The Role of Biomarkers and AI in the Future of Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are changing cancer treatment for the better, combining precision-targeting of cancer cells with the potency of chemotherapy.  

Perhaps one of the most exciting recent advances in ADCs was seen in a trial led by renowned oncologist Dr Thomas Powles. The combination treatment of enfortumab vedotin (EV), a nectin-4 ADC, and pembrolizumab (pembro), a PD-1 inhibitor, more than doubled the median survival of metastatic bladder cancer patients, from one year with standard chemotherapy, to two and a half years.   

Thanks to these transformative results, EV-pembro has superseded traditional platinum-based chemotherapy as the first-line treatment, and Dr Powles believes a cure for bladder cancer is now possible—something that would have seemed unimaginable just a few years ago.  

In our latest Let’s Talk webcast, we had the privilege of talking to Dr Powles about the future possibilities of ADCs. While in our previous blog we discussed his thoughts on the future of ADCs in cancer treatment, here we summarize his insights on the pivotal role that biomarkers and AI could play in their development.  

The importance of biomarkers in future ADC development

As with many other new precision medicine therapeutic strategies, a key hurdle in ADC development is understanding why some patients benefit more than others. While EV-pembro is broadly effective in treating bladder cancer, since nectin-4 is expressed in 90% of the cancer cells, there are still some patients that show limited benefit, and understanding why has proven challenging. Identifying biomarkers to stratify subtle differences in patient profiles may be crucial to achieving better outcomes.  

“If we’re going to cure bladder cancer, we may not do so with EV-pembro alone,” said Dr Powles. “While it could serve as a baseline treatment for many, we must understand why some patients don’t respond as well, and how we can improve their response, if we are going to achieve a cure.”  

“That’s where the second generation of biomarkers come in“ he continues. “Using transcriptomics and multiplex analysis, we could see what’s expressed in non-responders and find out whether we should be using other agents or more complex immune therapy for those patients.” 

Dr Powles believes that biomarkers will be key to ADC breakthroughs beyond bladder cancer, too. “Deep down, I think the transformative result we’ve seen with EV-pembro in bladder cancer is not a black swan event,” he said. “I think it’s possible in subsets of other cancers.” 

While other ADCs have shown promise, such as those directed at TROP2 and HER2, patient selection criteria remain imprecise, confounding their real effectiveness.  

For TROP2 ADCs, such as sacituzumab govitecan, despite rapid progress, a more refined biomarker strategy is still needed to identify the patients who will benefit the most from this treatment. Similarly, with the HER2-low breast cancer ADC trastuzumab deruxtecan, there is debate around how HER2 expression levels correlate with response rates. HER2 scoring methods can produce inconsistent results, therefore more precise biomarker assessment could substantially improve treatment outcomes.

The role of AI in future ADC development

To help in advancing ADC development, researchers are looking to leverage AI technologies to improve biomarker assessment. Traditional pathology methods rely on human interpretation, which can lead to inconsistencies in how biomarkers are assessed across different labs and clinical settings.

“Diagnostic pathology using AI can bring a standardization that currently isn’t possible with traditional methods,” said Powles. “So far, we haven’t been overly successful with biomarker development. To move forwards, we need AI technology to reduce variability and improve accuracy in patient selection.”

Currently, researchers are investigating the use of AI in identifying responders and non-responders for TROP2 ADCs. When it comes to their use in lung cancer treatment, Dr Powles states: “If you can find the 30% of patients that have a strong response, that could potentially be transformative. If we’re not currently seeing any improvement over traditional chemotherapy with TROP2 ADCs, then we need to find a smarter way of assessing biomarkers, and that could be through AI.”

Looking ahead

The future of ADCs holds great promise, with refined biomarker assessment and AI potentially playing a pivotal role in the development of more personalized therapies in finely-stratified patient cohorts.  

In the full webcast, Dr Powles shares his thoughts on the current and future treatment landscape of ADCs, including where he believes there is most potential for another breakthrough ADC treatment, and the technologies and strategies that could drive their development.  

Don’t miss out on hearing the firsthand insights of a true ADC expert—watch the webcast on demand today: Webcast – Thomas Powles – Gated | CellCarta