Experts Discuss Current Standards, Selection, and Uncertainties in Bladder and Renal Cancer Care

Bradley G. Somer, MD

As the array of treatment options and management strategies for urothelial cancer and renal cell carcinoma (RCC) expands, the question of optimal patient selection and treatment sequencing, as well as the potential integration of effective agents into earlier lines of therapy, remains to be elucidated through ongoing research, according to faculty from an OncLive State of the Science Summit™ on bladder cancer and RCC.

The event was chaired by Bradley G. Somer, MD, who is president of West Cancer Center & Research Institute, where he also serves as a medical oncologist and senior partner on the Executive Cancer Council, in Germantown, Tennessee.

Presentations outlined tips for navigating treatment selection across first- and later-line bladder cancer, discussed frontline tyrosine kinase inhibitor (TKI)–based treatment options in advanced RCC, and highlighted emerging treatment regimens in metastatic RCC. The panelists also held extensive discussions on 2 case studies in metastatic urothelial cancer and advanced RCC.

Somer was joined by his following colleagues:

• Kathryn E. Beckermann, MD, PhD, assistant professor of medicine, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center
• Holger L. Gieschen, MD, radiation oncologist, West Cancer Center & Research Institute
• Nikhil Gopal, MD, assistant professor of urology, College of Medicine – Memphis, Department of Urology, The University of Tennessee Health Science Center
• Daniel Vaena, MD, director, Genitourinary Oncology and Interim Phase 1 Program, West Cancer Center & Research Institute

Below, Somer, Beckermann, Gieschen, Gopal, and Vaena delineate the latest developments and lingering questions in the treatment landscape of bladder and renal cancers, covering pivotal trials, emerging therapies, and optimal management approaches.

Somer Details Remaining Questions Regarding the Optimal First-Line Management of Urothelial Cancer

Somer: There are 2 phase 3 trials in first-line, metastatic urothelial carcinoma whose data showed improved overall survival [OS] in recent months: the CheckMate901 trial [NCT03036098] of nivolumab (Opdivo) with gemcitabine/cisplatin and the EV-302/KEYNOTE-A39 trial [NCT04223856] of enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda]. [Concurrent] nivolumab plus gemcitabine and cisplatin [followed by nivolumab maintenance] was the first chemoimmunotherapy combination to show an OS benefit, with a median OS of 21.7 months. However, the combination of enfortumab vedotin plus pembrolizumab almost doubled the median OS compared with chemotherapy and showed a median OS of 31.5 months, [making it the] new standard of care.

Based on this [research data], there are [several outstanding] questions. If you think that neuropathy and early toxicities might be a barrier [for] some of our patients [who] are borderline chemotherapy candidates, could you start with a lower dose of enfortumab vedotin and go higher? What are the biologic drivers? What are the biomarkers that might give us good insight into who might respond to platinum-based chemotherapy? Which patients [experience the most benefit] with this? Then there is the question of [whether this regimen] works in an earlier setting. If it works in the metastatic setting well compared with chemotherapy, maybe it works in an earlier setting. Hopefully we can address that.

[Additionally], the cost [of enfortumab vedotin plus pembrolizumab] is much more than gemcitabine plus cisplatin or gemcitabine and carboplatin; [also,] when we had a shortage of platinum-based chemotherapy, I would use [financial barriers] as a definition for platinum ineligibility because you just couldn’t get your hands on platinum.

[Further], what if patients received immunotherapy in an adjuvant setting? How long do we have to wait before we use this therapy? [And does this research signal] the end of platinum eligibility as a [necessary] classification? What do we do with [the data from] the phase 3 JAVELIN Bladder 100 trial [NCT02603432]? Obviously, some patients may not be ideal candidates for the [EV-302] combination. Maybe those are the patients with brittle diabetes or terrible neuropathy. [Lastly, regarding first-line approaches,] what do you use as a next-line therapy?

Beckermann Expands on Enfortumab Vedotin and Sacituzumab Govitecan as Alternative Options for Refractory Bladder Cancer

Beckermann: The treatment landscape has changed in the frontline setting for bladder cancer, with enfortumab vedotin plus pembrolizumab as a new frontline option. The question is what data do we have to think about and how do we treat [patients] in the refractory setting.

[The phase 3 EV-301 trial (NCT03474107) was the first [trial with data] showing that enfortumab vedotin had an objective response rate [ORR] of approximately 40%, improved progression-free survival [PFS] from approximately 3 months [with chemotherapy] to 5 months, and improved OS. This was one of the first approvals that we had for patients in the third-line setting for bladder cancer that was not just a standard single-agent docetaxel [regimen]. We will still be seeing some patients who’ve progressed after [frontline] cytotoxic chemotherapy or PD-1 agents, so enfortumab vedotin as monotherapy in the refractory setting still has great use.

