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Precision Pathways in RCC
Precision Pathways in RCC: Experts Discuss Key HCP Questions

Released: July 15, 2026

Bradley A. McGregor
Bradley A. McGregor, MD
Brian I. Rini
Brian I. Rini, MD, FASCO
Karine Tawagi
Karine Tawagi, MD
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Key Takeaways
  • Belzutifan monotherapy is being used in the second-line setting after frontline immunotherapy or in the third-line setting, and patients report it is highly tolerable while preserving quality of life.
  • Other agents used in patients with previously treated, advanced RCC, like axitinib, cabozantinib, nivolumab, and tivozanib, achieve ORRs of approximately 20% and mOS of approximately 2 years.
  • Clinical trials are tracking patient biomarkers correlating with target engagement to develop validated biomarkers for HIF-2-α inhibition, which may yield results in the next 1-3 years, since diagnostic/prognostic biomarkers ctDNA and KIM-1 lack validation of analytical sensitivity.

Introduction
During a live presentation, “Precision Pathways in RCC: Translating Immunotherapy and Targeted Therapy Advances Into Personalized Patient Care,” expert faculty discussed data from clinical studies evaluating frontline, adjuvant, and neoadjuvant therapy for various subtypes of renal cell carcinoma (RCC). In this commentary, Bradley A. McGregor, MD; Brian Rini, MD, FASCO; and Karine Tawagi, MD, provide their answers to questions posed during the live event. You can find the related educational activities here. 

How are you currently integrating belzutifan into your refractory treatment sequences, and if the combination of lenvatinib plus belzutifan secures regulatory approval, will you prescribe the combination to all second-line patients or maintain a role for belzutifan as monotherapy?

Bradley A. McGregor, MD:
We have extensive experience using HIF-2-α inhibitors in clinical trials, and when patients respond, they maintain an excellent quality of life. I prescribe belzutifan monotherapy in the second-line or third-line setting for patients presenting with low-volume, indolent visceral disease who lack severe underlying pulmonary comorbidities, as their physiologic reserve allows them to tolerate potential disease progression. For a patient presenting with rapidly progressive, high-volume symptomatic disease where an immediate objective response is mandatory, I prescribe a fast-acting TKI combination off label to avoid the primary progression associated with belzutifan monotherapy.

Brian Rini, MD, FASCO:
If the combination of lenvatinib and belzutifan is approved, would you preferentially reserve the combination for high-volume disease and maintain a role for monotherapy?

Bradley A. McGregor, MD:
Yes, because patients who maintain a long-term response on belzutifan monotherapy report that it is a highly tolerable regimen, and I want to preserve that quality-of-life benefit.

Karine Tawagi, MD:
I agree. I would restrict the lenvatinib and belzutifan combination to select high-volume visceral presentations. For the majority of patients receiving third-line therapy who have already experienced the cumulative toxicity of long-term frontline TKI therapy, protecting their daily quality of life with a highly tolerable monotherapy is paramount.

Brian Rini, MD, FASCO:
What if the combination demonstrates a clear overall survival benefit over monotherapy?

Karine Tawagi, MD:
An overall survival benefit would be highly compelling.

Bradley A. McGregor, MD:
If an overall survival benefit emerges, we must analyze how many patients in the cabozantinib control arm successfully crossed over to receive subsequent belzutifan. A survival difference might simply reflect the absolute necessity of receiving an HIF-2-α inhibitor at some sequential point in their care rather than a true requirement for early combination therapy.

Brian Rini, MD, FASCO:
That crossover data has not been fully presented yet. Dr. Tawagi, where do you typically insert belzutifan monotherapy in your sequence?

Karine Tawagi, MD:
I use it in the second-line setting after frontline immunotherapy, or in the third-line setting if the patient received frontline ipilimumab/nivolumab. Dr. Rini, if the lenvatinib plus belzutifan combination is approved for second-line use, how would you sequence therapy for a patient who progressed on frontline lenvatinib plus pembrolizumab regimen? Would that frontline TKI exposure alter your second-line selection?

