A Widening Scope of Treatment Options Advances Care in Bladder Cancer and RCC

Mark T. Fleming, MD

The treatment landscape for patients with bladder cancer and renal cell carcinoma (RCC) is growing through novel agent combinations, explained Mark T. Fleming, MD, who also emphasized the array of treatment options that are paving the way for more effective and personalized patient care.

“Patients have options. Approximately 16 years ago, for bladder cancer, there was chemotherapy. Now, we have chemotherapy, immunotherapy, and targeted therapy, including FGFR-targeted therapies. For RCC, there’s targeted therapy and immunotherapy,” Fleming said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on bladder cancer and RCC, which he chaired.

In the interview, Fleming, a physician at Virginia Oncology Associates, a practice in the US Oncology Network, and the medical director of the Genitourinary Research Committee at US Oncology, reviewed key points from each presentation shared at the meeting, including the use of first-line checkpoint inhibitors in bladder cancer, the efficacy of enfortumab vedotin-ejfv (Padcev) in urothelial cancer, and the clinical benefits of using different mechanisms of action to treat RCC. Fleming also highlighted the importance of using novel immunotherapy combinations to build on individual patients’ previous lines of treatment.

OncLive^®: Your colleague, Ayham Deeb, MD, FACP, of Virginia Oncology Associates, spoke on first-line treatment in metastatic bladder cancer. How has the use of checkpoint inhibitors such as atezolizumab (Tecentriq), pembrolizumab (Keytruda), and avelumab (Bavencio) affected treatment sequencing?

Fleming: [These checkpoint inhibitors give] patients options. My colleagues and I are engaged in research because we want to create as many options as possible for patients. Cisplatin-based chemotherapy has been vital to the treatment of patients with bladder cancer. Introducing immunotherapy allows treatments that work by a different mechanism, allowing us to harness the immune system.

Checkpoint inhibitors have allowed us greater choices. We commonly divide patients into cisplatin-eligible or cisplatin-ineligible groups. [In clinical trials, patients are enrolled if they] fit certain criteria. In the real world, however, we encounter many more cisplatin-ineligible patients. The introduction of immunotherapies such as atezolizumab, pembrolizumab, and avelumab has been vital.

Manojkumar Bupathi, MD, MS, of Rocky Mountain Cancer Centers, presented on the treatment of patients with previously treated locally advanced or metastatic urothelial cancer. What has been shown in the phase 2 EV-201 trial (NCT03219333) regarding the use of enfortumab vedotin?

[The EV-201 trial] highlighted that enfortumab vedotin is a very active drug. It’s one of those drugs that I have been more impressed with in my real-world clinical experience than I have been with the clinical data. Although the clinical data were impressive, it’s exciting to see its use in real-world patients.

Often, enfortumab vedotin was introduced to real-world patients as third-line therapy, [after chemotherapy and immunotherapy]. [A patient of mine, who I had been speaking to about end-of-life wishes, started enfortumab vedotin.] She had a dramatic response to the point where we felt comfortable having her go back and get a hip replacement, [so she could alleviate what] was bothering her the most.

As Dr Bhupathi outlined, this is an active drug. It does have some [adverse] effects [AEs]. But what we do is we learn how to manage those [AEs], neuropathy being the biggest issue that we encounter, as well as hyperglycemia, which we can manage well.

What efficacy was observed with cabozantinib (Cabometyx) and atezolizumab in the phase 1/2 COSMIC-021 trial (NCT03170960)?

That trial was exploratory, looking at other possible mechanisms of action. It highlighted that we are constantly looking for ways to attack and treat patients with these complex diseases. [COSMIC-021 showed] that one size doesn’t fit all and that cancer is a heterogeneous disease. [In the future,] we’re looking forward to [exploring whether cabozantinib is] truly an active drug.

Yue Zhang, MD, MPH, of Virginia Oncology Associates, spoke on frontline treatment in metastatic RCC. How have immunotherapy-based combinations played a role in this space so far?

Dr Zhang broke down a complex field in simple terms that effectively highlighted how immunotherapy is now the standard of care in the first-line setting [and how going forward, we are looking at combination immunotherapy. In other words,] one immunotherapy plus another immunotherapy, such as ipilimumab [Yervoy] or nivolumab [Opdivo], or other combinations with treatments like tyrosine kinase inhibitors [TKIs] or cabozantinib.

