Biomarkers & AI in Future ADCs: Dr. Powles’ Insights

March 17, 2025

Céline Vandamme

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Thanks to these transformative results, EV-pembro has superseded traditional platinum-based chemotherapy as the first-line treatment, and Dr Powles believes a cure for bladder cancer is now possible—something that would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

About the author:

Céline Vandamme is a Scientific Business Director at CellCarta, specializing in the flow cytometry platform. With a PhD in immunology, and a broad expertise gained through her work at various academic and pharmaceutical institutions, Céline has profuse experience in designing flow cytometry assays to support immune monitoring activities in clinical trials.

Biomarkers & AI in Future ADCs: Dr. Powles’ Insights

March 17, 2025

Céline Vandamme

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

The importance of biomarkers in future ADC development

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

The role of AI in future ADC development

Looking ahead

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.

About the author:

Development of a Pathologist Scoring Method to Determine Inflamed, Excluded or Desert Immune Phenotype in Carcinoma

March 5, 2025

Pierre Gontard, Koen Marien, Konstantinos Avraam, Paula Lopez-Arias, Yannick Waumans, Nicholas Dupuis, Elizabeth Ross, Mark Kockx

Development of a Pathologist Scoring Method to Determine Inflamed, Excluded or Desert Immune Phenotype in Carcinoma

March 5, 2025

Pierre Gontard, Koen Marien, Konstantinos Avraam, Paula Lopez-Arias, Yannick Waumans, Nicholas Dupuis, Elizabeth Ross, Mark Kockx

Development of a Pathologist Scoring Method to Determine Inflamed, Excluded or Desert Immune Phenotype in Carcinoma

How Antibody-Drug Conjugates (ADCs) Are Advancing Precision Cancer Treatment

February 18, 2025

Cancer treatment is undergoing a transformation, with antibody-drug conjugates (ADCs) at the forefront of this progress¹. ADCs consist of a monoclonal antibody conjugated to a cytotoxic payload, offering precise targeting and a potent killing effect against cancer cells¹. The potential of these targeted therapies was exemplified in the groundbreaking work of Dr Thomas Powles, Director of the Bart’s Cancer Center, in which an ADC combination treatment more than doubled the median survival of bladder cancer patients.

Dr Powles’ work has earned him a spot in Nature’s 10 and TIME’s 100 lists for most influential people in science and health in 2024. He recently joined Christopher Ung, our Chief Scientific Business Officer, on our Let’s Talk webcast to share his first-hand, in-depth insights into ADCs. Here, we break down his research success and share his thoughts on the current and future ADC treatment landscape.

Dr Powles’ bladder cancer breakthrough

Dr Powles describes bladder cancer as a ‘Cinderella cancer’ due to there being little treatment progress over the last 40 years. The traditional approach — platinum-based chemotherapy — offers patients only modest benefits, with a median survival of around one year and a progression-free survival (PFS) of just six months.

However, Dr Powles’ trial of enfortumab vedotin (EV), a nectin-4 ADC, in combination with PD-1 inhibitor pembrolizumab, redefined expectations. The treatment more than doubled the median survival of patients, from one year with standard chemotherapy to 2.5 years, and doubled the PFS.

“We had tried many times to beat platinum-based chemotherapy and always failed. This was the first time we succeeded, but we didn’t just succeed—it was transformative,” said Dr Powles. “I wouldn’t have said this two years ago, but I think we might cure bladder cancer.”

The results of the EV-pembro trial highlight the potential of ADCs to reshape the cancer treatment landscape.

Expanding horizons: the growing role of ADCs in cancer treatment

In bladder cancer, EV-pembro has already replaced the traditional platinum-based chemotherapy as the front-line treatment. Dr Powles views ADCs as a “second-generation, targeted chemotherapy” with the potential to replace traditional approaches in some cancers. In the webcast, he highlighted several areas where ADCs are already in use, and where they hold future promise:

Breast cancer: The ADC trastuzumab deruxtecan (TDXd) has been approved to treat HER2-low breast cancers, an area where treatment options were previously limited. Research continues in potentially redefining biomarker selection to improve patient outcomes.
Lung cancer: Lung cancer research is currently undergoing rapid developments, with several ongoing trials of ADCs targeting Trop-2 (such as sacituzumab govitecan).
Urothelial cancer: In addition to EV-pembro, HER3-EGFR ADCs are showing promise in urothelial cancer, with an overall response rate of 43.5% in a recent trial.²
Hematological malignancies: ADCs targeting cluster of differentiation (CD) markers are currently being explored for lymphomas and leukemia.