The phase 2 TROPHY-U-01 trial [NCT03547973] of sacituzumab govitecan-hziy [Trodelvy] was similar to EV-301. The ORR [in cohort 1] was approximately 30% in patients who’d experienced progression on 2 prior lines of therapy. You see nice tumor shrinkage in the waterfall plot again [indicating that sacituzumab govitecan is] another [effective] treatment option, which sometimes our patients need if they’ve progressed on chemotherapy and PD-1 therapy. Similar to what’s been done with enfortumab vedotin, we’re [investigating whether] we can use sacituzumab govitecan in combinations and move it into earlier lines in studies.

Gopal Provides Insight Into Optimal Management Approaches in a High-Risk Bladder Cancer Case

Gopal: [The patient in this case study] had high-grade recurrence after 2 intravesical treatment regimens, and I would certainly classify her as very high risk. [There are a] couple of things to point out here in terms of management. She had an approximate year-long response after receiving inductionbacillus Calmette-Guérin [BCG]. She also received adjuvant gemcitabine and docetaxel after she experienced recurrence, but one thing to consider is to rechallenge with repeat induction BCG. We’ve seen that approximately 30% to 50% of patients do convert to a durable response [with rechallenge], and she had a year-long response with BCG.

There are other options, both intravesical as well as systemic. Nonetheless, I would talk to her about the likelihood that she [will develop] progressive disease. Generally, there’s approximately an 80% chance of recurrence for T1 patients and a 50% chance of progression within 3 to 4 years. For this kind of patient, I would put her [risk of] progression at 80%. The concern is also that she now [has] carcinoma in situ [CIS] after her most recent trans urethral resection of bladder tumor.

CIS is associated with a higher rate of upstaging on final cystectomy specimen, so I’d be concerned about the potential for undiagnosed muscle-invasive bladder cancer [MIBC]. She’s generally healthy, so I would push her toward an early cystectomy because even if she is T1 or [has] CIS, she would enjoy a significant PFS after cystectomy, as opposed to waiting and risking the chance of undiagnosed MIBC, [which would] put her at a much poorer prognosis.

Vaena Discusses Criteria Guiding the Use of First-Line Ipilimumab Plus Nivolumab in Clear Cell RCC

Vaena: In the first line, it’s mostly a selection issue because we have so many regimens. Around 2014, the phase 3 CheckMate 214 trial [NCT02231749] of ipilimumab [Yervoy] plus nivolumab began accruing patients. That’s when we entered the current era where we have immunotherapy combinations. Over the last several years, we’ve had 5 different studies, all of which had positive findings. Since 2014, we have had updates on all these studies of [regimens including] ipilimumab plus nivolumab, pembrolizumab plus axitinib [Inlyta], cabozantinib [Cabometyx] plus nivolumab, avelumab [Bavencio] plus axitinib, and pembrolizumab plus lenvatinib [Lenvima]. The control arm for all these trials was sunitinib [Sutent], which was regarded as the optimal control arm at that point in the first line. The result of this is that we have all these positive trials, and we don’t have comparisons among them.

It’s complicated to choose the first regimen because you must balance all issues and look at the patient in front of you. We shouldn’t be directly comparing trial results, but we have to [make some comparisons when] choosing what we’re going to do for the patient. I tend to think about [treatment] for patients in my clinic [based on] short-term, medium-term, or long-term goals.

The short-term goal is to make a patient feel better if the patient is feeling sick, and to get through the first 90 days. The question I always ask myself is, How can this patient switch to a second-line [regimen] if they progress up front? If a patient is very sick with liver metastases, bone metastases, impending cord compression, impending respiratory failure, et cetera, and is treated with ipilimumab plus nivolumab and progresses, they barely [have] any reserve to get a VEGF TKI in the second line. If that patient is very sick, I want to have more of a guaranteed response rate up front.

The medium-term goals [consider the] first 3 to 5 years. In all these studies, the first 5 years are great—[these regimens are] better than sunitinib, have an OS benefit, and everything’s about the same as if you’re going to shoot for 5-year survival. For someone who’s [over] 65 years [of age] in the clinic, it’s very hard to discern [whether] a long-term goal of 8 years will make a difference or not. You put the [patient’s] age, how sick they are, and their long-term goals into perspective.

