Trastuzumab Deruxtecan Exhibits Favorable Safety Profile in DESTINY-Breast04 Follow-Up


Trastuzumab deruxtecan outperformed investigators choice of therapy, in terms of safety, among patients with HER2-Low Metastatic Breast Cancer.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

Patients with HER2-low unresectable and/or metastatic breast cancer who received fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) experienced lower rates exposure-adjusted incidence rates (EAIRs) per patient-year of treatment-emergent adverse effects (TEAEs) than those who received investigators choice of therapy, according to a detailed safety analysis from the phase 3 DESTINY-Breast04 trial (NCT03734029).1

Findings, which were presented by Hope S. Rugo, MD, FASCO, at the 2023 ESMO Breast Cancer Annual Congress and had a data cutoff date of January 11, 2022, also demonstrated a similar incidence of any-grade drug-related TEAEs in patients less than or at least 65 years of age or older and low-grade interstitial lung disease (ILD) that resolved over time.

“T-DXd demonstrated a manageable safety profile consistent with prior reports and results from this safety analysis continue to support its use as a new standard of care in patients with HER2-low metastatic breast cancer,” Rugo said. Rugo is a professor in the Department of Medicine, director of Breast Oncology and Clinical Trials Education, and medical director of Cancer Infusion Services at UCSF, Helen Diller Family Comprehensive Cancer Center in San Francisco, California.

Enrolled patients included those with HER2-low (immunohistochemistry (IHC)1+ or IHC2+ and in situ hybridization–negative), unresectable and/or metastatic breast cancer treated with 1 to 2 prior lines of chemotherapy in the metastatic setting. Patients with hormone receptor–positive disease were required to be refractory to endocrine therapy.

Patients were randomly assigned 2:1 to 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 373) or treatment of physician’s choice including capecitabine (Xeloda), eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane; n = 184).

The primary end point of progression-free survival assessed by blinded independent central review (BICR) in the hormone receptor–positive population was met, as were secondary end points of BICR-assessed PFS in all patients (HR, 0.50; P < .0001), overall survival in the hormone receptor–positive and all-comer populations (HR, 0.64; P = .001), as well as global health score and quality of life. Safety served as an additional secondary end point.

In August 2022, the FDA approved the antibody-drug conjugate for the treatment of patients with unresectable or metastatic HER2-low breast cancer based on earlier data from the trial.2 “DESTINY-Breast04 established HER2-low metastatic breast cancer as a new targetable patient population, with T-DXd as a new standard of care,” Rugo said.

EAIRs were evaluated to account for differences in treatment exposure between trastuzumab deruxtecan and treatment of physician’s choice, “providing a more meaningful comparison,” Rugo noted.

Following the adjustment, all parameters for TEAEs were lower with trastuzumab deruxtecan compared with treatment of physician’s choice, respectively:

  • Any-grade TEAE: 1.30 vs 2.66
  • Grade ≥3 TEAE: 0.69 vs 1.82
  • Any-grade serious TEAE: 0.36 vs 0.68
  • Grade ≥3 serious TEAE: 0.28 vs 0.49
  • TRAE associated with drug discontinuation: 0.21 vs 0.22
  • TEAE associated with dose reduction: 0.30 vs 1.04
  • TEAE associated with dose interruption: 0.50 vs 1.13

EAIRs per patient-year for anemia (T-DXd, 0.50; physician’s choice, 0.74, respectively), neutropenia (0.44 vs 1.42), alopecia (0.52 vs 0.90), and fatigue (0.70 vs 1.31) were higher with treatment of physician’s choice compared with trastuzumab deruxtecan. Conversely, EAIRs per patient-year for nausea (0.99 vs 0.82), vomiting (0.53 vs 0.36), thrombocytopenia (0.34 vs 0.25), and ILD (0.16 vs 0.02) were higher with trastuzumab deruxtecan compared with treatment of physician’s choice.

