Aptitude Health recently spoke with Dr Kathleen Moore, from the Stephenson Cancer Center (SCC), University of Oklahoma. Dr Moore is director and associate director for clinical research, and professor in the Department of Obstetrics and Gynecology at SCC. Dr Moore is principal investigator for SCC’s National Cancer Institute U10 National Clinical Trials Network Lead Academic Participating Site award, the SCC UM1 Experimental Therapeutics Clinical Trials Network award, and co-principal investigator on the Cancer Screening Research Network award. In these roles, she oversees clinical research development and operations. She works to establish collaborations between scientists and clinicians to develop translational and biomarker-driven studies and clinical trials, and develop the infrastructure for clinical trials and translational research. She has leveraged success in some of these trials into more-directed studies in specific gynecologic populations to help move promising agents into larger, more-accessible trials through the cooperative-group mechanism. She has overseen phase I trials and safety lead-ins for her site since 2009. Dr Moore also serves as chair of NRG Oncology’s Ovarian Cancer Committee and as a member of the NRG/Gynecologic Oncology Group (GOG) Phase I Working Group and Developmental Therapeutics Committee. She is a member of the American Society of Clinical Oncology and serves on the board of directors as well as the GOG Foundation board of directors. Her research has appeared in several respected peer-reviewed publications, including Journal of Clinical Oncology, New England Journal of Medicine, Cancer, and Gynecologic Oncology. Here is a recap of our conversation:
From your perspective, how significant is the issue of gynecologic cancers within the broader oncology landscape?
Of course, I am biased because I’m a gynecologic oncologist, so I think it is very important. Even though patients with gynecologic malignancies constitute a small percentage of those diagnosed with cancer globally each year, the numbers are rising for some gynecologic cancers, particularly for endometrial cancer, which is the only cancer increasing in both incidence and mortality. It is especially important among women of color, where the impact is very high. Similarly, while ovarian cancer also does not constitute a large percentage of new diagnoses of cancer, we are very behind a lot of other cancers in terms of adequate screening and the ability to provide a cure. That small number of patients face a poor prognosis. . . . Although there has been improvement over the past 2 decades, it is still largely a terminal diagnosis.
Additionally, cervical cancer in the US is very rare but would be a zero event if we vaccinated and screened, as the US has the capability to do. The significance is that it should not be here, and we should be focused on initiatives that eradicate it globally. With broad-based screening, we could eradicate this cancer, which affects approximately almost half a million people born female and leads to a quarter million deaths globally per year. So I think gynecologic cancers are incredibly important on the global stage, but maybe not for reasons people are thinking about. They may not be the most common cancers, but they have a lot of significant issues we need to address.
What recent advancements in the management of gynecologic malignancies do you consider the most groundbreaking? Which areas require more research?
There have been several tremendous breakthroughs recently. For both endometrial and ovarian cancers, the global recognition that separating these tumors by molecular subtype is incredibly important in terms of being able to design interventions that will impact these subgroups. In the past, endometrial and ovarian cancers were lumped into a single study. We have made huge advancements by recognizing distinct, molecularly driven subgroups and designing interventions that focus on those. For ovarian cancer, it really comes down to recognition of homologous recombination deficiency (HRD), which includes BRCA1 and BRCA2 mutations, as well as other high-penetrance genes and epigenetic molecular changes. This makes tumors more susceptible to platinum-based therapies, and is a prognostic as well as predictive biomarker for response to those therapies and, more importantly, to poly(ADP-ribose) polymerase (PARP) inhibitors. The introduction of PARP inhibitors as maintenance in frontline chemotherapy has been transformational, mainly for biomarker-positive patients, for whom baseline cure rate is around 20%, maybe a little less. With PARP inhibitors, the baseline cure rate is about 45%. Outside of BRCA, the impact of PARP inhibitors—while definitely the standard of care with phenomenal progression-free survival—on overall survival for patients with BRCA wild-type HRD remains to be seen. But these patients are in remission much longer, and patients are on [PARP] therapy for a prespecified amount of time in the front line, then it is stopped and patients come off therapy. This is very important, and we’re probably going to see that positively impact the length of survival—maybe not disease-free survival, but the length of survival by virtue of the fact that we’re not continuously treating patients. But more to come there. Also, antibody-drug conjugates (ADCs) are on the rise and moving up in lines of therapy. I think we will see a lot of advancement there. Lastly, in platinum-resistant disease, we have the receptor alpha-targeted ADC mirvetuximab soravtansine.
For endometrial cancer, the identification of subgroups, which came out with the Cancer Genome Atlas program a long time ago, has been crucial. We have known about these 4 subgroups—mismatch repair (MMR) deficient or microsatellite instability (MSI) high, copy number low, copy number high, and TP53 mutation in that last group—for a long time. We have not really used it to change therapy until very recently, and that, of course, is with the immune checkpoint inhibitors among tumors that are MSI-high or MMR deficient. The incorporation of both pembrolizumab and dostarlimab was transformational in the treatment of patients with metastatic endometrial cancer in the front line. Those patients were not curable in the past; their median survival was measured in 1 to 2 years. Now we are showing progression-free survival curves that have leveled off. We do have, at least according to a press release, overall survival that sounds positive from the RUBY trial with dostarlimab. We will see as the NRG-GY018 study with pembrolizumab matures a little more. It probably will look the same in MMR-deficient or MSI-high patients. So we may be curing some of those individuals in the future.
Which emerging trends or approaches do you believe hold the most promise for advancing the treatment of gynecologic malignancies?
Sequencing will be important going forward. We have a lot to learn about how to use ADCs in endometrial cancer. The data already exist in other solid tumors, so we can borrow from them, but endometrial cancer is a different disease and that population is different. Understanding the safety of these medications in this population will be important, and ongoing trials are crucial for this understanding. All the ADCs have a low but present risk of pneumonitis and impact on ejection fraction, so it is not as clear as it may seem. There is still a lot to learn before we can use these drugs to their best effect and safety. ADCs have been phenomenal for our patients. . . . Trying to figure out how to use them to their best effect is the current question.
How do you see the multidisciplinary approach evolving in the treatment of gynecologic cancers with these novel therapies?
Multidisciplinary care is essential for the safe utilization of novel therapies. For adoptive cell therapies, it is crucial to have a team well versed in rescue medications to get patients through adverse events safely. An example is eye toxicities with ADCs, which make partnerships with ophthalmology necessary. For drugs with pneumonitis risk, collaboration with pulmonology is key. Team-based practice and multidisciplinary care are vital to providing patient-centered care safely. It’s a balance, and learning how to use these effective drugs safely is crucial. Novel therapies are very complicated, and a team-based approach is needed to manage toxicities: recognizing them early, managing them appropriately, and, when possible, keeping patients on these very effective medications without harming them.
