Over the last decade, much progress has been made in developing a range of antibody–drug conjugates to treat breast cancer, with the construction of bespoke agents for individual patients and exciting prospect for the future
The idea behind antibody–drug conjugates (ADCs) is to deliver high doses of a cytotoxic payload selectively to cancer cells while minimising toxicity to healthy cells. There was an early disappointment with first-generation ADCs and the withdrawal of gemtuzumab ozogamicin due to toxicity, but since then, ADCs have continued to evolve in a positive way, particularly in the treatment of breast cancer.
The anti-HER2 agent ado-trastuzumab emtansine was the first approved ADC for breast cancer in 2013. More recently, two new trastuzumab-based ADCs containing a topoisomerase I inhibitor payload have been approved: sacituzumab govitecan is an anti-trophoblast cell-surface antigen 2 (Trop-2) ADC for pretreated metastatic triple-negative breast cancer (TNBC), while trastuzumab deruxtecan has gained approval for HER2-positive advanced breast cancer.
As the technology advances even further, we may be able to construct the most appropriate antibody, linker and payload based on the patient’s tumour antigens and other characteristics.
ADC development continues at pace and there are two novel compounds currently in trials that warrant particular attention. [Vic-]trastuzumab duocarmazine is a HER2-targeting ADC in which trastuzumab is bound to a linker compound containing duocarmycin. In the phase III TULIP trial in patients with pretreated HER2-positive breast cancer, [vic-]trastuzumab duocarmazine significantly improved progression-free survival compared with physician’s choice chemotherapy (Ann Oncol. 2021:32 suppl_5:S1283–S1346). The second novel agent is the Trop-2-targeting therapy, datopotamab deruxtecan, with preliminary results from the phase I TROPION-PanTumor01 trial indicating activity against solid tumours, particularly in patients with refractory metastatic TNBC (Ann Oncol. 2021:32 suppl_2:S60–S78). The phase III TROPION-Breast01 trial is ongoing in patients with metastatic hormone receptor-positive, HER2-negative breast cancer, with results expected in 2025 (NCT05104866).
Currently, we select ADCs based on tumour characteristics, such as HER2-positive or TNBC, but one can envisage that, similar to choosing therapies based on genotype, we will be able to select therapies based on profiling tumour antigens. Indeed, we are already seeing trials in which patients are screened for the antigen first, before enrolment. Tusamitamab ravtansine is an ADC composed of a monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) linked to the anti-tubulin agent, DM4, and an ongoing phase I/II trial is selecting participants based on CEACAM5 expression (Ann Oncol. 2021:32 suppl_5:S949–S1039). A potential barrier is that antigen expression may change over time, as we see with mutations. Additionally, selecting antigens expressed highly in tumours, but not normal cells, remains an important key to success.
As the technology advances even further, personalised ADCs may be a possibility in the future. We may be able to construct the most appropriate antibody, linker and payload based on the patient’s tumour antigens and other characteristics. Of course, trying to generate personalised ADCs within an acceptable timeframe and without prohibitively high costs will be a challenge.
In the era where everything is ‘smart’, I see ADCs as ‘smart chemotherapy’. Wherever chemotherapy is currently used, ADCs could serve as the replacements of the future, and with personalised ADCs, the opportunities are enormous.
Don't miss:
Antibody–drug conjugates (ADCs). ESMO Targeted Anticancer Therapies Congress 2022
Educational session, 08.03.2022, h. 16:45 – 18:00, Channel 1
