In this interview, Dr Robert Figlin discusses the promising clinical activity of belzutifan combined with cabozantinib in advanced clear cell renal cell carcinoma, highlighting its potential role in future treatment pathways, practical considerations for sequencing, and the importance of monitoring unique toxicities such as anemia.

Please introduce yourself by stating your name, title, and any relevant clinical experience you’d like to share.

Robert A. Figlin, MD: I'm Robert Figlin, the Steven Spielberg Family Chair in Hematology Oncology, professor of medicine and biomedical sciences, and the interim cancer center director at Cedars-Sinai Cancer in Los Angeles.

How does this study fit into the broader development program for belzutifan, particularly in terms of where it may be positioned in future treatment pathways for advanced clear cell renal cell carcinoma (ccRCC)?

Dr Figlin: It's important for everyone to understand that we—and others—have been looking forward to understanding the hypoxia-inducible factor (HIF)-2 pathway in ccRCC for some time through phase 1 trials and then ultimately through phase 2 and phase 3 trials.

We know that ccRCC is a disease predominantly driven by abnormalities in the HIF pathway, which are associated with VHL mutations and hypermethylation. We've always had downstream inhibitors, such as VEGF receptor tyrosine kinase inhibitors (TKIs). It's been interesting for those of us that have been interested in this pathway to see how some of the HIF-2 inhibitors—in this specific situation, belzutifan—have entered the clinic, both with respect to benefits and toxicity.

The manuscript that we published in Lancet Oncology in January 2025 is really an illustration of how, when combined with cabozantinib—a known VEGF receptor 2 inhibitor—belzutifan produces activity in previously untreated patients with metastatic disease that seems to be greater than what one would have expected from either of these agents delivered alone. With response rates in the 70% range and approximately 8% of patients having complete remissions, I can tell you that my own personal experience, both in the clinical trial as well as outside of the clinical trial, that this combination has important clinical activity for patients and has produced durable remissions that have allowed us to continue to offer them a substantial improvement in their quality and quantity of life.

Cohort 1 showed a remarkably high objective response rate of 70% with a median progression-free survival of over 30 months. How do you interpret these results in the context of currently approved first-line options for ccRCC?

Dr Figlin: That's a great question. One needs to recognize both the successes and challenges of small, n = 50, phase 2 trials.

We saw a 70% response rate. We saw an 8% complete response rate. We saw an extension in progression-free survival, but we have not yet seen comparisons to other trials, such as IO-IO, ipilimumab and nivolumab, for example, or IO-TKI, where trials have been done.

I can tell you that, anecdotally, with cross-trial comparisons that are limited in terms of their ability to be objective, this looks like a very promising combination. Ultimately, the proof will be when these combinations are tested against other available combinations that have been US Food and Drug Administration (FDA)-approved, so that we can understand what the true role will be in the future of inhibiting HIF in combination with TKIs in this clear cell population of patients.

How might these results affect sequencing decisions for patients who progress on current first-line IO/VEGFR combinations?

Dr Figlin: The best way to share that with you is what do I do in my own clinic. If a person has been on an IO-IO in the frontline setting and then has progressive disease, they have clear cell metastatic renal cell carcinoma and are about to receive a TKI, I combine that TKI with HIF-2 inhibition with belzutifan.

If a person has been on a treatment regimen of IO-TKI, such as lenvatinib and pembrolizumab, which is a commonly used, level 1, evidence-based treatment, they're about to receive second-line therapy because of progressive diseas, and they're thinking about another TKI, I often combine that with a TKI and  belzutifan.

So, while the clinical pathways of the National Comprehensive Cancer Network (NCCN) and other organizational structures may take some time in waiting for the level 1 evidence with pivotal phase 3 trials, in the clinic, for the patients with clear cell carcinoma who have progressed on standard-of-care, high-level evidence-based treatments, I'd give strong consideration to the addition of the HIF-2 inhibition in that population of patients.

Grade 3 or higher treatment-related adverse events were reported in more than half the patients in both cohorts. How manageable were these events in clinical practice, and are there particular toxicities that warrant closer monitoring?

Dr Figlin: The big change with the addition of  belzutifan or HIF-2 inhibition when combining it with a VEGF receptor TKI, such as cabozantinib or lenvatinib, is that it doesn't seem to have synergistic toxicities, but it does have some unique toxicities. One of the things that we know about HIF-2 inhibition is that it turns off erythropoietin production, which means anemia could become an important part of the paradigm of toxicity management.

We certainly have patients who have become anemic. We certainly have patients that have required erythropoietin products to support their anemia. You can do that intermittently because they recover very quickly, as their bone marrow is quite functional. Anemia is something to be aware of.

In addition, sometimes the fatigue can be additional, so we need to be aware of that. One of the risk toxicities associated with  belzutifan and HIF-2 inhibition is the possibility for shunting, hypoxia, and shortness of breath. It's very infrequent, does not occur often, does not require oxygen, but something that our colleagues should be aware of.

Are there any other points you’d like our audience to take away from this study?

Dr Figlin: The key is to remember that HIF-2 inhibition is basically a paradigm for how VHL syndromes, such as ccRCC, act. It will become an increasing part of our portfolio of treatments. We have to await the pivotal phase 3 trials and address that with high-level evidence.

The toxicity profiles make it an acceptable combination, whether it's alone or in combination with immunotherapy or other TKIs. I encourage my colleagues, medical oncologists, when thinking about using a TKI in a patient with ccRCC, to consider the addition of  belzutifan or other HIF-2 inhibitors.