The future of ADC development

While current ADCs have already transformed cancer treatment in some areas, Dr Powles believes there is still significant room for improvement. With advances in technology and drug design, future ADCs could be more effective and have fewer side effects.

“Even the established ADCs have a long way to go” said Dr Powles “I want to see new payloads, I want to see improved linker molecule technology, and I want to see duality of targeting. I think some of the issues we see today, like off target toxicity, could be resolved with these advancements.” He continues: “I foresee that we’re going to see a second generation of ADCs, and it’s going to be really promising.”

AI and biomarker-driven approaches are set to be key drivers of ADC advancement. Biomarkers are already essential in selecting patients for ADC treatments, but future ADCs may require more precise patient stratification. AI-powered digital pathology tools could improve the accuracy of biomarker detection, refining patient selection to ensure that treatments reach those most likely to benefit.

With these developments on the horizon, ADCs are poised to play an even greater role in cancer treatment — potentially redefining the standard of care across multiple cancer types.

To hear more of Dr Powles first-hand insights into the future of ADCs, watch the full webcast on-demand now: Webcast – Thomas Powles – Gated | CellCarta

About the Author:

References

Colombo R, Tarantino P, Rich J, et al. The Journey of Antibody–Drug Conjugates: Lessons Learned from 40 Years of Development. Cancer Discovery. 2024; 14 (11): 2089–2108.
Ye D, Bian X, Yang T, Jiang S, et al. BL-B01D1, an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic urothelial carcinoma (UC). Ann Oncol. 2024; 35(suppl_2): S1135-S1169.

How Antibody-Drug Conjugates (ADCs) Are Advancing Precision Cancer Treatment

February 18, 2025

Dr Powles’ bladder cancer breakthrough

The results of the EV-pembro trial highlight the potential of ADCs to reshape the cancer treatment landscape.

Expanding horizons: the growing role of ADCs in cancer treatment

Breast cancer: The ADC trastuzumab deruxtecan (TDXd) has been approved to treat HER2-low breast cancers, an area where treatment options were previously limited. Research continues in potentially redefining biomarker selection to improve patient outcomes.
Lung cancer: Lung cancer research is currently undergoing rapid developments, with several ongoing trials of ADCs targeting Trop-2 (such as sacituzumab govitecan).
Urothelial cancer: In addition to EV-pembro, HER3-EGFR ADCs are showing promise in urothelial cancer, with an overall response rate of 43.5% in a recent trial.²
Hematological malignancies: ADCs targeting cluster of differentiation (CD) markers are currently being explored for lymphomas and leukemia.

The future of ADC development

With these developments on the horizon, ADCs are poised to play an even greater role in cancer treatment — potentially redefining the standard of care across multiple cancer types.

To hear more of Dr Powles first-hand insights into the future of ADCs, watch the full webcast on-demand now: Webcast – Thomas Powles – Gated | CellCarta

About the Author:

References

Colombo R, Tarantino P, Rich J, et al. The Journey of Antibody–Drug Conjugates: Lessons Learned from 40 Years of Development. Cancer Discovery. 2024; 14 (11): 2089–2108.
Ye D, Bian X, Yang T, Jiang S, et al. BL-B01D1, an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic urothelial carcinoma (UC). Ann Oncol. 2024; 35(suppl_2): S1135-S1169.

Measuring Tumor Burden: Current and Emerging Approaches

January 24, 2025

Nathalie Bernard and Luca Genovesi

Traditional endpoints in oncology clinical trials, such as progression-free survival (PFS) and overall survival (OS), while definitive, often require extended follow-up periods and substantial patient cohorts. These requirements can significantly extend development timelines and increase costs.

Monitoring tumor burden through measurable residual disease (MRD) assessment — measuring the presence of residual cancer cells during or after treatment — has emerged as a promising alternative, offering an early biomarker of treatment response or relapse that could accelerate clinical development decisions.

This article examines current practices and recent developments in MRD measurement across both blood and solid malignancies.

Measurable residual disease in myeloma and other blood cancers

In hematologic malignancies, MRD assessment has gained significant traction, with the FDA’s Oncologic Drugs Advisory Committee (ODAC) recently recognizing MRD as an accepted endpoint for accelerated approval in multiple myeloma studies. MRD in multiple myeloma is currently measured using a highly specific, sensitive CE-marked next-generation sequencing (NGS)-based test, clonoSEQ.

