Patritumab deruxtecan (HER3-DXd; Daiichi Sankyo, Merck) met its primary end point of overall response rate (ORR) in patients with hormone receptor-positive (HR+)/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC) in the ICARUS-BREAST01 trial (NCT04965766). The data were published in Nature Medicine.1,2
3D visualization of an antibody drug conjugate | Image Credit: © Alpha Tauri 3D – stock.adobe.com
HR+/HER2– mBC is the most common BC subtype, accounting for nearly 72.7% of all cases. Treatment of these patients is difficult due to the aggressive nature of tumors with HER2 alterations, highlighting the critical need for advanced therapies. Antibody-drug conjugates (ADCs) pair a monoclonal antibody with a cytotoxic agent, aiming to expand the therapeutic window by directing the toxic payload to tumor cells while reducing systemic toxicity. These agents demonstrate significant efficacy and safety for the treatment of patients with HR+/HER2– mBC. However, only a small portion of these drugs are capable of reaching the tumor cells—calling for the development of agents that overcome this limitation.3,4
HER3-DXd is an ADC composed of an anti-HER3 monoclonal antibody conjugated to a topoisomerase-I inhibitor by a cleavable peptide linker. In the phase 2, open-label ICARUS-BREAST01 trial, researchers reported statistically significant response rates in patients with HR+/HER2– mBC treated with HER3-DXd. The trial enrolled a total of 99 patients from May 2021 to June 2023 who received HER3-DXd at a dose of 5.6 mg kg−1 intravenously every 3 weeks.2
The study met its primary end point, showing an ORR of 53.5% (90% confidence interval [44.8–62.1%]). Of the population, 2 patients achieved a complete response, 51 achieved a partial response, and 37 presented with stable disease. There was a clinical benefit rate (CR, PR or SD ≥ 6 months) of 62.6% (95% CI [52.3–72.1%]).2
At a median duration of 15.3 months, 62 patients experience disease progression of death with a median progression-free survival (PFS) of 9.2 months (95% CI [8.0–12.8 months]). Overall survival data were immature at the time of the data cut-off.2
The researchers also performed a post-hoc analysis of ORR and PFS and reported an ORR of 60% (95% CI [40.6–77.3%]) in the HER2-low (1+, 2+) and of 48.7% (95% CI [32.4–65.2%]) in the HER2-0 patient populations. They reported a median PFS of 12.8 (95% CI [8.11–N/A]) months and 9.1 (95% CI 6.7–N/A) months in HER2-low and HER2– subgroups, respectively.
The most frequent adverse events were fatigue (83%), nausea (75%), diarrhea (53%) and alopecia (40%).2
“In conclusion, the ICARUS-BREAST01 study shows a substantial efficacy and a manageable safety profile of HER3-DXd in patients with HR+/HER2− breast cancer that make it an optimal candidate for further larger studies in this setting,” the authors wrote. “This study also identifies potential biomarkers of treatment response and provides some insights into the mechanisms of action of HER3-DXd.”2