Debate Ensues With Integrating Multimodal Approaches in RCC, Sequencing Agents in Bladder Cancer

Earle Burgess, MD

Despite the level of evidence supporting the use of systemic and local therapy in renal cell carcinoma (RCC) and urothelial carcinoma, there is room for debate regarding the optimal timing and choice of each intervention, according to Earle Burgess, MD.

“Both renal and urothelial diseases have gotten exceedingly complex, so it’s good to have multidisciplinary involvement anytime you have advanced cases,” said Burgess, an associate professor of medicine at Levine Cancer Institute, Atrium Health, who moderated a panel discussion during a 2020 Institutional Perspectives in Cancer (IPC) webinar on genitourinary malignancies, highlighting such scenarios in RCC and urothelial carcinoma that require careful consideration of available data.

Burgess was joined by 3 panelists:

• Claud M. Grigg Jr., medical oncologist, Levine Cancer Institute
• Jason Zhu, MD, medical oncologist, Levine Cancer Institute 
• Justin Matulay, MD, urologist, Levine Cancer Institute

During the question-and-answer portion of the virtual IPC meeting, Burgess relayed pressing questions from the audience to the speakers, who provided insight into how they are navigating the evolving treatment landscape of RCC and bladder cancer. 

Burgess: Dr. Grigg, once you’ve decided to use an immunotherapy/TKI combination, would you pursue cabozantinib [Cabometyx] and nivolumab [Opdivo] or axitinib [Inlyta]/pembrolizumab [Keytruda] if the patient had intermediate-risk RCC? 

Grigg: We don’t have head-to-head data. There are multiple ways to think about those different regimens. It’s sort of a balance of efficacy and toxicity. Cabozantinib is the only drug that has been shown to be more effective than sunitinib in the first-line setting. [Cabozantinib] is a tyrosine kinase inhibitor [TKI] with a broader spectrum of kinases that it inhibits, and it has been shown to be active in other TKI refractory settings. Some of us think of it as probably a slightly more active TKI, but whether that really translates into clinical benefit in terms of overall survival for these patients I don’t know; we may not ever know. When I think about a patient who is very sick, very symptomatic with poor-risk disease, I might lean more heavily in that direction, given what we know about cabozantinib specifically from prior studies. 

Claud M. Grigg Jr.

Some of the toxicities may be a little better with axitinib compared with sunitinib, which may have to do with [the fact that it is] a more specific TKI; it’s more specific to the VEGF receptors. Perhaps an intermediate-risk patient who is minimally symptomatic, because of their tumor burden, I might lean more towards that combination, thinking that perhaps it’s a little bit more easily tolerated than cabozantinib, but again, these are all kind of cross-study comparisons that are not always easy to make [and base a] definitive recommendation [on]. 

Burgess: Dr. Matulay, if the patient received an immunotherapy/TKI combination up front and had a nice response and seemed to be tolerating it well, should medical oncology send them to you for a delayed nephrectomy, or, if they’re doing well, leave them alone? 

Matulay: The jury is still out there. It’s becoming more and more difficult as we’re seeing better and better responses. Some retrospective data have [tried] to assess for a cut off of response in the primary tumor as an indication that the patient is having a good response [and] will be a good long-term responder and should undergo cytoreductive nephrectomy, but those data are not really mature enough at this point to [provide us with a] good evidence-based approach to that. However, I do think it’s reasonable in somebody who has had a reduction in their tumor size, has had a good response in the metastatic sites, especially, to consider cytoreduction with the hope that at that point maybe removing the tumor as a source of maybe sucking up the antibodies or the immune response that’s causing them to have a good response to immunotherapy, which may [provide] a better long-term response as well.

Burgess: Dr. Grigg, would your decision change for a patient who has a high percentage of sarcomatoid features? 

Grigg: Essentially all these phase 3 trials, not yet with CheckMate-9ER, but all the other phase 3 trials as well as IMmotion151, which evaluated the combination of atezolizumab [Tecentriq] and bevacizumab [Avastin], did have post-hoc subgroup analyses in the sarcomatoid population. Not only was there an advantage to the combination therapies in the sarcomatoid population, but that advantage seems to be even more [apparent] than in the non-sarcomatoid population.

