Investigators Set Their Sights on Novel Targets in Genitourinary Malignancies

Manojkumar Bupathi, MD, MS

With an abundance of combination strategies in frontline metastatic renal cell carcinoma (RCC) and maintenance immunotherapy in advanced urothelial carcinoma that have shown overall survival (OS) benefits, research has turned to developing a more refined sequencing strategy that takes into account newer targets, such as interleukin-2 (IL-2), HIF1-α, FGFR, and EphB4, respectively.

“It was impressive to see all the changes that have happened in the genitourinary space over the past few years. We have seen a big difference in PFS [progression-free survival] and OS. The number of options that we have seen come up for patients is also quite impressive. Toxicity hasn’t really changed substantially over the past few years, but [we have seen] better outcomes. Treatments are getting more specific, which is another good thing that we have seen. It’s good to have options,” said Manojkumar Bupathi, MD, MS, in an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies.

In the interview, Bupathi, a medical oncologist at Rocky Mountain Cancer Centers, shared the main highlights from the meeting, which centered on frontline, second, and later-line treatment of metastatic urothelial carcinoma and metastatic RCC.

OncLive^®: How have immune-based therapy combinations changed the outlook on advanced RCC?

Bupathi: The state of RCC has advanced quite rapidly over the past 3 years or so. Several trials have shown significant improvement in PFS and OS. [In terms of] OS, [we are looking at] pembrolizumab [Keytruda] plus lenvatinib [Lenvima] from the CLEAR trial [NCT02811861], as well as the data from CheckMate 9ER [NCT03141177] and CheckMate 214 [NCT02231749] trials. [We are] definitely [seeing] a lot of exciting treatment options that have had come up and are coming up in the future with HIF1-α inhibitors and such. A lot has happened and has yet to happen.

In your presentation, you highlighted several studies such as CheckMate 9ER, CABOSUN (NCT01835158), and CheckMate 214. How do those studies contribute to best practices in the frontline treatment of patients with advanced RCC?

Every one of these studies was done slightly differently. CheckMate 9ER looked at untreated patients in the first-line setting with cabozantinib [Cabometyx] plus nivolumab [Opdivo]. CABOSUN evaluated cabozantinib vs sunitinib [Sutent], and Checkmate 214 tested doublet immunotherapy. The population for Checkmate 214 was intermediate- and poor-risk patients, and CheckMate 9ER included all risk [groups].

When you look at all these studies, the underlying theme is that there are better options with better response rates compared with the traditionally used drugs of sunitinib or pazopanib [Votrient] in the first-line setting. How do we treat these patients? Risk stratification is important, as well as the possible toxicities that patients may see. Taking those factors into consideration are important along with comorbidities to figure out what treatment to go with. Also, one of the things is how symptomatic an individual is from their disease, [which may indicate whether we need to] to try to get a faster or quicker response.

When you look at CheckMate 9ER, you look at the overall response rates or the PFS, which is quite substantial when you compare it with sunitinib. CABOSUN is the same thing. When you look at CheckMate 214, you look at the CR [complete remission] rates, which compared with sunitinib is quite substantial, and the toxicities are quite manageable among all these options.

How have these trials affected treatment sequencing strategies?

One of the big things in sequencing is trying to figure out what the patient got as first-line therapy, which really dictates how patients should be treated in the second-line setting. For example, if someone got pembrolizumab plus lenvatinib as first-line therapy, you can’t really use lenvatinib in the second-line setting. You probably need to use a different drug. If they got ipilimumab [Yervoy] and nivolumab as first-line therapy, then maybe cabozantinib should be given in the second-line setting. If they got cabozantinib with nivolumab as first-line therapy, then our traditional thought of using cabozantinib in the second-line setting won’t really work, and we’ll need to use a different option.

Sequencing is becoming a little bit more challenging at this point because we don’t have all the information, and a lot of the drugs that we use in the second-line setting have been moved up.

Jeffrey Yorio, MD, of Texas Oncology, discussed later-line treatment options for patients with advanced RCC. What has been your approach to later-line treatment?

The big thing is: What drugs were used first? All our therapies in the first-line setting have become so good that it’s kind of like dealer’s choice. [We] can’t really say that one is overly better than the other. They are all good options. How you sequence therapies really depends on what you choose for first-line therapy. As we see more data evolve, we’ll get a better understanding of that, and as newer targets are coming up [for which we’re developing drugs for], such as HIF1 inhibitors, or IL-2 [agents] then we’ll be able to, hopefully, get more information on sequencing.

Nauman Moazzam, MD, of Rocky Mountain Cancer Centers, discussed frontline treatment for patients with metastatic urothelial carcinoma, and one of the studies he highlighted was JAVELIN Bladder 100. What stood out to you from that trial?

JAVELIN Bladder 100 [NCT02603432] was an impressive trial. This is the first time that we have seen such a significant OS benefit in patients with advanced bladder cancer. Traditionally, if you have advanced disease or metastatic disease, half of the population generally doesn’t make it to second-line treatment. With this maintenance therapy, whether you have PD-L1 positivity or not, there was a statistically significant OS improvement vs control across all patients. [The OS] was longer in the avelumab [Bavencio] arm vs the control group, and specifically in those that got systemic chemotherapy in the first-line setting. This is the first time we have ever seen this, and it’s impressive and has changed the entire landscape of how patients with advanced or metastatic bladder cancer are treated nowadays.

What is being done for the patients who don’t respond to avelumab?

There are a lot of unmet needs in bladder cancer even though we’ve seen this improvement in OS with maintenance therapy. There is still a large subset of patients who don’t have that great of a response. The question is: Why and how do we help that group of patients? Looking at genomic analyses and looking at targeted therapies has been quite substantial.

Some of the upcoming regimens that have been shown to be quite promising are FGFR inhibitors in conjunction with immunotherapy. Some data from the 2021 ESMO Congress showed that an FGFR inhibitor plus a PD-1 inhibitor has a good response. We have also seen data using antibody-drug conjugates, such as enfortumab vedotin-ejfv [Padcev] in conjunction with pembrolizumab, which have been shown to have good responses as well. Recently, at the 2021 ESMO Congress, there was a phase 2 trial of pembrolizumab in combination with an EphB4 inhibitor, which showed some response as well. We have certainly seen more targeted therapies coming up that seem to have some responses. There is more to come on this and understanding the tumor biology and more specific targets is really where [the field] is moving towards.