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

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.

FIG 1.

Best percent change in tumor size and percent change in tumor size, respectively, over time for individual patients in (A, D) the entire human epidermal growth factor receptor 2 (HER2)-low population, (B, E) the HER2 immunihistochemistry (IHC) 2+ group, and (C, F) the HER2 IHC 1+ group. Data cutoff was February 1, 2019. Dotted lines denote 30% decrease and 20% increase in tumor size cutoffs for partial response and progressive disease, respectively. Tumor responses shown are per independent central review. The IHC status subgroups represent the IHC status as determined by local assessment. (*) HR negative. HR, hormone receptor.

FIG 2.

The Kaplan-Meir estimates for (A) duration of response (DOR) and (B) progression-free survival (PFS) based on independent central assessment. Data cutoff was February 1, 2019. Tick marks within the graphs and a “+” in the text indicate censoring. NE, not estimable.

FIG 3.

Objective response rates and 95% CIs for subgroups of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer. Data cutoff was February 1, 2019. Dashed line separates the objective response rate (ORR) for the overall HER2-low population from the that for the subgroups. ORR was calculated with tumor responses per independent central review. The immunohistochemistry (IHC) status subgroups represent the IHC status as determined by local assessment. CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ECOG, Eastern Cooperative Oncology Group.