I refer to combination immunotherapy as a MEK inhibitor that has multiple prongs of action. We’re now in an era where using immunotherapy in the frontline setting is the standard of care. Within my US Oncology research group, we won’t do a clinical trial that does not have immunotherapy as a standard treatment arm, given the accumulating data to support using immunotherapy plus another agent.

Currently, we don’t have head-to-head trials [to determine] which combinations are best. Physicians and clinicians need to take care of their patients by understanding their [ECOG] performance statuses [PSs] and other comorbidities to identify the best combinations. I try to use all the combinations to gain an understanding and appreciation of the nuances of one [vs another]. Again, one size does not fit all in the care of patients.

Additionally, now patients have options. Sometimes, for instance, patients don’t like the idea of an intravenous treatment they need to come to the office for. Other ways to deliver immunotherapy are currently being explored in clinical trials. Overall, immunotherapy, which Dr Zhang did an excellent job of providing an overview of, is the standard of care for frontline therapy in RCC.

Looking at the phase 3 KEYNOTE-426 trial (NCT02853331), how has the use of axitinib (Inlyta) plus pembrolizumab shaped clinical care?

The KEYNOTE-426 trial is another example of combining a TKI with immunotherapy. This trial showed impressive overall response rates [ORRs], [with responses in 59.3% of patients who received axitinib plus pembrolizumab vs 35.7% in patients who received sunitinib (Sutent)].

These results give patients options. [Axitinib plus pembrolizumab] was one of the first combination therapies to be approved in this setting, so clinicians are very comfortable using that regimen. Although we now have other options, axitinib plus pembrolizumab remains a great combination for our patients.

Jeff Yorio, MD, of Texas Oncology, spoke on second-line and later treatment in RCC. How has lenvatinib (Lenvima) plus everolimus (Afinitor) found a role in this space?

Clinical trials give us academic evidence to support combinations and doses. Oftentimes, from there, we can adjust based on patient tolerability.

The exciting thing about the combination of lenvatinib and everolimus is that it combines 2 drugs that work by different mechanisms of action, different ways to attack the cancer, and there doesn’t appear to be toxicities that overlap too significantly. There’s a TKI, as well as an mTOR inhibitor, [which are different ways of treating the same disease]. Lenvatinib has other mechanisms, as well.

This is a useful combination for introducing different mechanisms of action. Now you can use a checkpoint inhibitor plus a TKI in the first-line setting. We’re now also introducing a third mechanism, which is the mTOR inhibitor class.

Now we have options with TKIs, MEK inhibitors, mTOR inhibitors, VEGF-antibody therapy, and immunotherapy. HIF hypoxia inducible factor targeting [is also being studied]. I use an analogy for patients that the treatment for [patients with] RCC is like my wife’s closet of black shoes. My wife doesn’t look in her closet and say she has 1 best pair of black shoes. She chooses the right shoe for the right occasion. Just as my wife has multiple options in her shoe closet, patients with RCC have multiple treatment options.

What factors do you consider when selecting second- or later-line treatment options?

The first thing is the patient’s wishes. Every oncologist always wants to incorporate the goals of their patients. From there, knowing what their prior therapies were is important. We use an algorithm that includes patients’ prior therapies, wishes, and different mechanism of action.

A useful analogy to think of is that patients in second- and third-line therapy are often not at the same performance status as patients in front-line therapy. A useful analogy is that it’s tough to wear heels all day. If the heels stop working and your feet are tired, you need to switch to a sandal or something that is more comfortable. If patients can’t wear the heels they started off with, they might need a different shoe that’s more comfortable and better fits their needs.

What is a main message you would like to leave with colleagues about the evolving treatment paradigms in RCC and bladder cancer?

I encourage all patients and family members to talk with their oncologists about the wide array of treatment options they have. We can tailor treatments based upon patients’ performance statuses and priorities.

[This space is also growing.] The investigators who spoke at the IPC event are engaged [in research] and trying to find new therapies. Ideally, the goal is to try to cure patients of advanced disease. However, we’re definitely improving lives and extending life and quality of life, as well.