In the ICARUS-BREAST 01 study, more than half of patients with metastatic breast cancer saw their disease decrease or disappear completely thanks to the treatment, and in some patients, this response has now lasted for more than two years.
Dr. Barbara Pistilli, head of the breast pathology committee at Gustave Roussy, and Guillaume Montagnac, Inserm researcher within the "tumor cell dynamics" unit he leads at Gustave Roussy, coordinated this study whose results have just been published in the journal
Nature Medicine. They highlight the effectiveness of patritumab deruxtecan (HER3-DXd), a HER3 antibody-drug conjugate, in patients with hormone-dependent metastatic breast cancer who had already received several treatments, including hormone therapy, chemotherapy and a specific targeted treatment.
The study also provides initial clues to understanding why some patients respond better than others to this targeted therapy. This research was conducted as part of the UNLOCK program within the IHU Prism, in partnership with Daiichi Sankyo.
Breast cancer remains the most common malignant tumor in women, with 2.3 million new cases and 685,000 deaths worldwide in 2020[1]. These figures demonstrate the urgent need to develop new treatments for this indication.
Antibody-drug conjugates (ADCs) are a new therapeutic class that combine an antibody, which will identify the tumor cells to be destroyed, with a cytotoxic agent, most often a chemotherapy molecule. The antibody reaches the cancer cell to deliver its toxic payload while sparing healthy tissues as much as possible.
ADCs have already shown very encouraging clinical results in many solid and hematological tumors. But while these innovative treatments offer real hope, their effectiveness remains variable between patients. To date, the biological mechanisms that explain this variability, particularly the causes of resistance, remain poorly understood. The identification of predictive biomarkers of response remains a challenge to best personalize the use of these treatments.
Published in
Nature Medicine, ICARUS-BREAST 01 is a phase II trial promoted by Gustave Roussy, which evaluated the efficacy and tolerance of patritumab deruxtecan (HER3-DXd) in 99 patients with HR+/HER2- metastatic breast cancer that had progressed after treatment with a CDK4/6 inhibitor and one line of chemotherapy. The trial also included an exploratory component aimed at identifying predictive biomarkers of response or resistance to this innovative treatment.
Patritumab deruxtecan is an antibody-drug conjugate designed to target the HER3 protein, present on the surface of tumor cells in hormone-dependent breast cancers. This protein is involved in resistance mechanisms to certain standard treatments, particularly 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 development of severe toxicity. The study results show that the primary evaluation criterion was met, since 53.5% of patients saw their tumor significantly decrease with patritumab deruxtecan, and approximately 63% of patients derived clinical benefit from the treatment (reduction or stabilization of the disease for at least six months). Finally, two patients experienced complete disappearance of visible signs of their disease, a response that has now persisted for more than 2 years.
The median follow-up lasted 15.3 months. The median duration of disease progression-free survival was 9.2 months, and the response to treatment lasted on average 9.3 months. The most frequent adverse effects were fatigue (83%), nausea (75%) and diarrhea (53%). The safety profile was identical to what had been previously reported.
The exploratory research component of ICARUS-BREAST 01 helped better understand why some patients respond more favorably than others to patritumab deruxtecan by identifying biomarkers involved in resistance mechanisms. This research, conducted as part of the UNLOCK program of Gustave Roussy within the IHU Prism, was based on exploratory analysis of tumors before and after treatment, using biopsies, imaging examinations and genetic analyses.
These exploratory analyses suggest that the response rate to the drug could be related to how the target (HER3) is distributed within the tumor, as well as the absence of certain mutations (ESR1). Another observation indicates that the duration of disease control could be longer in patients whose tumors express more HER3.
Analyses of samples taken during treatment show that the drug's effectiveness seems to depend on its good diffusion within the tumor and the activation of a specific immune response characterized 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 treatment showed promising efficacy and good tolerance in patients with advanced hormone-dependent breast cancer who had failed standard treatments," concludes Dr. Pistilli. She adds:
"The ICARUS-BREAST 01 study also highlights interesting biological leads that could, in the long term, help us better select patients likely to benefit from this approach. These initial results must now be confirmed by larger trials, some of which have already started internationally and will soon arrive in France. Another study, ICARUS-BREAST 02, is ongoing with HER3-DXd. The latter aims to evaluate the effectiveness of this ADC in combination with Olaparib after cancer progression on a previous ADC, which is trastuzumab deruxtecan (T-DXd)."
[1]Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 2024;74(1):12-49.