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 trastuzumab deruxtecan and TPC arms, respectively.
Overall survival was also significantly longer for patients treated with trastuzumab deruxtecan (39.2 months with trastuzumab deruxtecan vs. 26.5 months with TPC).
Krop noted that adverse events in patients who received trastuzumab deruxtecan were consistent with prior studies. trastuzumab deruxtecan-related interstitial lung disease was observed in 10.4 percent of patients who received the therapy; most of these cases were grade 1 or 2, but two cases of grade 5 interstitial lung disease were reported.
“The results of DESTINY-Breast02 confirm the findings of DESTINY-Breast01, demonstrating high levels of efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine,” said Krop.
“Furthermore, they extend these findings, demonstrating that trastuzumab deruxtecan is not only highly active, but also superior to conventional chemotherapy-based regimens in this patient population.”
Follow-up analyses may assess patient-reported outcomes from this trial, and additional studies may examine adverse events, efficacy, and safety of the treatment in patients with metastases to the central nervous system, Krop noted. Ongoing studies are also evaluating trastuzumab deruxtecan as a first-line therapy for patients with HER2-positive metastatic breast cancer and for patients with early-stage disease.
A limitation of this study was that the control arm was limited to therapies based on capecitabine, precluding direct comparison of trastuzumab deruxtecan to treatment regimens containing other chemotherapeutic agents.
An additional limitation is that patients with progressive metastases to the central nervous system were not eligible for the trial.
A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1) – NCT03248492
DS-8201a in Pre-treated HER2 Breast Cancer That Cannot be Surgically Removed or Has Spread [DESTINY-Breast02] – NCT03523585
Highlight of prescription information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) [Prescription information]
Capecitabine (Xeloda®; Genentech/Roche) [Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche)[Prescribing Information]
Lapatinib (Tykerb®; Novartis) [Prescribing Information]
 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. Abstract: GS2-01 presented during the 2022 San Antonio Breast cancer Symposium, held December 6 – 10.
 Siddiqui T, Rani P, Ashraf T, Ellahi A. Enhertu (Fam-trastuzumab-deruxtecan-nxki) – Revolutionizing treatment paradigm for HER2-Low breast cancer. Ann Med Surg (Lond). 2022 Sep 16;82:104665. doi: 10.1016/j.amsu.2022.104665. PMID: 36268293; PMCID: PMC9577648.
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