A conversation with Agendia CMO William Audeh, MD

More than 17,000 patients have enrolled in Agendia’s FLEX trial studying full genome profiling and complete clinical data for those diagnosed with stages I, II, or III breast cancer. In particular, the study intends to follow patients of diverse backgrounds and genders for more than 10 years.

While observational studies are different from investigational studies in many ways, this particular study attempts to enroll increasingly diverse patients and in large numbers — two goals often top of mind for all clinical researchers.

Here, CMO William Audeh, MD, details Agendia’s diverse, high-enrolling trial and how sponsor companies of investigational trials might benefit from its experiences.

Clinical Leader: Has Agendia attempted this large of a study before? If so, what were some lessons learned from previous trials you implemented in this one?

William Audeh, MD: This is Agendia’s largest study to date. The FLEX Study, which aims to enroll 30,000 patients, is a first for us in terms of scale. Each enrolled patient has both clinical data and whole transcriptome data collected and entered into a common real-world database. To make sure we succeed, we started with comprehensive planning and setting clear milestones and timelines to keep us on track. Our team also has built a strong network of over 100 participating sites around the world, which helps us reach a diverse group of patients.

The study is designed with the patients in mind, prioritizing their individual needs and optimizing convenience. It is also designed with clinician researchers in mind, providing them access to a large and diverse database of patients. This approach has helped us maintain high enrollment and retention rates. On top of that, we’re using advanced data management systems to handle the large volume of data efficiently and accurately. We’ve also kept in constant touch with our study participants, as well as clinician researchers and patient advocacy groups, to ensure everyone is aligned and supported throughout the study.

Agendia has enrolled a diverse population. What does that mean, in terms of race, ethnicity, gender, and/or other criteria?

The FLEX Study has enrolled a highly diverse group of patients, which is key for getting comprehensive and representative data. This includes patients from various racial and ethnic backgrounds, including 1,377 self-identified Black patients, 530 Latin American/Hispanic patients, and 353 Asian and Pacific Islander patients enrolled to date. While the main focus is on women with early-stage breast cancer, the study is also open to male patients to ensure a full understanding of the disease across genders. Additionally, with over 100 sites participating across the United States and internationally, we’ve secured a wide geographic representation.

How does this differ from or improve upon observational research for EBC that’s been done or is currently being done?

The FLEX Study takes observational research for early breast cancer (EBC) to a much deeper level than what has been done before. FLEX is one of the largest studies of its kind, giving researchers a much bigger and more comprehensive data set to work with. We are unique in collecting whole transcriptome data, which allows for the analysis of the expression of all genes in a tumor. This method offers a more detailed and comprehensive understanding of the genetic landscape of breast cancer compared to traditional methods that might focus on specific genes or markers. This deeper genetic insight can lead to the identification of new gene associations with prognostic and predictive value. By including a highly diverse group of patients, we’re able to look at racial and ethnic disparities in breast cancer, based on self-described categories, which is something that has been underrepresented in past studies. Furthermore, FLEX encourages investigator-initiated sub-studies, which fosters innovative research and brings in diverse perspectives. To date, our investigators have conducted over 40 sub-studies on several topics.

What are or what do you suspect will be some of the learnings about race and ethnicity and their role in the prevalence or progression of breast cancer?

The FLEX Study is set to yield significant insights into how race and ethnicity play a role in breast cancer. We understand that self-reported race is an imperfect indicator of genetic ancestry, but it is the most useful indicator of the possible effects of genetic ancestry on breast cancer biology. We’re looking to identify genetic variations that might explain why breast cancer prevalence and progression differ among various racial and ethnic groups.

The study also sheds light on how patients of a specific racial background might respond to a particular treatment regimen. Results from FLEX highlight disparities in breast cancer outcomes and pinpoint the factors that may be contributing to this difference, both social determinants of health outcome as well as genetics. These insights assist physicians in making informed decisions about the best path forward for each patient, therefore optimizing treatment success.

Agendia enables investigator-initiated sub-studies. Why is it important to provide this opportunity? And what are some of the sub-studies PIs are embarking on?