Brian Rini, MD, FASCO:
I do not select my frontline therapeutic regimen based on what I might prescribe sequentially in the future because a patient might remain on frontline therapy for 3 months or 3 years; I select the most effective option for their current presentation. If a patient progresses on frontline lenvatinib plus pembrolizumab, I would not prescribe a lenvatinib-based combination in the second line. I would prescribe belzutifan monotherapy or an alternative TKI like cabozantinib, which highlights why preserving a monotherapy indication is important.

On June 12, 2026, the FDA approved belzutifan in combination with pembrolizumab for the adjuvant treatment of adults with clear cell RCC at intermediate to high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Other than belzutifan and lenvatinib, are there other agents that can be used for patients with advanced RCC undergoing refractory treatment?

Brian Rini, MD, FASCO:
There are several therapeutic options useful in refractory kidney cancer: axitinib, cabozantinib, nivolumab, and tivozanib. If you look at objective response rate, these numbers are comparatively consistent in the 20% range, with axitinib (19%), cabozantinib (17%), nivolumab (22%), and tivozanib (18%), although lenvatinib plus everolimus at 35% stands out. However, the latter was only a randomized phase II trial, whereas the other ORRs were measured in phase III trials. Median overall survivals measured from all of these options are also in the range of 2 years.

Are you integrating circulating tumor DNA testing into your daily practice or do you plan to do so moving forward?

Brian Rini, MD, FASCO:
I am not using it to make real-world clinical decisions. Current commercial assays lack the analytical sensitivity required for reliable kidney cancer tracking. We will get there in the next 2-3 years as tumor-informed next-generation assays mature, but current data should not be used to guide therapy.

Bradley A. McGregor, MD:
I agree. Few high-risk patients test positive for circulating tumor DNA post nephrectomy. Whereas a positive result carries poor prognostic weight, many patients who test negative repeatedly still experience a systemic relapse, so the current negative predictive value is insufficient to withhold adjuvant therapy.

Why are we not using circulating KIM-1 as a population screening tool for early RCC detection?

Bradley A. McGregor, MD:
KIM-1 is markedly elevated in kidney cancer and not expressed by healthy kidney cells. It is expressed in the setting of renal injury, but it is markedly higher in the setting of metastatic renal cell, but specifically clear cell and papillary. Looking at 180 patients from the EPIC study with RCC, KIM-1 was elevated in banked plasma up to 5 years prior to diagnosis vs matched controls. The KIM-1 data are evolving and highly intriguing, but transitioning an exploratory biomarker into a validated screening tool requires establishing strict commercial assay cutoffs, sensitivity parameters, and regulatory validation. Although it appears to be elevated in plasma years prior to diagnosis, the exact thresholds vary across clinical trial assays, so more research is required before it is ready for real-world screening.

Are there promising or clinically actionable biomarkers currently available to predict therapeutic response in RCC?

Brian Rini, MD, FASCO:
Developing clinically actionable biomarkers in kidney cancer has been a historic struggle. Investigators evaluating casdatifan are doing an exceptional job of tracking a drop in serum erythropoietin as a direct biomarker of target engagement, so we may have validated biomarkers for HIF-2-α inhibition in the next 1-3 years. However, we lack clinically actionable biomarkers for standard TKIs or immunotherapies in daily practice.

Bradley A. McGregor, MD:
To expand on that, although we lack a positive predictive biomarker, we also lack a negative biomarker to exclude patients from HIF-2-α therapy. If a patient’s next-generation sequencing panel reveals wild-type VHL without a formal mutation, that does not mean they will fail to respond to belzutifan or casdatifan. These agents are approved for clear cell RCC independent of somatic VHL mutation status, so therapy should not be withheld based on a next-generation sequencing profile.

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