"It really is a fun time to be doing urothelial cancer research, as we see patients living longer, with more durable responses, impacting their overall survival and long-term outcomes," says Arlene Siefker-Radtke, MD.
In this interview, Arlene O. Siefker-Radtke, MD, discusses advances in adjuvant treatment for bladder cancer, the treatment erdafitinib (Balversa), and her own research interests. Siefker-Radtke is a professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston. She was interviewed at the 2022 LUGPA Annual Meeting in Chicago, Illinois.
The treatment of patients who've had surgery has always been quite complicated. We've had a long-standing history of chemotherapy adjuvant trials, which did not show statistically significant improvement in survival, yet on subset analyses suggested benefit with adjuvant chemotherapy in the highest risk cohorts. Those were usually patients with T3B or greater disease at surgery. As a result, chemotherapy with cisplatin has been the mainstay in the perioperative management of urothelial cancer. More recently, though, we've seen advances with the application of immune checkpoint inhibitors, especially in patients with metastatic disease. And recently, in the adjuvant setting, there were early data presentedsuggesting that nivolumab [Opdivo] can improve disease-free survival compared with observation or placebo on a clinical trial. However, the limitation of these data is we do not yet have survival data. And although the disease-free survival does appear to be statistically significant, we do not yet know if that translates to the ultimate cure of patients in the adjuvant setting. The risk of this approach is that we are overtreating a group of patients who may already be cured by their surgery. So there are risks and benefits with each approach.
A lot of research is ongoing to try to pick out better subsets of patients who are more likely to need that adjuvant therapy so we can hopefully avoid overtreatment with potentially toxic therapies. Looking at circulating DNA strategies to predict those at greatest risk is [quite exciting]. Adjuvant treatment will be changing over time. I look forward to these clinical trials that are investigating novel strategies for selection to pick the cohort at the highest risk of recurrence, because in the perioperative management of bladder cancer, the goal is cure. The bar is high; we want to be curing these patients, not just delaying a recurrence of their cancer.
Erdafitinib is a novel targeted therapy that targets FGFR3-altered urothelial cancers. In a phase 2 clinical trial that was recently published in the New England Journal of Medicine1 with follow-up data, we saw that erdafitinib had an objective response rate of around 40% in patients who received prior chemotherapy for their metastatic disease. So it is a very promising strategy in this patient population, where FGF may be driving their malignancy. There are currently phase 3 clinical trials ongoing to confirm this finding. Interestingly, FGFR3 alterations appear to be enriched in immunologically cold tumors. So one of the questions that we need to answer is, does it matter how we sequence therapies for an FGFR3-altered patient? Do these patients do better if they receive immune checkpoint inhibition first or if they receive erdafitinib earlier in their disease strategy? There is a trial that is currently ongoing called THOR [NCT03390504], where patients who have had prior chemotherapy but have not yet received an immune checkpoint inhibitor are randomized between erdafitinib and pembrolizumab [Keytruda] to answer this very important question.
One of the biggest unmet needs for our patients with urothelial cancer is treating this elderly, very frail patient population. This is a geriatric population in the majority of patients, with all of the comorbid conditions associated with their age, but also potentially impacting their underlying disease. We see a lot of patients who were smokers. Bladder cancer is a smoking-related malignancy, so they have emphysema, they have heart disease. We see patients who have diabetes, and the diabetic pathways and hyperglycemia have also been implicated in urothelial malignancies. Finding a therapy that works for elderly patients, and also patients with comorbid conditions, is extraordinarily important. The standard of care, cisplatin-based chemotherapy, is typically only available for less than half of patients diagnosed with a metastatic urothelial cancer. More recently, we are seeing advantages. We've seen immune checkpoint inhibitors approved for patients who are not eligible for platinum-based therapies in general. But another promising approach is the development of antibody-drug conjugates. Specifically, enfortumab-vedotin [Padcev], which in the second-line setting is associated with an objective response rate of around 40%. But what is especially thrilling is early data combining enfortumab-vedotin with pembrolizumab, which is showing objective response rates in around 60% of patients. So there are currently frontline strategies studying this option in patients who are not eligible for standard of care cisplatin-based therapies, in the hopes of finding a treatment that really does meet this unmet need for our urothelial cancer patients.
As far as advances in bladder cancer, it remained stagnant probably for the first 15 years of my career, where we had cisplatin-based regimens that were studied, and yet none of them overcame the benefits that were observed with dose dense mVAC. It has really taken the development of novel treatments and novel pathways to make those advances. The first advance was the approval of immune checkpoint inhibitors—medications that modulate a person's immune system to help them look at the cancer more carefully and potentially attack it. We've also seen tyrosine kinase inhibitors, specifically with erdafitinib, which targets FGFR3 alterations on urothelial cancer, showing objective response rates that are quite promising, and an early accelerated approval of the strategy with phase 3 trials ongoing.
And finally, antibody-drug conjugates are also making an impact in this disease, by the ability to selectively target what is found on the tumor tissue and bring chemotherapy more directly to the patient's tumor, allowing that chemotherapy agent to be released inside the tumor, resulting in cell death. We have 2 therapies in that setting: enfortumab vedotin, which has proven benefit with level 1 evidence based on a randomized clinical trial, and sacituzumab govitecan [Trodelvy], another antibody-drug conjugate that is also showing promise in this strategy.
With these novel agents and novel classes of drugs and novel strategies, we are starting to see the survival of our patients expand. Patients are living longer than they did when I started doing research in urothelial cancer. It really is a fun time to be doing urothelial cancer research, as we see patients living longer, with more durable responses, impacting their overall survival and long-term outcomes.
I've long worked in the field of urothelial cancer and very early on was intrigued by the development of FGFR3 targeting agents. FGFR3 has been implicated quite early in the development of urothelial cancer tumors. In fact, over 60% of patients with low-grade, low-stage tumors will have an FGFR3 alteration present. So clearly, it is a pathway worth examining —and also targeting—to try to help improve patient outcomes. When we look at metastatic disease, we see only a small fraction of FGFR3-altered tumors, and with erdafitinib, which appeared to be a potential best-in-class drug at that point in time, we saw evidence of early response rates around 40% and clinical efficacy that was very promising for future randomized trials.
What we are also learning about FGF targeted strategies is how to give them earlier in the disease state—in neoadjuvant, the perioperative management, and also in superficial bladder cancer. There are some clinical trials studying these novel agents, putting them in pretzels that might slowly release them inside the bladder, resulting in control.
Finally, [we're] trying to understand this pathway better, because it does appear immunologically cold. Could we enhance the impact of immune checkpoint inhibitors by combining FGF-targeted agents with immunotherapy? One of the trials that we've been leading is the NORSE clinical trial, combining erdafitinib with cetrilumab, another PD-L1 inhibitor, and early data from the phase 1 trial suggest an objective response rate of around 60% with this combination. So with these novel agents and strategies, we are starting to understand the biology of bladder cancer and also the fact that bladder cancer is no longer just one disease. It's actually composed of multiple diseases, which may have different targets and potentially different sequences that may be useful in impacting patients' outcomes. I look forward to seeing the development of further personalized therapies and strategies that help our patients live longer with better quality of life.
1. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. NEJM. 2019;381(4):338-348. doi:10.1056/NEJMoa1817323