Investigator-initiated sub-studies are an extremely important aspect of the wider FLEX Study for multiple reasons. First, they spark innovation by letting researchers dive into new hypotheses and areas that the main study might not cover. This allows for an even greater opportunity to shed light on current gaps in our understanding of early breast cancer behavior and treatment. These sub-studies bring in diverse perspectives and expertise, which enriches the overall research. They also allow for a tailored research approach that can address specific questions relevant to different patient populations or clinical scenarios. Some of the sub-studies we’re working on include looking at the genomic profiles of different racial and ethnic groups to understand variations in tumor biology and examining the outcomes of various treatment regimens in diverse populations to find the most effective approaches for a specific tumor type.

We have submitted multiple abstracts and presentations of data to major oncology meetings since the inception of FLEX, and we continue to generate important and valuable outcomes data as substantial proportions of the enrolled patients are reaching five years of follow-up since diagnosis.

Although FLEX is an observational study, there are likely applicable learnings that apply to investigational trials. What lessons learned or best practices would also benefit investigational trials?

First, prioritizing the recruitment of a diverse patient population is crucial to ensure the results apply to a broader demographic. Racial and ethnic diversity in breast cancer clinical trials helps researchers understand the effects of socioeconomic disparities in healthcare access and genetic differences, which can significantly impact treatment outcomes. For example, non-Hispanic Black women have a lower incidence of breast cancer compared to non-Hispanic white women, but they have a higher overall mortality rate¹.

Designing studies with a patient-centric approach helps boost enrollment and retention rates. By focusing on the needs and experiences of patients, trials can become more appealing and accessible, leading to higher participation and more reliable data. Building strong collaborative networks with multiple sites makes large-scale studies more feasible. Advanced data management systems allow us to handle large data sets efficiently and accurately. These practices can significantly improve the quality and impact of investigational trials.

Diverse patient recruitment is a challenge among sponsor companies, and the challenge is especially dire given the FDA’s latest guidance on diversity and its requirement for a Diversity Action Plan (DAP). What can you recommend to other sponsor companies — be it site selection, patient recruitment, or patient enrollment strategies — to help them in their diversity pursuits?

It is crucial to choose sites that serve diverse populations of underrepresented groups and have enrolled those patients in prior clinical trials. The intent is to seek sites that not only have a high proportion of an underrepresented group in their patient population but also that the site participates in clinical research. Engaging with community leaders, such as Learn, Look, Locate, Tigerlily Foundation, and Living Beyond Breast Cancer, and patient advocacy groups can build trust and encourage participation. Getting information from these groups allows us to better understand what matters to patients in terms of disparities and allows us to incorporate these insights into study design. For example, going to where patients are, rather than just sticking to large urban areas that may be inconvenient for some transportation-wise, can significantly improve participation. Training staff on cultural competency ensures respectful and effective communication with diverse populations. It’s also important to design flexible study protocols, such as frequency and timing, that accommodate the needs and preferences of diverse participants.

Finally, developing and implementing DAPs, as recommended by the FDA, sets clear goals and strategies for achieving diverse enrollment. For example, at Agendia, we have incorporated these guidelines by prioritizing the recruitment of a racially and ethnically diverse patient population and conducting sub-studies focusing on various topics, including racial and ethnic disparities, leading to more than 10 pieces of clinical evidence assessing diversity.

References:

1.  Ellington TD, Henley SJ, Wilson RJ, Miller JW, Wu M, Richardson LC. Trends in breast cancer mortality by race/ethnicity, age, and U.S. Census region, United States—1999–2020. Cancer. 2023;129(1):32–38.

About The Expert:

William Audeh is a medical oncologist specializing in breast cancer, with nearly 30 years of experience as a clinician and clinical researcher at the Cedars-Sinai Cancer Center. Before joining Agendia, and in addition to his clinical practice, he served as the director of the Cedars-Sinai Cancer Center and medical director of the Wasserman Breast Cancer Risk Reduction Program. Dr. Audeh also served as director of the Medical Oncology Training Program for Breast Surgery and Surgical Oncology Fellowships at Cedars-Sinai and is an associate clinical professor of medicine at the UCLA David Geffen School of Medicine. Dr. Audeh has been a principal investigator on national and international clinical and translational trials and has authored publications in the fields of breast cancer, cancer genomics, and targeted cancer therapy. Dr. Audeh received his medical degree from the University of Iowa and an M.S. in genetics from the University of Minnesota. He completed a residency in internal medicine and a fellowship in medical oncology at Stanford University Medical Center.

See interview via Clinical Leader