Successful Treatment Options Expand to Earlier Lines in RCC and Urothelial Cancer

Tian Zhang, MD

Increasingly effective treatments in renal cell carcinoma (RCC) and bladder cancer are shifting forward from later lines and broadening the frontline landscape, said Tian Zhang, MD, who also emphasized that a heightened focus on treatment sequencing can help optimize the utilization of the various options available for all disease stages. 

“These landscapes are expanding, and we are seeing great growth, development, and life-prolonging treatments for both bladder cancer and kidney cancer,” Zhang said in an interview with OncLive^® following a State of the Science Summit™ on RCC and bladder cancer, which she chaired.

In the interview, Zhang, an associate professor in the Department of Internal Medicine at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, highlighted key points from each presentation shared at the meeting, including the benefits of multidisciplinary collaboration, how to select the best agents for each patient, and how treatments such as radiation in RCC and bladder-sparing chemoradiation in urothelial cancer fit into the overall treatment paradigms for these diseases. She also noted the importance of referring eligible patients to clinical trials that could provide them with the most effective treatments, and shed light on several clinical trials that are currently accruing patients with RCC and urothelial cancer. 

OncLive^®: Since 2017, there have been 9 FDA approvals for frontline treatments for patients with metastatic RCC. What factors go into making treatment decisions with all these options?

Zhang: The treatment landscape has expanded quite a bit, just in the past 5 years for first-line metastatic kidney cancer. When we approach patients in the clinic to make those first-line treatment decisions, we consider their degree of tumor burden, their International Metastatic RCC Database Consortium [IMDC] risk stratification, and whether [their tumor is] more inflamed or less inflamed and driven by angiogenic factors.

Treatments can range from single-agent cabozantinib [Cabometyx], for example, for patients who are not candidates for immunotherapy, all the way to pure immunotherapy combinations with ipilimumab [Yervoy] and nivolumab [Opdivo], or VEGF TKIs and immunotherapy combinations. We currently have a host of these combinations, the most common of which are axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab. All these [regimens] are great options. 

[When making these decisions,] we think about patient characteristics. Now, we also use a lot of clinical characteristics. I am hopeful that we will start to use more molecular typing and gene signatures to tailor treatments for individual patients. For example, we currently have some data on sarcomatoid features. We know patients with sarcomatoid features respond well to immunotherapy-based combinations, so they should receive checkpoint inhibition. On the other hand, pancreas metastases seem to be more driven by angiogenic factors. Therefore, I favor more of a VEGF antiangiogenic agent in those cases.

Could you highlight the rationales for the phase 3 PDIGREE (NCT03793166), PROBE (NCT04510597), COSMIC-313 (NCT03937219), and MK-6482-012 (NCT04736706) trials that are exploring different combinations of approved frontline agents in RCC?

Several large first-line phase 3 trials are ongoing. Two are being done in the cooperative group setting, 1 of which I am fortunate to lead. The PDIGREE trial is an adaptive trial where all patients have IMDC intermediate- and poor-risk disease and start with a pure immunotherapy combination of ipilimumab and nivolumab. At 3 months, they are randomized to either nivolumab or nivolumab with cabozantinib and assessed for radiographic response. Our key end point is overall survival. Hopefully, studying this sequence of treatments and including the early addition of the doublet VEGF/immunotherapy combination will make a difference and help patients live longer.

The other cooperative group trial is the PROBE study. This trial is specifically addressing the role of cytoreductive nephrectomy with immunotherapy-based combinations. All patients are put on their immunotherapy combination of choice. At the 3-month mark, they are randomized to either consolidative nephrectomy to resect the primary tumor, or a continuation of the systemic treatment. Both trials are open and accruing across the cooperative group settings.

The COSMIC-313 trial is an industry-sponsored triplet trial that has closed to accrual. The triplet [under examination] is ipilimumab, nivolumab and cabozantinib. We anticipate some results of COSMIC-313 soon.

Finally, the last trial that is ongoing globally is MK-6482-012, an industry-sponsored study investigating a triplet [comprised] of lenvatinib, pembrolizumab, and belzutifan [Welireg]. This trial is investigating whether adding the hypoxia inducible factor-2 alpha [HIF2α] inhibitor belzutifan to lenvatinib plus pembrolizumab makes a difference. A third cohort in that trial is receiving lenvatinib with pembrolizumab and the novel CTLA-4 inhibitor quavonlimab [MK-1308].

