Trastuzumab Deruxtecan New Second-Line Option for HER2+ Metastatic Breast Cancer

Every year, the European Society for Medical Oncology (ESMO) Congress is an opportunity for ‘’connecting and engaging those who care about cancer’’. Due to the Covid-19 pandemic, more than 23,000 attendees from around the globe, for the second consecutive year, attended the congress virtually (from 16-21 September) to hear about the latest advances, challenges, and controversies in multidisciplinary cancer management. Thanks to Covid-19 vaccination and testing, several international presenters and discussants of this year’s meeting were able to present live from Paris, further enhancing discussions of new achievements and practice-changing data. Nearly 2000 abstracts and 68 late-breaking abstracts were presented. During the first Presidential Symposium, Javier Cortés, MD, PhD (International Breast Cancer Center [IBCC] and Vall d’Hebron Institute of Oncology, Barcelona, Spain), presented the eagerly awaited results from the multicenter, randomized, open-label, phase 3, DESTINY-Breast03 study. This is the first study comparing the efficacy and safety of two HER2-targeting antibody-drug conjugates (ADCs), trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), in patients with HER2+ metastatic breast cancer (mBC) who had previously been treated with trastuzumab and taxane-based chemotherapy. T-DXd is approved for patients with heavily pre-treated HER2+ mBC (after two or more anti-HER2 regimens) based on results from the DESTINY-Breast01 trial.

In DESTINY-03, 524 patients with HER2+ mBC, previously treated with trastuzumab and a taxane were randomized to receive either T-DXd or T-DM1. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). The median PFS was not reached in the group of patients receiving T-DXd and was 6.8 months in the T-DM1 group (hazard ratio [HR], 0.28; P=7.8 x 10¯²²). According to investigator assessment, PFS with T-DXd was more than tripled when compared with T-DM1 (25.1 months versus 7.2 months; HR, 0.26; P=6.5 x 10¯²⁴). Subgroup analysis also favored T-DXd regardless of hormone receptor status, prior pertuzumab treatment, visceral disease at baseline, presence of brain metastases, and prior lines of therapy. Despite follow-up of only 16 months at this interim analysis, there is an encouraging trend for overall survival (OS) benefit. The estimated 12-month OS rate was 94.1% for T-DXd and 85.9% for T-DM1 (HR, 0.56; P=0.007172); however, this has not yet reached the pre-defined cut-off for statistical significance. Of note, the confirmed overall response rate (ORR) was more than doubled in the T-DXd group (79.7%) compared with the T-DM1 group (34.2%). Furthermore, 16% of patients in the T-DXd group achieved complete response compared with 8.7% in the T-DM1 group. The median treatment duration was also more than twice as long with T-DXd (14.3 months versus 6.9 months). Importantly, the safety profile was manageable and comparable between T-Dxd and T-DM1. Most drug-related treatment-emergent adverse events (TEAEs) were gastrointestinal or hematological. The most common TEAE associated with treatment discontinuation for T-DXd was interstitial lung disease (ILD)/pneumonitis (8.2%), and thrombocytopenia for T-DM1 (2.7%). Although the rate of ILD/pneumonitis was higher with T-DXd (10.5% vs. 1.9%), less than 1% were grade 3, and in contrast to DESTINY-Breast 01, no patients died.

Based on the impressive efficacy and manageable toxicity, Dr Cortés concluded that T-DXd should become the new standard of care for second-line HER2+ mBC. A discussant of the abstract, Dr Shanu Modi, MD (Memorial Sloan Kettering Cancer Center, New York, US), agreed and highlighted that T-DXd efficacy in mBC is unprecedented. Importantly, the risk of lung toxicity is lower than in the DESTINY-Breast01 trial; this is likely due to its use in an earlier-line setting and better awareness of lung toxicity with careful vigilance and early interventions. She emphasized that although there are still unanswered questions following this research – namely, how using T-DXd as a second-line treatment might impact the efficacy of subsequent treatments including T-DM1 – this should not deter physicians from using T-DXd as a second-line treatment for mBC.  

Cortés J, et al. ESMO 2021; Abstract LBA1.