Episode 12: Antibody-drug conjugates: the evolving field of targeted chemotherapy in breast cancer
Presented by Dr Kevin Punie (GZA Hospitals) and Prof Evandro De Azambuja (Institut Jules Bordet)
The review article discussed systematically assesses the impact of ADCs in BC treatment. Presently, three ADCs are deployed in clinical settings: two targeting HER2 and one directed against Trop2.
These pharmaceutical agents leverage the Trojan horse principle. The core mechanism involves the combination of chemotherapy with a monoclonal antibody through a linker. Subsequently, the ADC is internalized within cancer cells then releasing the chemotherapeutic agent or payload for cellular destruction. The objective is to realize a more precisely targeted and efficacious chemotherapy approach with diminished side effects. TDM-1, the first ADC, validated this modality and was approved for treatment in HER2-positive breast cancer patients in metastatic and post-neoadjuvant setting.
Beyond the localized impact on cancer cells, ADCs exhibit a cytotoxic effect on adjacent cells with low antigen expression. In the case of cleavable linkers, the bond between the antibody and the payload is broken before ADC internalization, destroying not only target cells but also neighbouring cells—a phenomenon known as the bystander effect. This bystander effect has enabled the efficacy of T-DXd in patients with HER2-low breast cancer, expanding the application of ADCs to TNBC patients.
The utilization of SG, a Trop2-targeted ADC, demonstrated favourable outcomes in TNBC patients compared to conventional chemotherapy. Despite a higher incidence of >grade 3 adverse events with SG compared to traditional chemotherapy, the discontinuation rates did not significantly differ. These findings signify the potential of a new generation of ADCs to effectively target proteins highly expressed in tumours, even when they do not belong to the oncogenic pathway.
Despite the positive trajectory of ADC development, a considerable timeframe lapsed between the approval of the first and second ADCs for breast cancer treatment. Studies affirm the favourable efficacy and safety profile of ADC treatment, yet it remains associated with traditional chemotherapy toxicities, primarily attributable to the bystander effect.
The introduction of TDM-1 was followed by the development of other ADCs, but these exhibited limited activity and severe toxicity, impeding their integration into clinical practice. The subsequent generation of ADCs, although displaying slightly elevated toxicity, demonstrates manageable side effects and significantly enhanced efficacy.
Addressing side effects early in treatment is crucial for sustained patient adherence to ADC therapy. Consequently, evaluating ADCs in earlier treatment lines is imperative. Continued investigation is essential to establish robust data on optimal treatment sequencing with these compounds.
To overcome existing challenges, biomarkers assume a pivotal role. Presently, there is a lack of biomarkers to identify patients likely to benefit from or be resistant to ADCs. The effectiveness of ADCs in patients not meeting traditional antigen positivity criteria marks a paradigm shift. Additionally, the sequencing of ADCs presents a regulatory challenge across countries. Defining the optimal position of these agents in treatment algorithms and establishing a data-driven approach to sequence different ADCs for maximal efficacy remain critical challenges.
References:
Nader-Marta G. et al. (2023) Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment. Ther Adv Med Oncol. 15: 1-24.