Trastuzumab Deruxtecan Demonstrates Durable Efficacy in Phase 2 DESTINY-Breast01 Trial

Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, showed durable objective responses in patients with HER2-positive breast cancer who were heavily pretreated with other HER2-targeted treatments including trastuzumab emtansine (T-DM1), according to the results of the phase 2 DESTINY-Breast01 clinical trial presented at the San Antonio Breast Cancer Symposium in San Antonio, Texas and also published in The New England Journal of Medicine.

There are a variety of treatment options for HER2-positive breast cancer, but the durability of benefit from these therapies have become an issue highlighted by study author and abstract presenter Ian Krop, MD, PhD, associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute. “Although HER-2 directed therapies such as trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs,” said Krop.

To combat the unmet medical need left by patients becoming resistant to current therapies, researchers examined the efficacy of T-DXd, which is similar to T-DM1 in having a monoclonal antibody targeted toward HER2. However, these 2 therapies become different through the type and influence of the cytotoxic payload, in which T-DM1 has 4 molecules assigned to its payload microtubule inhibitor and T-DXd has 8 molecules attributed to its payload topoisomerase 1 inhibitor. The cytotoxic payload in T-DMd is a “kind of chemotherapy not typically used in HER2-positive breast cancer so it’s less likely that cancer will develop resistance to this agent,” said Krop.

In the phase 1 study, data showed that T-DXd exhibited an objective response rate (ORR) of 59% in patients with advanced HER2-positive breast cancer previously treated with T-DM1. The open-label, multicenter, phase 2 DESTINY-Breast01 trial enrolled 184 patients with metastatic HER2-positive advanced breast cancer who had previously undergone T-DM1 and had received a median of 6 prior treatments for advanced disease, including targeted therapeutics:

• Patients received recommended phase 2 dose of 5.4 mg/kg T-DXd
• Primary endpoint was confirmed ORR measured by independent central imaging facility review (ICR)
• Secondary endpoints were investigator assessed ORR, disease control rate (DCR), clinical benefit rate (CBR), duration of response, progression-free survival, overall survival, PK, and safety

Study results showed that for the primary endpoint, confirmed ORR by ICR was 60.9% (95% CI, 53.4% to 68%) (n = 184), with 6% complete responses, 54.9% partial responses, and median PFS of 16.4 months. Both of these measures of efficacy are substantially higher than that seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” said Krop.

Further secondary endpoint measurements shown as 97.3% for DCR (95% CI, 93.8% to 99.1%), 76.1 % for CBR at 6 months (95% CI, 69.3% to 82.1%), 14.8 months of median duration of response (95% CI, 13.8-16.9), and 1.6 months of median time to response (95% CI, 1.4-2.6). Among patients categorized by prior treatment, those having undergone pertuzumab and administered T-DXd were shown to have an ORR of 64.5% (95% CI, 55.2% to 73.0%).

Safety analyses showed that 99% of patients reported treatment-emergent adverse events (TEAEs), with 57% experiencing TEAEs of grade 3 or higher (nausea, neutrophil count, anemia, decreased lymph node count, and fatigue) and 15% discontinuing treatment due to severity. Krop explained that most of the TEAEs were of low-grade, however, interstitial lung disease (ILD) proved a serious concern previously documented through T-DXd treatment in the phase 1 trial and was observed in 25 patients.

“While these events were primarily grade 1 or 2, there were unfortunately 4 grade 5 ILD-related deaths (2.2%) on the study. Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended,” said Krop.

After accounting for ILD risk, the clinical benefit found throughout the trial showed the potential of T-DXd and warrants its ongoing phase 3 trials. “The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population,” said Krop.

Reference

Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. [published online December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914510.