For a patient who is very young, I feel strongly that 5 years is not good enough. I’m going to see if there is a way that we guarantee more of a plateau in the [survival] curve. It may be that all these other studies may also end up with a plateau, we just don’t know. Right now, we just [have data for] ipilimumab plus nivolumab, with a 32.9% OS [rate] at 90 months. Again, you have to balance how much disease a patient has up front. The last thing that I want to do for my patients is to give them something that they’re progressing on 3 months later, and then they don’t have a chance to get [treatment in the] second line [and beyond]. I tend to use ipilimumab plus nivolumab for someone who can tolerate the [regimen’s associated] immunotoxicities if they develop them and who has a relatively lower burden of disease.

Belzutifan Shows Promise in Earlier Lines and Combination Regimens in Refractory RCC

Beckermann: A lot of data have come out between the 2023 European Society for Medical Oncology Annual Meeting and the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium [for] belzutifan [Welireg]. The phase 3 LITESPARK-005 study [NCT04195750], data from which were presented at [last year’s] ESMO Congress, [evaluated] patients in the refractory setting as they’d received 1 to 3 prior systemic therapies. They were randomly assigned to belzutifan or the comparator arm everolimus [Afinitor]; there was a lot of discussion on whether that was the best comparator arm, but in this refractory patient population I don’t think it was unreasonable at the time the study was started.

Interestingly, data from this trial showed that the curves overlapped until approximately 6 months—a subset of patients driven by HIF-2α biology in the refractory setting started to separate and benefit. The ORRs with belzutifan compared with everolimus were 22.7% vs 3.5%, respectively. Based on these data, the FDA approved belzutifan for all patients [in the relapsed/refractory setting]. There’s no biomarker testing required, but we think the majority of patients are driven by this loss of VHL and upregulation of HIF-2α.

One of the questions that came about was whether 120 mg is the right dose for belzutifan, and there was a phase 2 trial that looked at a dosing of belzutifan at 200 mg vs 120 mg; there was no significant difference [in efficacy between the doses]. Interestingly, what we’re starting to see, and what I think will be coming in the future, is belzutifan being studied in combination with various TKIs.

[One] example is the phase 2 LITESPARK-003 trial [NCT03634540] of belzutifan in combination with cabozantinib. It was a 2-cohort group: cohort 1 was patients who had never been treated [who received] frontline belzutifan plus cabozantinib and cohort 2 [included patients who had] progressed on prior systemic therapy. In cohort 1, the untreated patient population had a high ORR of 70%. In cohort 2, [the ORR] in the refractory setting was 31%.

Ongoing studies include the [phase 3 LITESPARK-011 trial (NCT04586231) of] lenvatinib plus belzutifan vs cabozantinib, which has completed enrollment—we look forward to seeing what that shows. There’s also [the phase 3 LITESPARK-012 (NCT04736706)] trial looking at the frontline triplet of pembrolizumab, lenvatinib, and belzutifan. Belzutifan is going to be moving earlier and earlier in treatment.

[Overall], we now have more regimens and more mechanisms of action in the refractory setting for RCC. We [are going to] see lots of exciting things [coming down the] pipeline. We’re seeing bispecific T-cell engagers being tested, [as well as] metabolic adenosine receptor antagonists, and I look forward to seeing new drug targets as they come out in the next 5 years.

Gieschen Notes Challenges Characterizing Oligometastatic Disease in Kidney Cancer Case Study

Gieschen: This is a problem that’s not just seen at this disease site. The concept of oligometastatic disease, progressive disease, and those kinds of things is something we struggle with. It’s also something that we’re struggling with [when working with] insurance [companies]. The concept that we have of some patients who are somewhere in between multiple metastases and disease-free [status] is something that we look at all the time. The question [is], What is oligometastatic disease? Do you cut it off at 1 metastasis or 3 metastases? There are different definitions. [According to] the American Radium Society, they consider 3 sites of metastases to be oligometastatic disease. Then there’s the American Society for Radiation Oncology definition, and they look at 5 sites. It’s difficult to find out where this aligns [as] there are even trials looking at 10 sites and treating all this.

It becomes not only an issue of whether there’s a benefit to the patient, but an issue of practicality. Can you treat all those different sites in a reasonable amount of time and have low toxicity? In a case like this, where you have 1 metastatic site 3 years down the road, most practitioners would probably say that it is worthwhile doing either resection or stereotactic body radiation therapy and would recommend this to the patient. However, we know cases where it gets a bit borderline [once a patient develops] 2 or 3 lesions, and it’s hard to say.