All these trials are ongoing in the front line and are open at UT Southwestern, so we encourage our patients to participate when they are good candidates.

Tivozanib (Fotivda) is now approved in the second-line setting for patients with RCC. What has been observed with this agent, and what is the rationale of ongoing trials that are investigating it in combination with nivolumab?

[Tivozanib was approved in March 2021.] The registrational trial, [the phase 3 TIVO-3 trial (NCT02627963)], compared tivozanib with sorafenib [Nexavar] and showed an improvement in progression-free survival in patients who had been previously treated with VEGF inhibition. Tivozanib is a good option and is generally tolerable—even in the refractory setting, where patients who are frailer may be able to tolerate it.

Several ongoing trials are studying tivozanib in combination with nivolumab. For example, 1 trial that is about to open at UT Southwestern is the [phase 3] TiNivo-2 trial [NCT04987203]. It is already open in multiple [sites] across the world. Another ongoing trial in the refractory space that is investigating combinations with immune checkpoint inhibitors is the [phase 3] CONTACT-03 trial [NCT04338269], which is looking at cabozantinib with atezolizumab [Tecentriq]. That trial is fully accrued, and it [randomized patients to either] cabozantinib with atezolizumab or cabozantinib alone. We are looking forward to seeing the results.

Finally, as my colleague, [James Brugarolas, MD, PhD, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center] highlighted, HIF2α inhibitors have also made a splash in refractory disease, particularly for patients with von Hippel-Lindau syndrome. Multiple trials are now looking at belzutifan in the refractory space for clear cell kidney cancer, as well as belzutifan in combination with cabozantinib and other VEGF TKIs.

An ongoing phase 3 study, [MK-6482-005 (NCT04195750)], is comparing belzutifan with everolimus [Afinitor] and is enrolling across the country. Another trial, [the phase 3 MK-6482-011 trial (NCT04586231)], is studying belzutifan and lenvatinib compared with cabozantinib in the phase 3 setting. Those are 2 other trials to look out for that may inform the refractory landscape.

In your presentation, you spoke about MET inhibitors in the second line and later. What contributing factors go into selecting those agents as treatment options in these patients?

In the refractory setting, tivozanib is a good option, even after patients have received immunotherapy-based combinations with cabozantinib, for example. We also have mTOR inhibition in the refractory setting, so many patients will see either everolimus alone or everolimus with lenvatinib, [which is] an approved combination. Those are all good treatment options.

In terms of sequencing treatments, each of the trials [I have mentioned] have shown improvements in prolonging overall survival in population-based data. However, when we are able to treat a single patient with these life-prolonging therapies, that is when we see a difference in terms of getting individual patients to live longer with sequential treatments. We are in a time where we are lucky enough to have multiple agents in the first line, as well as in the refractory space, so we need to optimize sequencing all these agents to help our patients live longer.

Raquibul Hannan, MD, PhD, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, spoke about radiation in oligometastatic RCC. How does radiation fit into the treatment paradigm for these patients?

Oligometastatic kidney cancer is a special disease state where there are only a few sites of metastasis. If those sites can be ablated, perhaps we can delay systemic treatments and toxicities. That was the premise of Dr Hannan’s discussion. He was able to prospectively conduct a phase 2 trial [NCT02956798] at UT Southwestern, [which evaluated] oligometastatic radiation to the oligometastatic disease, [and showed] a delay in systemic treatment. He is currently in the process of developing a potential further noninferiority trial that will likely be [done] in the cooperative group setting.

Yair Lotan, MD, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, spoke about the multidisciplinary approach to localized urothelial cancer. How important is this approach for these patients?

In non–muscle invasive bladder cancer and muscle-invasive bladder cancer [MIBC] in the localized settings, we have many multidisciplinary discussions about optimizing treatments. For MIBC, we often do neoadjuvant chemotherapy followed by surgery, or we think about chemotherapy, radiation, and bladder preservation. [We certainly employ] a multidisciplinary approach for disease management in these patients.

