Trastuzumab deruxtecan shows durable activity in previously treated HER2-positive breast cancer

Trastuzumab deruxtecan (DS-8201) has shown durable antitumour activity in patients with HER2-positive metastatic breast cancer (BC) previously treated with trastuzumab emtansine.

These results, from the global, phase II DESTINY-Breast01 study, led to the US FDA’s recent accelerated approval of trastuzumab deruxtecan for use in patients with unresectable or metastatic HER2-positive BC who have received ≥2 prior anti-HER2–based regimens in the metastatic setting.

In the study, a dose of 5.4 mg/kg was recommended for trastuzumab deruxtecan based on balance of safety and efficacy. Over a median follow-up of 11.1 months, the confirmed response rate (RR) was 60.9 percent (95 percent confidence interval [CI], 53.4 to 68.0), with complete and partial response rates of 6 percent and 54.9 percent, respectively. The disease-control rate was 97.3 percent (95 percent CI, 93.8 to 99.1), with a clinical-benefit rate of 76.1 percent (95 percent CI, 69.3 to 82.1). A response to trastuzumab deruxtecan was shown after a median time of 1.6 months (ie, at the time of the first imaging after baseline), and the median duration of response was 14.8 months (95 percent CI, 13.8 to 16.9). [N Engl J Med 2019, doi: 10.1056/NEJMoa1914510]

Prespecified subgroup analysis showed consistent RRs across demographic and prognostic subgroups, including previous pertuzumab use (64 percent), hormone-receptor status (positive, 58 percent; negative, 66 percent), and receipt of trastuzumab deruxtecan immediately after trastuzumab emtansine (64 percent).

The median progression-free survival (PFS) was 16.4 months (95 percent CI, 12.7 months to not reached) among all patients, and 18.1 months (95 percent CI, 6.7 to 18.1) in those enrolled with treated and asymptomatic brain metastases.

In this two-part, open-label, single-group, multicentre phase II trial, trastuzumab deruxtecan was evaluated in 184 patients (median age, 55 years; hormone receptor-positive tumours, 52.7 percent) with HER2-positive metastatic BC previously treated with trastuzumab emtansine. The patients had received a median of 6 previous lines of therapy for metastatic BC.

Part 1 of the study consisted of pharmacokinetics (PK) and dose-finding stages, with patients randomized (1:1:1) to receive trastuzumab deruxtecan at 5.4 mg/kg, 6.4 mg/kg or 7.4 mg/kg intravenously every 3 weeks.

The efficacy and safety of the recommended 5.4 mg/kg dose were subsequently assessed in part 2 of the study, which involved patients with tumour progression during or after previous trastuzumab emtansine treatment, and those who had discontinued trastuzumab emtansine for reasons other than progressive disease.

Trastuzumab deruxtecan is an antibody-drug conjugate composed of a humanized monoclonal antibody targeting HER2. Compared with trastuzumab emtansine, trastuzumab deruxtecan has a higher drug-to-antibody ratio while retaining a favourable PK profile as well as a released pay-load that easily crosses the cell membrane, potentially allowing for a potent cytotoxic effect on neighbouring tumour cells regardless of target expression. [Lancet Oncol 2017;18:1512-1522; Cancer Sci 2016;107:1039-1046]

The most common grade ≥3 adverse events reported in the study were decreased neutrophil count (20.7 percent), anaemia (8.7 percent) and nausea (7.6 percent). Interstitial lung disease occurred in 13.6 percent of patients, with 4 attributable deaths.

“Trastuzumab deruxtecan had a high level of clinical activity in patients with HER2-positive BC who had received extensive previous therapies,” concluded the researchers. “Attention to pulmonary symptoms and careful monitoring are, however, needed due to its substantial risk of interstitial lung disease.”