Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study

Shanu Modi, Haeseong Park, Rashmi K. Murthy, Hiroji Iwata, Kenji Tamura, Junji Tsurutani, Alvaro Moreno-Aspitia, Toshihiko Doi, Yasuaki Sagara, Charles Redfern, Ian E. Krop, Caleb Lee, Yoshihiko Fujisaki, Masahiro Sugihara, Lin Zhang, Javad Shahidi, Shunji Takahashi

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Abstract

PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported. PATIENTS AND METHODS: Eligible patients had advanced/metastatic HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd-induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

Original languageEnglish
Pages (from-to)1887-1896
Number of pages10
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume38
Issue number17
DOIs
StatePublished - Jun 10 2020

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    Modi, S., Park, H., Murthy, R. K., Iwata, H., Tamura, K., Tsurutani, J., Moreno-Aspitia, A., Doi, T., Sagara, Y., Redfern, C., Krop, I. E., Lee, C., Fujisaki, Y., Sugihara, M., Zhang, L., Shahidi, J., & Takahashi, S. (2020). Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(17), 1887-1896. https://doi.org/10.1200/JCO.19.02318