Traditionally, MRD assessment in blood cancers has relied on bone marrow (BM) extracts. However, obtaining BM extracts is an invasive and painful procedure for patients, and may no longer be necessary. In fact, recent research suggests that less-invasive liquid biopsies could be a suitable alternative.

Mass spectrometry (MS) can detect soluble BCMA, a protein expressed on multiple myeloma cells, and M-protein, an abnormal protein produced by precancerous and cancerous bone marrow cells, in peripheral blood. Notably, MS applied to liquid biopsies has demonstrated greater sensitivity compared to NGS-based testing (clonoSEQ) of bone marrow extracts for M-protein detection.

MS offers the distinct advantage of tracking the specific M-protein clone produced by cancer cells and monitoring for additional clones as treatment progresses. This is facilitated by frequent sampling of peripheral blood, allowing for shorter intervals between assessments. Its high analytical range also enables the detection of signal even with reductions exceeding 90% of the original M-Protein amount, providing confidence in the quantification. The data generated by MS complements NGS-based testing and can guide decisions on further testing, including bone marrow biopsies. Importantly, MS can simultaneously measure both M-protein and BCMA from a single sample, making it an efficient tool for assessing tumor burden biomarkers.

Flow cytometry offers another approach for MRD measurement, specifically for detecting the presence of abnormal plasma cells, and can also be used to confirm target expression and identify new targets on abnormal cells. It has several advantages over NGS-based approaches for MRD measurement, including the fact that it is a standalone assay, and that there is no need to normalize to the screening timepoint and may help identify new phenotypes of abnormal cells.

Measurable residual disease in solid tumors

While MRD assessment originated in hematologic malignancies, its application in solid tumors is rapidly evolving.

Measuring MRD in solid tumors is typically done by tracking changes in levels of circulating tumor DNA (ctDNA) — DNA released into the bloodstream by dying tumor cells — using liquid biopsies, which are less invasive than tissue biopsies and enable earlier and more frequent monitoring of tumor burden. Since ctDNA originates from multiple lesions throughout the body, it also provides a more comprehensive view of tumor heterogeneity than single-site tissue biopsies.

Two main approaches have emerged for solid tumor MRD testing:

Tumor-informed MRD involves tracking specific known mutations identified from a patient’s tumor. This personalized approach typically monitors 10–50 variants throughout treatment. Often, NGS is used to measure tumor-informed MRD, where specific panels are preferred over whole genome sequencing approaches owing to the cost of sequencing (since cell-free DNA also contains normal DNA, and thus very deep sequencing is required to detect mutations with a low variant allele frequency (VAF) in the ctDNA). Known, specific mutations can also be measured with digital droplet PCR (ddPCR).
Tumor-naïve MRD examines a predefined panel of common mutations associated with treatment resistance, prognosis, or therapeutic response, and is used when a specific mutational profile of the patient’s tumor is unavailable. However, some patients may lack the common mutations in the predefined panel. NGS panels such as the TSO500 panel, the Oncomine Dx Express Test, or kits from Pillar Biosciences, are typically used for tumor-naïve MRD measurement.

The FDA recently released new guidance for those planning to use ctDNA assays for curative intent solid tumor drug development, with the guidance dedicating significant focus to ctDNA assay considerations for MRD measurement in particular.

Beyond tumor burden: investigating resistance pathways

Sequencing technologies offer value beyond MRD monitoring, too. There is a growing focus in oncology trials on understanding whether patients are developing therapeutic resistance, driven by mutations that emerge during treatment.

Advanced sequencing techniques can track these mutational changes throughout treatment, helping to identify resistance pathways and inform therapeutic adaptation. This application is currently most established in solid tumors, though it is also employed, albeit less frequently, in hematologic malignancies.

The ability to monitor mutation drift by sequencing liquid biopsies represents another powerful application of sequencing tools in personalizing cancer treatment, ensuring therapies can be adapted based on a patient’s evolving disease profile.

Optimizing clinical studies with measurable residual disease measurement

The integration of MRD assessment into clinical trials can offer earlier indication of treatment efficacy and enables more frequent disease monitoring. These capabilities can support more rapid development decisions in oncology trials.

Crucially, the field continues to evolve, with ongoing technological advances improving the sensitivity and reliability of MRD detection. A growing range of validated tools and approaches — from next-generation sequencing to mass spectrometry and flow cytometry — now provides options for accurate MRD measurement across different cancer types and clinical contexts.

