Belzutifan Regimens Show Promise in RCC as Frontline IO/TKI Armamentarium Expands


Nikhil A. Gopal, MD, discusses the benefit of belzutifan in addition to effective immunotherapy-based regimens in advanced RCC.

Nikhil A. Gopal, MD

Nikhil A. Gopal, MD

Treatment decision-making in advanced renal cell carcinoma (RCC) has become increasingly nuanced with the integration and ongoing development of immuno-oncology (IO)-TKI combinations, according to Nikhil A. Gopal, MD. He added that belzutifan (Welireg) regimens have the potential to reshape approaches to frontline therapy alongside a growing arsenal of immunotherapy-based regimens being evaluated in earlier lines.

Findings from the phase 3 LITESPARK-005 trial (NCT04195750) showed that the HIF2a inhibitor significantly improved progression-free survival (PFS) vs everolimus (Afinitor) (HR, 0.75; 95% CI, 0.63-0.90; 1-sided P =.0008) in patients with advanced RCC following progression on a PD-(L)1 inhibitor and VEGF TKI.1 The median PFS with belzutifan was 5.6 months (95% CI, 3.9-7.0) vs 5.6 months (95% CI, 4.8-5.8) with everolimus. Despite being immature at the time of analysis, overall survival (OS) data did not trend towards a detriment with belzutifan.

Based on these data, the FDA approved belzutifan for the treatment of patients with advanced RCC who have undergone treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI. The agent is currently being evaluated alongside cabozantinib (Cabometyx) in the phase 2 LITESPARK-003 study (NCT05239728)in patients with treatment-naive and immunotherapy-exposed clear cell RCC (ccRCC).

“[In RCC], we’ve gone past the era of TKIs into IO-TKI combinations, with the exception of nivolumab [Opdivo] plus ipilimumab [Yervoy],” Gopal said in an interview with OncLive® following his participation in a State of the Science Summit™ on bladder cancer/RCC. “We’re going to see a lot more utilization of those types of oral agents in the frontline setting [moving forward].”

In the interview, Gopal discussed the promising efficacy of belzutifan in advanced RCC, highlighting its unique mechanism of action as a HIF2a inhibitor; the importance of navigating the current landscape of immunotherapy-based regimens in RCC based on both efficacy data and patient-specific considerations; and the need for increased research focusing on non-ccRCC.

Gopal is an assistant professor of urology and assistant professor in the College of Medicine - Memphis, in the Department of Urology at The University of Tennessee Health Science Center, in Knoxville, Tennessee.

OncLive: What benefit has been seen with belzutifan in advanced RCC, and how does the agent’s mechanism of action make it a unique option for patients in this setting?

Gopal: There are several promising agents slowly moving up to the frontline setting. For instance, the LITESPARK-005 trial showed that belzutifan was superior to everolimus in patients who had treatment-refractory metastatic ccRCC and progressed on localized therapy. Now there’s the phase 2 [LITESPARK-003] study of belzutifan plus cabozantinib in the treatment-naive setting showing an overall response rate of [57%with belzutifan], which is similar to that of pembrolizumab [Keytruda] plus axitinib [Inlyta], and other kinds of frontline agents.

The real benefit of belzutifan is the fact that it’s highly selective. It’s a HIF2a inhibitor. We know from studies that the majority of ccRCC is characterized by loss of von Hippel-Lindau [VHL], which is a suppressor of HIF2a. If VHL is lost, HIF2a is upregulated, and that leads to the increased transcription of angiogenesis factors like VEGF. By targeting HIF2a, we can block the angiogenesis pathways without [affecting] some of the other cross pathways that some of the older agents, such as sunitinib [Sutent] or even immunotherapy, did.

The only major adverse effect [AE] we’re seeing with belzutifan is anemia. A good way to conceptualize that [belzutifan is associated with] low risk is that the agent is approved in localized kidney cancer. In fact, its first approval was in patients with VHL [syndrome] that have kidney masses. These are patients who have localized kidney cancer and are very high functioning. Many patients continued therapy for over 2 years, which is when the initial trial was conducted, with very little treatment discontinuation. The fact that we can give effective agents without incurring AEs for patients who can enjoy a good quality of life is exciting.

