Patritumab Deruxtecan Meets Primary End Point in ICARUS-BREAST01 Trial

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 (HER2–) metastatic breast cancer (mBC) in the ICARUS-BREAST01 trial (NCT04965766). The data were published in Nature Medicine.^1,2

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 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% CI, 44.8%-62.1%). Of the population, 2 patients achieved a complete response (CR), 51 achieved a partial response (PR), and 37 presented with stable disease (SD). 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 experienced disease progression or death with a median progression-free survival (PFS) of 9.2 months (95% CI, 8.0-12.8). Overall survival data were immature at the time of the data cutoff.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-not available) months and 9.1 (95% CI, 6.7-N/A) months in the 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

REFERENCES

1. Patritumab deruxtecan (U3-1402) in unresectable locally advanced or metastatic breast cancer (ICARUS BREAST). ClinicalTrials.gov. Updated February 10, 2025. Accessed September 9, 2025. https://clinicaltrials.gov/study/NCT04965766?term=NCT04965766&rank=1

2. Pistilli B, Mosele F, Corcos N, et al. Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial. Nat Med. Published online September 4, 2025. doi:10.1038/s41591-025-03885-3

3. Howlader N, Altekruse S, Li C, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Can Inst. 2014;106(5):dju055. doi:10.1093/jnci/dju055

4. Gerlach A. The evolution of ADCs in breast cancer: challenges and innovations. Pharmacy Times. December 12, 2024. Accessed September 9, 2025. https://www.pharmacytimes.com/view/the-evolution-of-adcs-in-breast-cancer-challenges-and-innovations