Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

By S. Modi, C. Saura, T. Yamashita, Yeon-Hee Park, Sung-Bae Kim, K. Tamura, F. André, H. Iwata, Yoshinori Ito, J. Tsurutani and 15 more. New England Journal of Medicine, 2019

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BACKGROUND Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.)

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

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In Cancer Research

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Citations in the corpus

• ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. (2021, background): “Trastuzumab deruxtecan is a third-line treatment option for patients who have not received this agent in the second-line setting based on activity reported in a large, single-cohort phase II study (N = 184).(63) In heavily pretreated patients with a median of six prior lines of therapy, median PFS w”
• Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Indeed, a recent clinical trial (NCT03248492) testing trastuzumab deruxtecan (DS-8201), an anti-HER2 antibody linked to topoisomerase inhibitor, in metastatic HER2+ breast cancer patients who failed prior treatment has given positive results (Modi et al., 2019).”
• 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020, background): “1 score: 4 There are, however, no data on the use of this combination after progression on pertuzumab or T-DM1.”
• Antibody drug conjugate: the “biological missile” for targeted cancer therapy (2022, background): “0%).(207) Moreover, The recently updated data of DESTINY-Breast03, a global, head-to-head, randomized, open-label, pivotal phase 3 trial, demonstrated that DS-8201 had an significant superiority over T-DM1.”