ICARUS-BREAST01

During the 2024 annual ESMO meeting efficacy, safety and biomarker data were presented for the ICARUS-BREAST01 study evaluating the antibody drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) in patients with hormone receptor positive (HR+), HER2-negative (HER2 0 and low) metastatic breast cancer. In this video, Dr Eline Naert (Ghent University Hospital) and Dr Véronique D’Hondt (Centre Régional du Cancer, Montpellier, France) talks us through the key take aways from this presentation. 

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 academic, multi-centre, single-arm, phase 2 ICARUS-BREAST01 study this agent is used to treat patients with HR+/HER2- advanced breast cancer, who progressed on a CDK 4/6 inhibitor and one line of chemotherapy. During ESMO 2024, the results of the first 99 patients in the study were presented.

The median age of the patients in this analysis was 57 years, about half of the patients had a HER3 overall membrane positivity of ≥75% and 39.4% had an IHC 0 score for HER2 expression. At the time of the analysis, treatment was ongoing in 19.2% of the patients with a median overall treatment duration of 11 cycles. The confirmed overall response rate (ORR) was reported at 53.5% with a clinical benefit rate of 62.6%. Also the progression-free survival looked promising with a median of 9.4 months. The treatment did come at the cost of considerable toxicity with an incidence of grade ≥3 treatment-related adverse events of 50.1%. Most of these adverse events were gastro-intestinal in nature and were generally manageable with dose modifications. In total 7 cases of treatment-related interstitial lung disease were reported (all grade 1).

Interestingly, HER3-DXd exhibited clinical activity across a broad range tumoral HER3 and HER2 expression levels. Further exploratory biomarker analyses suggested that the distribution of HER3-DXd in the tumor could play a role in the selection of patients with a higher likelihood for a response. In addition, samples from patients with a response to the treatment frequently displayed an upregulation of genes with a known role in immune responses (e.g.,IFN alpha and gamma).

In conclusion, the results of ICARUS-BREAST01 indicate promising clinical activity of HER3-DXd in previously treated patients with HR+/HER2- advanced breast cancer. These data warrant a further evaluation of this agent in a randomized-controlled, phase III trial.