Want to find out how MRD measurement could help optimize your clinical studies? Reach out to one of our experts to find out more.

About the authors:

Nathalie Bernard (PhD) is the scientific business director for the Genomic Services unit within CellCarta. Her background is in molecular biology, and she has many years of experience in PCR and sequencing, technologies used to discover or identify DNA and RNA biomarkers of clinical utility. At CellCarta, Nathalie is using her expertise to guide our customers in finding the best solution to their genomic questions.

Dr. Luca Genovesi is the Group Leader of R&D at CellCarta, where he manages a team of scientists in developing mass spectrometry-based assays to quantify biologics and biomarkers in complex matrices for clinical and pre-clinical studies. He has a strong background in Analytical Chemistry, with over 15 years of experience in the regulated pharmaceutical industry, including roles in pharmaceutical companies, CMOs, and CROs. Dr. Genovesi holds an M.Sc. in Organic Chemistry and a Ph.D. in Industrial Biotechnology from Milan University, Italy.

Measuring Tumor Burden: Current and Emerging Approaches

January 24, 2025

Nathalie Bernard and Luca Genovesi

This article examines current practices and recent developments in MRD measurement across both blood and solid malignancies.

Measurable residual disease in myeloma and other blood cancers

Measurable residual disease in solid tumors

While MRD assessment originated in hematologic malignancies, its application in solid tumors is rapidly evolving.

Two main approaches have emerged for solid tumor MRD testing:

Tumor-informed MRD involves tracking specific known mutations identified from a patient’s tumor. This personalized approach typically monitors 10–50 variants throughout treatment. Often, NGS is used to measure tumor-informed MRD, where specific panels are preferred over whole genome sequencing approaches owing to the cost of sequencing (since cell-free DNA also contains normal DNA, and thus very deep sequencing is required to detect mutations with a low variant allele frequency (VAF) in the ctDNA). Known, specific mutations can also be measured with digital droplet PCR (ddPCR).
Tumor-naïve MRD examines a predefined panel of common mutations associated with treatment resistance, prognosis, or therapeutic response, and is used when a specific mutational profile of the patient’s tumor is unavailable. However, some patients may lack the common mutations in the predefined panel. NGS panels such as the TSO500 panel, the Oncomine Dx Express Test, or kits from Pillar Biosciences, are typically used for tumor-naïve MRD measurement.

Beyond tumor burden: investigating resistance pathways

Optimizing clinical studies with measurable residual disease measurement

Want to find out how MRD measurement could help optimize your clinical studies? Reach out to one of our experts to find out more.

About the authors:

Let's Talk: A Conversation with Dr. Thomas Powles

November 28, 2024

In this webcast, Dr. Thomas Powles, Chair of Barts Cancer Centre (UK), joins Christopher Ung, our Chief Scientific Business Officer, for an in-depth conversation on the latest on Antibody Drug Conjugates (ADCs) and other innovative cancer therapies.

Key topics discussed in this webcast:

The challenges of treating metastatic bladder cancer
Targeting metastatic bladder cancer with Nectin-4 ADC
New ways of thinking about biomarkers for ADCs
How spatial biology could improve ADC assessment
Bi-specifics and other innovative therapies for metastatic bladder cancer
Being a physician and running clinical trials

Dr. Powles is a renowned expert in urology cancer and drug development, serving as the Chair of the Barts Cancer Centre at St. Bartholomew’s Hospital, Queen Mary University of London. He leads numerous clinical trials across all phases. Notably, his work in bladder and renal cancer has been pivotal in establishing new immunotherapy and antibody drug conjugate treatments as standards of care globally. Dr. Powles has been included in TIME’s list of the 100 most influential people in global health and in the Nature10 list in 2023.

Christopher Ung is CellCarta’s Chief Scientific Business Officer and has served in the companion diagnostics field since its inception. He is one of the original pioneers of the personalized medicine field. Mr. Ung currently leads the development and execution of CellCarta’s strategic and business initiatives, leveraging the company’s solid tumor and anatomic pathology services.

Let's Talk: A Conversation with Dr. Thomas Powles

November 28, 2024

Key topics discussed in this webcast:

The challenges of treating metastatic bladder cancer
Targeting metastatic bladder cancer with Nectin-4 ADC
New ways of thinking about biomarkers for ADCs
How spatial biology could improve ADC assessment
Bi-specifics and other innovative therapies for metastatic bladder cancer
Being a physician and running clinical trials