Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

Abstract

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.).

Copyright © 2019 Massachusetts Medical Society.

Figures

Figure 1.. Enrollment and Study Design.

Of the 100 patients who were excluded from participating in the study, 94 either did not meet the criteria for inclusion or met the criteria for exclusion, 2 withdrew consent, 1 was receiving long-term glucocorticoid therapy for fibromyalgia, 1 had new intracranial metastatic lesions, 1 was lost to follow-up, and 1 missed the deadline for reconsent. Part 1 of the study consisted of two sequential stages: pharmacokinetics and dose finding. On the basis of these results, a dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight) was recommended for part 2 of the study. Part 2 consisted of an evaluation of the efficacy and safety of trastuzumab deruxtecan in patients treated at the recommended dose who had tumor progression during or after the administration of trastuzumab emtansine (part 2a) and in those who had discontinued trastuzumab emtansine for reasons other than progressive disease (e.g., toxic effects) (part 2b).

Figure 2.. Response to Trastuzumab Deruxtecan, According to Tumor Size and Subgroup Analyses.

Panel A shows the best percentage change from baseline in the sum of the largest diameters of measurable tumors in 168 of 184 patients for whom data from both baseline and postbaseline assessments of target lesions by independent central review were available. The upper dashed horizontal line indicates a 20% increase in tumor size in the patients who had disease progression, and the lower dashed line indicates a 30% decrease in tumor size (partial response). Panel B shows the objective partial or complete response to trastuzumab deruxtecan therapy in all the enrolled patients who received 5.4 mg per kilogram, according to subgroup. Data for patients with an immunohistochemical (IHC) score indicated as 1+ (IHC negative) or 2+ (IHC borderline) include data for patients for whom the result was equivocal or could not be evaluated; a score of 3+ indicates positivity for HER2 (human epidermal growth factor receptor 2). HER2 positivity is also indicated by an IHC score of 1+ or 2+ and positive results on in situ hybridization (ISH). The vertical dashed line at the 61% mark indicates the median response to therapy in the overall population. ECOG denotes Eastern Cooperative Oncology Group.

Figure 3.. Kaplan–Meier Analysis of Response Duration and Progression-free Survival.

Panel A shows the duration of response to trastuzumab deruxtecan therapy in the 112 patients who had a complete or partial response among the 184 patients who were enrolled in the study. Panel B shows the probability of progression-free survival in the overall population. Of the 184 patients, 48 had progressive disease and 10 had died by 20 months; data for 126 patients were censored, as indicated by tick marks in the two panels. Disease progression was assessed with the use of the modified Response Evaluation Criteria in Solid Tumors, version 1.1. In each panel, the dashed lines indicate the 95% confidence interval.