New Antibody–Drug Conjugates Are Emerging for Advanced Cancers

At the 2022 ESMO Congress, first-in-human trials of new antibody–drug conjugates in patients with advanced solid tumours reported promising findings.

What Is an Antibody–Drug Conjugate?

Antibody–drug conjugates use an antibody designed to bind a molecular target on a tumour, attached to a chemotherapy agent that can be delivered to a particular cancer cell. This is a "Trojan horse" approach. For more detail, see An Advance in Drug Discovery – Targeted Antibody and Chemotherapy Conjugates.

Two Presentations at ESMO 2022

The studies reported promising responses and safety profiles in patients with heavily pretreated cancers.

The first presentation reported a phase I/II dose-finding study of DS-7300, a B7-H3-targeting antibody–drug conjugate carrying a topoisomerase I inhibitor, in 147 patients with advanced solid tumours.

After a median of 5 previous treatment lines, the response rate was 32% and disease control rate 71.4%.

Small cell lung cancer (SCLC) patients included 19 individuals, of whom 11 (58%) achieved a partial or complete response, with median response duration of 5.5 months. No new safety signals emerged compared with earlier short-term data. However, more patients at the highest dose experienced grade 3 adverse effects, which appeared earlier than at lower doses.

Although each tumour subgroup was small, the largest response was seen in aggressive SCLC. Response duration may not be considered long compared with other solid-tumour treatments, but these are encouraging findings in a difficult, treatment-resistant disease.

The second presentation reported preliminary findings from a phase I dose-escalation and expansion study of zanidatamab zovodotin (ZW49), an antibody–drug conjugate containing a bispecific HER2-targeting antibody and an auristatin toxin. The study assessed 77 heavily pretreated patients with HER2-positive cancers: 27% gastro-oesophageal and 22% breast cancer. Dose-limiting toxicity occurred in one patient receiving 1.75 mg/kg weekly and another receiving 2.5 mg/kg every 3 weeks. Overall, 91% experienced treatment-related adverse effects, mostly grade 1 or 2, while 12% had grade 3 events.

Among 29 evaluable patients receiving ZW49 at 2.5 mg/kg every 3 weeks, confirmed objective response was 31% and disease control 72%.

Safety signals appeared reasonable, with early antitumour activity supporting further assessment across tumour types.

Conclusion

Antibody–drug conjugates offer considerable promise, but the lack of lasting disease control seen with standard systemic chemotherapy may remain a challenge. I look forward to studies of combinations, particularly those harnessing the immune system. Given conventional chemotherapy’s well-known toxicity, it is also important to explore whether these conjugates could be used earlier in cancers treated with neoadjuvant or adjuvant systemic therapy and offer a more favourable adverse-effect profile.

We also await the development of next-generation conjugates that can be combined with non-chemotherapy treatments, including agents that enhance anticancer immunity or positively modulate the tumour microenvironment. These may act directly against cancer or reshape the microenvironment to improve responses to other drugs.