Opportunities and challenges posed by the rise of antibody drug coagulates

Antibody drug clots (ADCs) are an inherently complex and rapidly evolving area of ​​oncology, offering both exciting treatment opportunities and difficult challenges related to drug resistance, side effects, and stakeholder education. This article explores the revolutionary rise of ADCs and the role medical communication can play in their success.

From a drug development perspective, ADCs are unique; they are the result of two strands of research that date back more than a century. First, there were groundbreaking advances in chemotherapy and payload technology, which included the identification of topoisomerase (Top1) inhibitors. Second, there were monoclonal antibodies, which have made significant progress over the past 50 years, including the approval of trastuzumab for the treatment of HER2-positive breast cancer.

Advances in medicinal chemistry brought two treatment approaches together in the early 2000s, ushering in the era of ADCs. The last decade has seen a large number of approvals for various solid and hematological cancers.

Shifting boundaries
Since then, technological advances have continued to push ADCs to new limits and improve treatment outcomes. For example, we now know that certain properties of the monoclonal antibody, such as subclass, can affect important aspects such as immunological effects and half-life.

In terms of payload, ADCs enable the efficient delivery of very potent cytotoxic drugs that would not normally be tolerated by the body if administered as systemic chemotherapy. Advances in linker technology, including the development of cleavable linkers, enable the payload to be released with the potential to spread beyond the target tumor cell into the surrounding microenvironment. This can induce side effects that have driven innovations in the treatment of breast cancer and other tumor types.

We recently saw data for the DESTINY-Breast06 trial evaluating trastuzumab deruxtecan – a HER2-targeted ADC with a top1 inhibitor payload that can cause side effects. The trial compared trastuzumab deruxtecan to physician's choice of chemotherapy in patients with previously treated hormone receptor-positive HER2-low and ultra-low metastatic breast cancer (MBC). This is a group of patients who historically would have been considered HER2-negative and not long ago would not have received HER2-targeted therapy.

We already know from other studies that HER2-low MBC can benefit from trastuzumab deruxtecan, but this study was unique in that it also included the ultra-low HER2 patient population, which is characterized by tumors with weak HER2 staining on a very small proportion of cells.

When we look at the results, we can see positive outcomes for every patient group, including those with low and ultra-low HER2 levels. Overall, the data demonstrate the continued transformative potential of ADCs and how they are changing breast cancer treatment.

Adverse events and treatment resistance
However, that does not mean that this treatment and ADCs in general do not present challenges. And this is where medical communication can play an important role.

One of these challenges is to more precisely define the patient population to determine how to best integrate this data into the landscape. For trastuzumab deruxtecan, refining HER2 cutoffs and potentially incorporating additional biomarkers will help advance the identification of patient subgroups. These may also be influenced by other clinical factors such as previous treatments, risk of side effects and even patient preferences.

ADCs are associated with unique side effects, often related to the payload. Interstitial lung disease remains a challenge for trastuzumab deruxtecan, while other unique ADC side effects include ocular toxicity and dermatologic toxicity, among others.

Medical communication has a clear role to play in addressing these challenges, including improving understanding of treatment strategies for adverse events and raising awareness of patterns and mechanisms of treatment resistance. These strategies should be directed at all key stakeholders, including physicians, healthcare professionals and patients.

One of the biggest challenges for drug development teams is to gain a deeper understanding of treatment resistance to ADCs, which can arise through mechanisms related to individual components, such as binding of the monoclonal antibody or increased efflux of the payload.

Development of educational solutions
Despite these difficulties, ADCs will continue to have a transformative impact on oncology and are already being rapidly integrated into treatment algorithms, not only for solid tumors but also for hematological cancers.

At Inizio, we combine innovative strategies with medical and scientific expertise, real-world data and human empathy to advance life-saving cancer treatments.

If you are attending the ESMO Congress 2024, book an appointment with us at booth 431e here.

You can find out more about our oncology expertise here.