Refractory RCC: Third-Line Treatment Considerations

A roundtable discussion, moderated by Katy Beckermann, MD, PhD, discussed the treatment sequencing, management, and future directions of advanced or metastatic kidney cancer, as well as relevant clinical trial data from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Beckermann was joined by Yousef Zakharia, MD; Pavlos Msaouel, MD, PhD; Benjamin Maughan, MD, PharmD; and David McDermott, MD.

In the final segment of the roundtable series, the panel concludes with the clinical applications, challenges, and future prospects of belzutifan in treating advanced kidney cancer, emphasizing personalized treatment strategies and the need for biomarker-driven approaches.

View previous segments from this roundtable series.

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Dr. Beckerman: We have not discussed the refractory space yet, so let us do that briefly. We are all aware of the new therapy targeting HIF with belzutifan, which was presented at the 2023 ESMO meeting. We have seen subsequent updates, including quality of life data. How are you all using this in practice now? The trial primarily included patients in the third- and fourth-line settings. It is currently approved as a single agent but being tested in combinations. Dr. McDermott, considering the approval, how are you using it, knowing the ORR is about 20% in the third- and fourth-line setting and the median PFS is 5.6 months? Some patients benefit significantly, but many do not…

Dr. McDermott: I try to use belzutifan as early as possible, based on the inference that it works better earlier, especially as a single agent. We have seen this in the VHL patient population. The trial selected a setting where it was least likely to succeed, as patients had to fail two VEGFs to participate. I try to give it as soon as possible after one VEGF. Ideally, I would use it right after IO if insurance would cover it, but they often push back due to the cost. The earlier, the better.

We should work to define the population that benefits early. We can probably do a better job than with VEGF or PD-1, since those drugs target the microenvironment, while this targets the tumor. A genetic profile should predict who will benefit, and if we can identify that, we could use it more effectively as a single agent. Patients often feel better once they switch from VEGF to HIF inhibition and can remain on it for a long time with stable side effects, which is different from TKIs.

Dr. Beckerman: Do you think we might identify a biomarker or DNA signature? There was data on IMDC risk groups, and many of us thought good risk patients would benefit most since it is a tumor factor, but that did not necessarily follow.

Dr. McDermott: Yes, and without debating the predictive value of IMDC criteria, we need to move away from clinical criteria and focus on tumor-based markers, like in lung cancer. Prospective trials with samples from metastatic disease, not primary tumors, are necessary because we treat metastatic disease. Lung cancer research often uses tissue samples after subsequent treatments to define next steps. If they can do it, we can too. This could potentially double the response rate in a selected population, making a major difference and justifying prospective randomized trials to use it sooner. Currently, we are adding it to other treatments, which might give incremental improvement, but there is no evidence it enhances the immune response. We need more rational approaches.

Dr. Zakharia: I totally agree. Our lung cancer colleagues are ahead of us in kidney cancer research. The only personalized kidney cancer treatment is belzutifan for VHL mutation. The data shows that careful patient selection can make a single drug effective, without needing multiple drug combinations. We need more personalized approaches in kidney cancer, similar to thoracic oncology.