Treatment Sequencing in Refractory Urothelial Carcinoma Requires a Personalized Approach

Jue Wang, MD

With the continued addition of new agents and an increased understanding of disease biology, the sequencing of treatments for patients with relapsed/refractory urothelial carcinoma requires an individualized approach, according to Jue Wang, MD.

“Based on our understanding of refractory urothelial carcinoma, a trial-and-error approach doesn't work. Several factors can guide our selection in this era of relatively rich options because we have multiple active agents. However, each patient is different, and treatment in this era has become highly personal,” Wang said following an OncLive^® State of the Science Summit™ on bladder cancer and renal cell carcinoma.

In an interview with OncLive, Wang highlighted key takeaways from his presentation on treatment sequencing for patients with relapsed/refractory urothelial carcinoma, focusing on the key factors that could help inform decisions for individual patients.

Wang is a professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at UT Southwestern Medical Center, UT Southwestern Harold C. Simmons Comprehensive Cancer Center, in Dallas.

OncLive: Could you expand on the importance of switch maintenance and other treatment strategies being used to combat relapse in patients with urothelial carcinoma?

Wang: For many years, we used a one-size-fits-all approach for [patients with relapsed/refractory urothelial carcinoma]. We had limited options. The best way to [help patients] is to prevent a relapse from happening. Therefore, 2 new strategies have emerged.

One [new strategy] is switch maintenance. Instead of just giving [patients] a fixed number of cycles of treatment before giving a patient a break, we learned for many years that the cancer will inevitably progress, and when it comes back, the pace of the disease is rapid. The disease burden increases, the patient becomes frail, and organ dysfunction can prevent them from pursuing second- or third-line therapy, [which] is a missed opportunity. Therefore, a new strategy [of switch maintenance] emerged. Instead of giving the patient a break, you immediately switch now to immunotherapy maintenance in those patients who have not progressed after [frontline] chemotherapy.

[Switch maintenance] is based on long-term research. Chemotherapy and immunotherapy are good partners and have a complementary effect. In the past, we considered chemotherapy immune suppressive. However, now we understand immunotherapy can enhance the immune system by the immunogenic killing of cancer cells and releasing neoantigens. [Switch maintenance] has demonstrated improved survival.

[The second strategy] also takes advantage of the chemotherapy/immunotherapy synergy in our most vulnerable [patients]: the cisplatin-ineligible population. The combination of an antibody-drug conjugate and immunotherapy also showed us sustained survival benefit. These improvements benefit our most vulnerable patient groups.

If a patient has refractory disease, what are we going to do? In the past, if one chemotherapy approach didn’t work, we gave a different one. Now we know this doesn’t work. Chemotherapy puts therapeutic pressure onto this highly mutated cancer. When you [are presented] with a new chemotherapy refractory situation, patients vary, so you cannot use a one-size-fits-all approach. The current strategies [are] individualized. Now, we have multiple—at least four—groups of treatment to deal with [a refractory] situation. We can use a targeted monoclonal antibody to deliver the chemotherapy right to the cancer cells. Second, we can use immunotherapy, targeting the immune suppression associated with cancer. Third, [we can] target the molecular vulnerability of the cancer [in certain subgroups of patients]. Fourth, we have our traditional chemotherapies.

Currently in your practice, how are you approaching the sequencing of these different agents for patients with urothelial carcinoma?

There are several practical considerations for community oncologists. First, we need to know our patient. Second, we need to know the disease. The disease is a dynamic process, and refractory cancers do not [always follow] the textbook and fit our agenda for different lines of therapy. We have to know the disease [in front of us].

Although we are working with the patient, we are also dealing with the disease. [When selecting a treatment for a patient with] the refractory disease, [we also must consider] aging, potential multiple comorbidities, and residual adverse effects [AEs] from prior treatment. Every treatment has a different AE profile, and compared with frontline therapy, you may have overlapping AEs [with subsequent therapies].

I recommend that in the future, we move away from lines of therapy where we assign [specific lines for each treatment]. Rather, we should consider the disease biology from the beginning of treatment. We already understand their molecular profile, and hopefully, in the future, their molecular signature.

The most important current factor is still the art of medicine. We need to understand the patient who is sitting in front of us. We need to know comorbidities and their residual AEs from their last line therapy. For example, if a patient has diabetes, you need to consider a patient running into immediate AEs where you would later need to give steroid therapy.

The goal is to hopefully include the patient, their disease burden, disease progression, comorbidities, and AEs [in the treatment decision] to ultimately help patients personalize treatment choice. This is why we disseminate knowledge. We consider every patient for the best available drug, but we also consider the unique situation.

Overall, there is no [guide] to answer all these questions. There's no clinical algorithm to help us define every clinical scenario. Real-world patients are much more complex [than those treated in clinical trials]. That is why we need to band together as a community to design [more] clinical trials based on the [real-world] questions we face every day and utilize other approaches like real-world data to answer those mature questions.

How do you approach testing for molecular alterations in clinical practice?

Urothelial cancer has a highly frequency of mutations, but the good news is that [these alterations] are being studied in relation to molecular and precision medicine. For example, there are therapies approved for targeting FGFR2/3 [alterations]. The gold standard is through tissue testing, and in order to better understand the disease, we always test earlier and prepare for opportunities [to utilize targeted treatments]. Emerging liquid biopsies [to measure] circulating tumor [cells] can also help us identify those mutations.

In our experience in the real-world setting, [we have] utilized the tissue existing from previous biopsies. Cancer is a dynamic process, and molecular testing has a lot of limitations based on sample preparation, different isolated DNA, and complex situations. The lessons learned from taking care of patients with urothelial carcinoma during the disease process is that molecular events evolve over time.

Currently, we have only 1 targeted therapy, and when patients quickly deteriorate, you need to consider that, practically, we live in the real world, and we need to obtain pre-authorization for some treatments. Therefore, give your patient the opportunity to obtain molecular profiling earlier by making it an integral part of your care [for patients with] refractory cancer.

What is the value of sharing different treatment approaches and strategies?

We need to reach out to communities, as fighting cancer takes a whole village. [We cannot] just talk to community oncologists. It is important to learn from other oncologists and apply to [strategies into practice]. Health-care providers have the responsibility to educate and work with our communities for education. Education is double sided, and we also learn from feedback from the audience.

[If] we can identify the real-world problem and turn that into a research question, [we can design] new clinic trials and [create] a new opportunity for our patients. Our common mission is to work together as a community to solve cancer.