We’ve known for a long time that [patients with] sarcomatoid RCC [have a] higher expression of PD-L1, they tend to have unique immune infiltrates within the tumor microenvironment. It’s long been hypothesized that these are even more sort of immune susceptible tumors. We’ve seen that from these retrospective or these post-hoc analyses from all of these phase 3 trials. 

To partially answer your question, at a minimum, someone with a sarcomatoid component should receive something with a checkpoint inhibitor. I don’t think there’s a role for TKI monotherapy, where, in the past, we’ve known that the response rates of TKIs are lower in the sarcomatoid population. 

The results from CheckMate-214 in the sarcomatoid population were especially impressive, where the response rate was 60% compared with 40% for the overall population, and the CR rate was approaching 20%. I don’t think we can necessarily say the combination of ipilimumab and nivolumab is better in this population than one of the TKI/IO combinations, but that might [make me] slightly favor the trial [with] ipilimumab/nivolumab in the sarcomatoid patients.

Burgess: Does a histologic diagnosis of non-clear cell RCC change your choice of therapy?

Grigg: We really don’t have data here. In non-clear cell, there are responses to TKIs and checkpoint inhibitors. The rates are almost universally lower in non-clear cell than they are in a comparable clear cell population. It does depend to a degree on the histologic subtype that you’re discussing. In the papillary, we see higher response rates compared with, for example, chromophobe tumors, where the response rates are really quite low. 

Sunitinib [Sutent] is still considered to be the standard of care first-line treatment. If you look at the [National Comprehensive Cancer Network] guidelines, you’re still going to see that listed as the preferred choice. We know that checkpoint inhibitors are active in some of these patients with non-clear cell disease. Based on what we now have learned in the clear cell patients, even before we get the results from some of these ongoing phase 3 trials in the non-clear cell setting, if the patient is not eligible for a study, if you can get access to a checkpoint inhibitor in the frontline setting, I think I would add that.

Burgess: Dr. Matulay, most patients with [advanced RCC] will receive systemic therapy first. Is there a particular group of patients that you would push for cytoreductive nephrectomy up front, or should everybody get initial systemic therapy?

Justin Matulay, MD

Matulay: Certainly, intermediate- and poor-risk patients should be heavily considered for systemic therapy, especially given that any surgery could delay their receipt of those agents. In the good-risk patients, patients who are otherwise healthy, they can undergo surgery and most importantly, have a resectable primary tumor. Still doing cytoreduction up front will probably benefit them in the long run, assuming that their metastatic disease does not seem like it’s going to take off in a 4- to 6-week delay to therapy. It’s not clear how often [an unresectable patient becomes resectable after systemic therapy]. Anecdotally I have seen that happen with some pretty remarkable responses in primary tumors that did radiographically appear to be invading other organs and progressed to the point that they appeared surgically resectable later on after several months.

Burgess: Dr. Grigg, is there a certain setting in which you would consider neoadjuvant systemic therapy prior to resection in patients with local high-risk disease, either by way of high-volume or inferior vena cava tumor thrombus or local invasion, say hepatic invasion, who don’t have any evidence of distant metastatic disease? 

Grigg: A number of phase 2 trials have looked at primarily TKI monotherapy before surgery in variably defined borderline resectable locally advanced tumors, tumors that are felt to be at high risk if they’re going to be resected, so there’s a desire for tumor reduction before surgery or an attempt to make someone operable.

Interestingly, the response rates to TKIs are actually a little higher in the locally advanced setting than they are in the metastatic setting. A few trials of immunotherapy-based combinations are ongoing, as well as those evaluating immune monotherapy in the neoadjuvant setting. But we don’t really have data yet from those studies to really guide us. Perhaps we can extrapolate and say, most likely if the TKIs are a little bit more effective in the locally advanced setting than they are in the metastatic setting, that probably a combination therapy is going to be even more active in the locally advanced setting. I wouldn’t advocate for that strategy except in the setting of someone who really is not operable, and you’re trying to make them operable.

