Research Underway to Cure Locally Advanced Urothelial Carcinoma

Elizabeth Plimack, MD

An ongoing phase II clinical trial is exploring the efficacy of risk-adapted treatment for patients with muscle-invasive bladder cancer after receiving a neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen (NCT02710734). Researchers are hoping that this strategy will lead to bladder preservation as well as an improvement in quality of life, explained Elizabeth Plimack, MD.

In the open-label study, each baseline transurethral resection of bladder tumor sample will be sequenced while patients proceed with neoadjuvant accelerated MVAC chemotherapy. Based on the mutational profile and the post-MVAC outcomes, patients are either treated with active surveillance or standard intravesical therapy, chemoradiation, or surgery. The primary endpoint of the trial is metastasis-free survival at 2 years.

“We want to cure patients of their bladder cancer; that is our number one priority,” said Plimack. “However, a very close second is quality of life.”

OncLive: What did you discuss in your presentation?

During the 2017 OncLive^® State of the Science SummitTM on Renal Cell Carcinoma and Bladder Cancer, Plimack, who is chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center, spoke on the management of locally advanced urothelial carcinoma and the ongoing trials that are investigating treatments for this patient population.Plimack: I was invited to talk about one of my favorite topics, which is the management of locally advanced urothelial cancer. This is bladder cancer that has just made its way into the muscle layer of the bladder, but has not extended beyond that. It is a high-risk situation where, for many patients, if left untreated, it would progress to metastatic disease and [they would] die of their disease. However, it also presents an opportunity for us to cure patients.

Can you share more insight on this biomarker research?

What we are working on is developing the best strategy to increase the cure for action for this group of patients. We know that neoadjuvant cisplatin-based chemotherapy is proven to improve the cure rate and extend survival in this group of patients. However, we also presented some data on biomarker research that we and other groups have done, which is looking to see which patients benefit the most and perhaps can keep their bladder. That is part of a clinical trial that we have open now that I spoke about. We did 2 clinical trials of neoadjuvant chemotherapy regimens in bladder cancer and collected tissue prior to treatment. We then sequenced that tissue and correlated the mutation pattern that we saw with response. Separately, another group did the same thing, and, together, we found that 4 genes—DNA-repair genes, if altered—predict for response to platinum-based chemotherapy. The group of patients who had one or more of those alternations all did very well; they had a good response in the bladder and they also lived the longest of the patients overall.

What remaining questions are there in the landscape?

What we are hoping is to use those findings, which have now been validated across separate cohorts, to select out patients who can then keep their bladder after chemotherapy. If we can know that there is no cancer in there, why take it out? That is the question we are looking at next. Dr Daniel M. Geynisman at Fox Chase Cancer Center is leading a clinical trial that is open now looking to select patients who can preserve their bladder. There are many questions pressing in the field of bladder cancer. The optimum signature for response is not yet validated. We don’t quite know whether it’s going to be a genomic or a DNA-expression signature—maybe it will be a combination of those data. We still need larger trials to validate these biomarkers and findings, and we still need options for patients who aren't candidates versus platinum therapy or surgery. Therefore, optimizing combination radiotherapy, alternate immunotherapy, or chemotherapy regimens in this group will be critical.

What other ongoing trials are you interested in?

The future has been happening quickly. All of this research that has sort of been [building] over the last few years and we hope to keep the wave going. The key clinical trial I discussed is a risk-adapted therapy trial in muscle-invasive bladder cancer where patients with muscle-invasive bladder cancer are consented. We collect the tissue that was obtained from the bladder prior to treatment and then they receive chemotherapy. After chemotherapy, when we have the genomic results, we allocate their treatment based on what they see in the bladder on cystoscopy and the genomics together.

What clinical implications could this study have?

What do you hope community oncologists took away from your discussion?

If both look good, those patients can be observed with bladder evaluations every 3 months or so, without surgery or radiation. The rest of the patients, depending on how much cancer is left in the bladder on evaluation, can choose to receive either chemotherapy or surgery. This trial will be open at Thomas Jefferson University Hospital, Johns Hopkins Medicine, and is currently open at Fox Chase Cancer Center.Having a bladder removal alters one's quality of life; many people do well with it and continue to thrive after cystectomy or surgery to remove the bladder. But if it can be avoided, then certainly we want to do that. For a subset of patients, we think it can be done safely and we want to prove that. The takeaway should be that chemotherapy in the neoadjuvant setting is still the standard of care. Most patients can get it; it is safe and effective. We need to continue to optimize how we use old tools, even cisplatin, which is decades old.