Looking Ahead in RCC: Belzutifan, Triplets, Treatment Combinations, and More

A roundtable discussion, moderated by Rana McKay, MD, discussed the latest updates in frontline treatment for renal cell carcinoma, including how data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024 alters the treatment paradigm. Dr. McKay was joined by Nizar Tannir, MD; Hans Hammers, MD; and Katy Beckermann, MD.

In the final segment of the roundtable series, the panel forecasted some of the major questions that will likely be answered in the coming years regarding belzutifan, triplet combinations, and more.

Watch previous segments in this series.

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Dr. McKay: Are there any other highlights from today’s meeting on kidney cancer that you all would like to share?

Dr. Hammers: Well, one significant topic we have not touched upon yet, which is quite the elephant in the room, is the FDA approval of belzutifan since December of last year. It is a HIF2 inhibitor. I woul love to hear your thoughts on belzutifan, perhaps as a closing discussion.

Dr. McKay: Indeed, I believe it is a promising agent. It is different, still targeting angiogenesis, but specifically aiming at the HIF pathway. Interestingly, when you examine the raw data, the numbers do not appear substantially better compared to everolimus. The control arm sets a low bar here with a PFS of around 5.5 and a hazard ratio of 0.73. However, there is a notable tail on the curve, indicating significant PFS. Patients report feeling better, and the quality of life data presented today suggests minimal decrement in their quality of life. I suspect belzutifan’s place lies much earlier in the disease course when VHL solely drives the disease, rather than other resistant mechanisms. Nonetheless, it’s a win for our patients to have another treatment option. There is an unmet need in the refractory setting, but it is exciting to anticipate where this agent might fit in. I believe its place is earlier on in the treatment paradigm.

Dr. Tannir: There are trials exploring belzutifan in the adjuvant setting, including belzutifan plus pembrolizumab versus placebo plus belzutifan. Additionally, in the first-line metastatic setting, there is a triplet of belzutifan, lenvatinib, and pembrolizumab. However, I am uncertain if adding belzutifan will significantly impact the primary endpoint of PFS, given the high bar already set by pembrolizumab/lenvatinib. As for overall survival, considering patients often progress to second and third-line therapies, it remains uncertain if either triplet will demonstrate an OS benefit compared to pembrolizumab/lenvatinib. Nevertheless, I am pleased with belzutifan’s approval, despite its median PFS being identical to everolimus. The hazard ratio and landmark analyses at 12 and 18 months show a notable advantage for belzutifan. Moreover, its low toxicity rate, except for anemia, makes it an appealing option.

Dr. Hammers: Indeed, there was a poster demonstrating that administering erythropoietin doesn’t worsen outcomes, which is important to note. I believe belzutifan is a welcome addition to our treatment arsenal. Patients often experience considerable side effects from TKIs, such as hypertension, proteinuria, and diarrhea. Switching to a more tolerable option like belzutifan could greatly improve their quality of life.

Dr. Beckermann: I am curious about its future placement, particularly given its unique characteristics in the refractory space. While it may not offer quick responses, its tolerability is remarkable. Ideally, it should be used earlier in the treatment continuum. However, if it is combined with a TKI, I hope there is consideration for de-escalation, possibly discontinuing the TKI after a certain point to maintain quality of life.

Dr. Hammers: I completely agree. Belzutifan’s activity appears restricted to a subset of patients, but for those individuals, it provides significant benefit. Some of my patients have been on it for years with complete responses and minimal side effects, which is quite unusual. Using it earlier in the disease course, perhaps even as a palliative agent, seems ideal. Additionally, exploring biomarkers for patient selection and combining it with other agents in earlier stages holds promise.

Dr. McKay: Especially in VEGF-naive patients.

Dr. Hammers: Exactly. They should nothave to endure TKI therapy before trying belzutifan.

Dr. Tannir: Not all HIF2 inhibitors may be as effective as belzutifan, so we must await further data from ongoing trials to determine their efficacy. It is essential for patients to inquire about clinical trials to explore potentially beneficial combinations.

Dr. Hammers: Absolutely. Belzutifan is not a stagnant option. Patients should inquire about ongoing trials investigating combinations that may enhance its efficacy.

Dr. Tannir: Regarding anemia associated with belzutifan, it is crucial to conduct thorough evaluations to determine its cause. Many patients may have deficiencies in iron or vitamins, which should be addressed appropriately before considering erythropoietin-stimulating agents.

Dr. Hammers: In my experience, some patients require only 1 dose of erythropoietin to address anemia, and belzutifan’s slow but steady response is noteworthy. It may take time to achieve significant tumor shrinkage, but the agent effectively halts disease progression.

Dr. McKay: It certainly exhibits different kinetics compared to what we are accustomed to seeing.

This discussion leads me to emphasize the importance of clinical trials in advancing our understanding and treatment of kidney cancer. The data presented at GU ASCO indicate substantial progress that will undoubtedly influence our standard of care. We appreciate everyone’s contributions to today’s discussion. Thank you, and take care from San Francisco.