Burgess: Dr. Matulay, is there ever a scenario where a non-clear cell patient should undergo cytoreductive nephrectomy?

Matulay: I don’t see any difference in terms of the reasoning behind doing cytoreductive nephrectomy in a clear cell versus non-clear cell patient. If anything, for most non-clear cell pathologies, it would probably be more beneficial potentially, if you’re seeing the rare chromophobe metastatic patient or papillary type I patient that’s metastatic. I don’t think there’s any evidence to say that you shouldn’t be doing cytoreductive nephrectomy. But potentially if you’re concerned that the systemic therapy is not going to be as effective, maybe you push the envelope a bit more with cytoreductive nephrectomy in that group.

Burgess: Dr. Zhu, if you had a patient with [bladder cancer and] an FGFR aberration that progressed on a frontline platinum doublet, how would you think about which agents to use in sequence? In the context of immunotherapy with enfortumab vedotin[-ejfv (Padcev)] and an FGFR inhibitor, how you would sequence therapy?

Zhu: Right now, the question is really between a checkpoint inhibitor or an FGFR inhibitor. I don’t think we have the data yet for enfortumab in that second line right now. I will say that FGFR-mutated tumors are not all the same. There are probably some patients who will respond better to an immunotherapy up front and some that will respond better to FGFR3 inhibition, and we see this in the data that has been published so far.

Jason Zhu, MD

Some retrospective data that came out at [University of North Carolina] showed that patients who had FGFR3 mutations did not respond as well with checkpoint inhibitors compared with FGFR3 inhibitors. But if you look at the pivotal trial with erdafitinib, those patients who previously received checkpoint inhibitors had a higher response rate to erdafitinib as a cohort; 59% versus 40% for those who had not received checkpoint inhibitors, so the jury is still out as to what the best [option is]. Part of that will also be patient preferences. Erdafitinib is an oral therapy, so it does not require the infusion room and infusion spaces, and that’s something to think about during the pandemic as well.

Burgess: Do you have any concern about the potential for overlapping toxicities or ocular toxicities, which are not common, but can occur with erdafitinib [Balversa] with the use of enfortumab even if you sequence an immunotherapy agent in the interim? 

Zhu: I don’t know if we have enough data at this time. But the answer is yes. I would be concerned about that sequencing enfortumab afterwards with some of the toxicities. Erdafitinib has unique toxicities that we have not seen in our immunotherapies or chemotherapies, so thinking about those toxicities for patients will be important in making that decision.

Burgess: We have phase 2 data with sacituzumab govitecan[-hziy (Trodelvy)], and the phase 3 study is ongoing. If sacituzumab govitecan gains regulatory approval or at least accelerated approval in the post-IO, post-platinum setting similar to enfortumab vedotin’s current labeled indication, how might you think about sequencing sacituzumab govitecan with enfortumab vedotin, immunotherapy, or an FGFR inhibitor?  

Zhu: Right now, after a platinum I would go to immunotherapy if you haven’t done immunotherapy already in the maintenance setting. In the setting of an FGFR mutation, at that point, I will discuss whether or not to do that versus immunotherapy. The second line following that I would go for enfortumab vedotin, and then I would probably place sacituzumab govitecan after that. Those patients by that time are pretty heavily treated and have a lot of toxicities that are going to overlap. However, the mechanism of action between enfortumab vedotin and sacituzumab govitecan are different. They have different antibodies, one being Nectin-4 and the other being Trop-2, so I’m hopeful that those patients actually may still respond to another ADC [since] there’s a different payload and a different anybody. I would use it afterwards. I would definitely use an FGFR3 inhibitor prior though to giving 2 ADCs back-to-back.

Editor’s note: This event was held prior to the January 2021 FDA approval of nivolumab/cabozantinib for frontline treatment of patients with advanced RCC.