What might the role of belzutifan be in earlier settings within ccRCC?

We talked about the fact that we potentially have additional agents [in this space]. Obviously, there is the LITESPARK-003 study. What you’re probably going to see now is belzutifan coming into the frontline setting. The fact that belzutifan is well tolerated with a limited number of AEs [is advantageous]. The other benefit is that both [belzutifan and cabozantinib are] given orally, so it’s a lot easier to administer both from a practitioner and patient standpoint. Obviously, we await phase 3 data to make sure [this combination has benefit in the frontline], but the phase 2 data look very promising.

What factors are important to consider when selecting between/navigating the current landscape of immunotherapy-based regimens in RCC?

The talk by [fellow presenter] Dr Daniel Vaena [of West Cancer Center & Research Institute] was timely and excellent because we now have a burden of excess. Back in 2014 and 2015, we hardly talked about immunotherapy; now we have several agents approved in the frontline setting. The question is how to pick [between these] agents for each patient. The way that I conceptualize it is that from [the standpoint of] objective response rate [ORR], the IO-TKI combination[s] seem to be more effective. In other words, the ORR from ipilimumab and nivolumab, which is dual-IO regimen, is [42%]. However, if you look at [the ORR for] other [combinations] like pembrolizumab and axitinib it’s [approximately 60%]. It’s similar for cabozantinib and nivolumab, and lenvatinib [Lenvima] and pembrolizumab, [the latter of which] has the highest ORR at approximately 71%. If you have a patient with significant disease burden, and you’re concerned about issues should the disease progress even a little bit—let’s say they have impending cord compression, or just really debilitating bone pain [to the point where] they can’t even ambulate at all—then I would favor an IO-TKI combination over nivolumab plus ipilimumab.

Theoretically, we can’t compare trial results to each other, but for real-world experiences, we must. We have to come up with some kind of answer because patients expect that. On the other hand, the advantage of nivolumab plus ipilimumab is that it has the longest follow-up time of 8 years. Interestingly, the overall survival [OS] curves at 8 years still [show] a benefit with nivolumab plus ipilimumab vs sunitinib. You [can] contrast that with [data from] the CLEAR study [NCT02811861] of lenvatinib plus pembrolizumab. Even though [the regimen] improved ORR [vs sunitinib] and the survival curves seem to separate out nicely at [approximately] 2 years, the OS curves at about 5 years show some concerning crossover. Obviously, the data are immature because it is a newer study.

One of the things to consider when interpreting that is that patients who progress on the comparator arm now have a myriad of options to choose from, whereas with the [phase 3] CheckMate-214 trial [NCT02231749], which was conducted before immunotherapy [was a standard], patients didn’t have as many options. Perhaps that’s why you’re seeing a reduction of OS benefits. That said, we still have to go with the data. The longest OS benefit is seen with ipilimumab plus nivolumab because of its longevity on the market. If you have a patient who is younger, is concerned about quality of life, is of reasonable functional status, and can tolerate some of those increased AEs with dual IO therapy, that will favor giving ipilimumab plus nivolumab vs other agents. That is just an example of some of the decisions that we must make because we have so many different agents to choose from.

What future research still needs to occur to maximize the clinical benefit of IO/TKI combinations in other RCC histologies?

In the frontline metastatic ccRCC setting, we’re doing quite well. We have several agents, and it’s better to have an excess [of options] than none. The next step is to focus on non-ccRCC, particularly papillary RCC, which is the second most common type of kidney cancer. We’re starting to see some trials utilizing IO combinations for those patients. We have things like single-agent cabozantinib, but combination therapy [may] be critical. We just don’t have the data to support those assertions [now]. I’m hopeful that [we will see the benefit of these combinations] once these trial results come out. We know that [patients with] sarcomatoid histology respond well to immunotherapy, but we’re starting to see some of these variant histologies included in trials. The next few years [will hopefully] show an evolution of focus [in RCC research.] Now that we’ve answered [many of] the questions for ccRCC, we [need to] focus on non-ccRCC.


FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed February 28, 2024.

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