Episode 19: Efficacy of ADC therapy in HER2 low breast cancer: updated results from DESTINY-Breast04

In this episode of WND Breast, Dr Kevin Punie from GZA Hospitals and Prof Evandro de Azambuja from Institut Jules Bordet will discuss the latest findings of the DESTINY-Breast04 trial.

While ADCs have shown efficacy in HER2+ disease, this trial focuses on HER2-low patients, characterized by low HER2 IHC scores of +1 or +2 with negative FISH tests. Despite their low HER2 levels, these tumours still present potential docking sites for ADC treatment.

The trial, involving 557 metastatic patients, randomized participants to receive either T-DXd or chemotherapy based on physician preference. Initial findings revealed positive outcomes in terms of PFS and OS, with updated results at a median follow-up of 32 months confirming improvements in PFS. T-DXd demonstrated a significant over 6-month benefit in PFS compared to chemotherapy, with a positive OS benefit of 6%. This benefit was evident across the total population, predominantly comprising hormone receptor-positive patients, and even among the small hormone-negative subset.

Safety data indicated that T-DXd treatment led to slightly more nausea and vomiting compared to chemotherapy, with approximately 12% of patients developing ILD, necessitating careful monitoring, particularly in the first year of treatment with bi-monthly CT scans.

This trial holds significant implications for the landscape of ADC drugs in treating hormone receptor-positive disease. The experts discuss these clinical implications, noting that the drug is not yet available in Belgium. Reassessment of HER2 status may be warranted, considering the potential for initial misclassification and tumour heterogeneity after disease progression. Correlating imaging outcomes with actual biopsy results is crucial, and ongoing clinical trials are investigating this relation.

In Belgium, triple-negative patients are currently treated with anti-Trop2-antibody as the standard of care in the second line. The ASCENT trial established SG as the treatment of choice, and the current findings from DESTINY-Breast04 lack statistical power to suggest otherwise. While T-DXd may emerge as a subsequent treatment option,  no trials have explored the effect of using a sequence of ADCs.