Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that combine an antibody, designed to recognise and bind to cancer cells, with a cytotoxic agent, often a chemotherapy drug. The antibody delivers its toxic payload directly into the cancer cell while sparing as much healthy tissue as possible.
ADCs have already shown highly encouraging clinical results in a number of solid and haematological tumours. However, despite their promise, their efficacy remains variable across patients. To date, the biological mechanisms underlying this variability, especially the causes of resistance, are still poorly understood. Identifying predictive biomarkers of response is a key challenge in optimising the personalised use of these therapies.
Published in Nature Medicine, ICARUS-BREAST 01 is a phase II trial sponsored by Gustave Roussy. It evaluated the efficacy and safety of patritumab deruxtecan (HER3-DXd) in 99 patients with HR+/HER2- metastatic breast cancer whose disease had progressed following treatment with a CDK4/6 inhibitor and one line of chemotherapy. The trial also included an exploratory component aimed at identifying biomarkers predictive of response or resistance to this innovative therapy.
Promising Clinical Results
Patritumab deruxtecan is an ADC designed to target the HER3 protein, which is expressed in a high proportion of hormone receptor-positive breast cancer cells. This protein is known to play a role in resistance mechanisms to certain standard treatments, including hormone therapy and some targeted therapies.
From May 2021 to June 2023, ninety-nine women received patritumab deruxtecan by infusion every three weeks, until disease progression or the onset of a serious toxicity. The study met its primary endpoint: 53.5%of patients experienced a significant reduction in tumour size with patritumab deruxtecan, and around 63% of patients derived clinical benefit from the treatment (tumour shrinkage or disease stabilisation lasting at least six months). Notably, two patients experienced complete disappearance of visible signs of disease, a response that has now lasted more than two years.
The median follow-up period was 15.3 months. Median progression-free survival was 9.2 months, and the average duration of response was 9.3 months. The most common adverse events were fatigue (83%), nausea (75%) and diarrhoea (53%). The safety profile was consistent with that previously reported.
The Role of the UNLOCK Programme
The exploratory research component of ICARUS-BREAST 01 shed light on why some patients respond better than others do to patritumab deruxtecan, by identifying biomarkers linked to resistance mechanisms. This research, conducted within Gustave Roussy’s UNLOCK programme at the IHU Prism, was based on exploratory analysis of tumour samples taken before and after treatment, as well as imaging and genetic data.
These exploratory analyses suggest that the response to the drug may be linked to how HER3 is distributed within the tumour and to the absence of certain mutations, such as ESR1. Another finding indicates that disease control may last longer in patients whose tumours express higher levels of HER3.
Samples collected during treatment revealed that the drug’s efficacy appears to depend on its ability to penetrate the tumour, and on the activation of a specific immune response marked by an interferon signature, proteins naturally produced by the body that play a key role in stimulating the immune system.
“In this study, HER3-DXd demonstrated promising efficacy and good tolerability in patients with advanced hormone receptor-positive breast cancer who had exhausted standard treatment options,” says Dr Pistilli. She adds, “ICARUS-BREAST 01 also highlights interesting biological insights that could ultimately help us better identify patients who are most likely to benefit from this approach. These initial results now need to be confirmed by larger trials, some of which are already under way internationally and will soon open in France. Another study, ICARUS-BREAST 02, is currently ongoing with HER3-DXd. It aims to evaluate the efficacy of this ADC in combination with Olaparib following progression on a previous ADC, trastuzumab deruxtecan (T-DXd).”
Source
Nature Medicine
Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial
https://www.nature.com/articles/s41591-025-03885-3
Article published the 4th of september 2025
[1]Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 2024;74(1):12–49