Median time to first onset of nausea (T-DXd, 3 days; physician’s choice, 8.5 days, respectively), vomiting (9.5 vs 22), anemia (43 vs 22), neutropenia (23.5 vs 9), thrombocytopenia (29 vs 12), and ILD (129 vs 60) occurred mostly within the first month of treatment. Median duration of nausea (T-DXd, 10 days; physician’s choice, 5 days, respectively), vomiting (3 vs 3), anemia (34 vs 15), neutropenia (22 vs 8), thrombocytopenia (8 vs 19), and ILD (47 vs not evaluable) ranged from 3 to 47 days with trastuzumab deruxtecan vs 3 to 19 days with treatment of physician’s choice.

In addition to these AEs, the incidence of diarrhea and decreased appetite in both arms decreased substantially after the first cycle of treatment.

Although prophylaxis was not mandatory, 50.9% (n = 189/371) and 37.2% (n = 64/172) of patients in the trastuzumab deruxtecan and treatment of physician’s choice arms received antiemetic prophylaxis. Dose reduction, interruption, and discontinuation associated with nausea and vomiting occurred in 5.4%, 1.3%, and 0.6% of patients in the trastuzumab deruxtecan arm compared with 2.9%, 2.3%, and 0% of patients in the treatment of physician’s choice arm, respectively.

Any-grade treatment-related neutropenia and febrile neutropenia was lower with trastuzumab deruxtecan compared with treatment of physician’s choice, at 12.9% vs 18.0%, respectively, and 0.3% vs 2.9%, respectively. Additionally, collective rates of neutropenia and febrile neutropenia led to fewer drug interruptions and dose reductions with trastuzumab deruxtecan compared with treatment of physician’s choice, at 9.2% vs 23.9% and 3.3% vs 15.7%, respectively.

Fewer patients in the trastuzumab deruxtecan arm received granulocyte colony-stimulating factor within 28 days of neutropenia and febrile neutropenia onset vs those in the physician’s choice arm, at 6.7% vs 19.8%, respectively. “This suggests that T-DXd–induced neutropenia was likely manageable with routine clinical practice, dose modifications, and the use of supportive medication,” Rugo said.

Notably, the incidence of all-grade drug-related TEAEs was similar regardless of age, Rugo added, supporting the favorable median PFS benefit seen in those under the age of 65 years (HR, 0.47; 95% CI, 0.37-0.61) and those aged 65 years and older (HR, 0.57; 95% CI, 0.36-0.89). However, trastuzumab deruxtecan led to a higher incidence of grade 3 or greater TEAEs and TEAEs associated with drug discontinuations in patients aged 65 years or above compared with those below 65 years of age.

Adjudicated drug-related ILD occurred in 12.1% of patients who were given trastuzumab deruxtecan vs 0.6% of those who received physician’s choice of treatment. Most ILD events with trastuzumab deruxtecan were grade 1 (3.5%) and 2 (6.5%); 1.3% and 0.8% of patients experienced grade 3 and 5 ILD, respectively. At data cutoff, 68.9% of patients in the trastuzumab deruxtecan arm had recovered, were recovering, or had recovered with sequalae, whereas 22.2% of patients in the physician’s choice arm had not recovered.

Rugo also presented retreatment outcomes in 6 patients who had experienced grade 1 ILD, one of which had a second grade 2 ILD event. At data cutoff, 1 patient discontinued trastuzumab deruxtecan because of an AE; 2 patients discontinued because of progressive disease, leaving 3 patients on trastuzumab deruxtecan.

“ILD/pneumonitis remains an important identified risk and an AE of interest and proper adherence to management guidelines is highly recommended,” Rugo concluded.

Disclosures: Dr Rugo reported advisory and/or consultancy roles with Puma, NAPO, Blueprint, Daiichi Sankyo, and Scorpion Therapeutics; and institutional research grant and/or funding from Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Inc., Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., GlaxoSmithKline, Lilly, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Sermonix Pharmaceuticals Inc., Taiho Oncology, Inc., and Veru Inc.


  1. Rugo HS, Jacot W, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients with HER2-low unresectable and/or metastatic breast cancer: a detailed safety analysis of the randomized, phase 3 DESTINY-Breast04 trial. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 185O.
  2. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed May 11, 2023.
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