In addition, as our systemic treatments are active, and we are seeing improvements in the refractory settings, these treatments are also moving into the localized settings. Our urologists and radiation oncologists are [conducting] multiple trials [that are] adding systemic treatments that are effective in the refractory space to the localized setting.

Dr Lotan also talked about an interesting new way to deliver chemotherapy within the bladder. For a long time, we have had intravesical delivery of chemotherapy, but there is a novel tool called a pretzel, a little device that can be inserted into the bladder, where it dwells and slowly releases chemotherapy before it is retrieved. That is an interesting, and hopefully effective, way to treat intraluminal bladder cancer.

Neil Desai, MD, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, spoke about bladder sparing in localized urothelial cancer. What patients would be the ideal candidates for this treatment approach?

We carefully select patients for chemoradiation and talk through the risks and benefits when we are considering this option. Often, when tumors are less than 5 centimeters, we think radiation will be a definitive approach. My role in chemoradiation is to give radiosensitizing chemotherapy, oftentimes with agents such as a regimen from the UK of 5-fluorouracil and mitomycin, or a regimen of weekly cisplatin or twice-weekly gemcitabine. These are all standard options for patients when they are getting chemoradiation. These approaches are basically layering the chemotherapy on top of the radiation to hopefully improve the effects of definitive radiation.

Qian Qin, MD, and Waddah Arafat, MD, both of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, spoke about treatment options in the first, second, and later lines of metastatic urothelial cancer. What does the current treatment space look like in the metastatic setting, and how has it evolved in recent years?

Dr Qin gave a tour de force discussion about first-line metastatic bladder cancer treatments. She took us all the way through definitive trials looking at chemotherapy; methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin [MVAC]; dose-dense MVAC; gemcitabine with cisplatin; and gemcitabine with carboplatin. Those are still our go-to chemotherapy regimens for patients in the first-line setting. We often add maintenance avelumab [Bavencio], an immune checkpoint inhibitor, to frontline chemotherapy in patients who have achieved stable disease or better.

Finally, in the refractory space, we now have several good options in terms of standard-of-care treatments for patients who have FGFR alterations that are translocations, infusions, or mutations of FGFR2 or, more commonly, FGFR3. We have FGFR inhibitors, the approved one being erdafitinib [Balversa]. We also have accelerated approvals for 2 antibody-drug conjugates, enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan-hziy [Trodelvy]. Both [agents] are highly effective for stabilizing and managing patients with refractory urothelial cancer.

Because these treatments are so effective, we are also seeing them move into the frontline setting. The trial to watch out for is the [phase 3] EV-302 trial [NCT04223856]. This trial is based on the premise of the phase 2 [EV-103] study [NCT03288545], where enfortumab vedotin was combined with pembrolizumab [and showed] an objective response rate of 73.3% and a disease control rate of 93.3%. Almost all patients experienced disease control or better with the combination.

EV-302 is randomizing patients in the first-line metastatic setting to either enfortumab vedotin with pembrolizumab or standard gemcitabine and cisplatin chemotherapy. This trial, if successful, could unseat chemotherapy in the frontline setting. Stay tuned because it is still ongoing and accruing across the country. We are participating at UT Southwestern. Hopefully, we will see some good results and make the first-line metastatic urothelial [treatment] landscape even broader.

What studies is UT Southwestern currently involved in?

We participate in multiple trials, both at the industry-sponsored level as well as at the investigator-initiated level. We participate in these studies with collaborating institutions like Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and Fox Chase Cancer Center. I would encourage any referring physicians who are thinking that their patients might be a candidate for a trial to reach out to our group to see whether there is a trial that meets their patients’ needs.

What main message encapsulates the topics discussed at the meeting and the broader updates in RCC and urothelial cancer?

As these treatments develop, we are seeing great advances. We are also hopefully improving care and prolonging life-extending treatments for all our patients in the standard-of-care setting. [We should also be] thinking about clinical trials when our patients are good candidates. We have trials available in all lines and all spaces of both bladder and kidney cancer. We are seeing active systemic treatments move into earlier disease spaces and earlier disease settings, to hopefully help with disease control and to prevent metastatic disease.