The Role of RCC Second-Line Therapy in Frontline Decision-Making: Does the Approach Matter?

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a roundtable of expert panelists convened to discuss the latest research and practice updates related to advanced kidney cancer. Dr. Karine Tawagi of University of Illinois was joined by Drs. Regina Barragan-Carrillo, Benjamin Maughan, Laurence Albiges, and David McDermott in the discussion.

In the third part of the roundtable, the panel emphasizes a patient-centered approach to frontline therapy, balancing the potential for long-term treatment-free survival with nivo/ipi against the need for rapid disease control with IO-TKI combinations, while highlighting the evolving role of immunotherapy in favorable-risk patients and the importance of toxicity management in regimen selection.

View the next segment on From Infusion to Injection: The Promise of Subcutaneous Nivolumab.

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Dr. Tawagi: I think it is really exciting that we are hearing new data, possibly for the frontline setting for metastatic clear cell RCC.

This brings us to updates from regimens that we have been using for years, including the updates from CheckMate 9ER, which we will hear about, and CheckMate 214. I would love to hear what your approach is for a new diagnosis of clear cell metastatic RCC.

Dr. Barragan-Carrillo: There has been an ongoing debate about whether IMDC should guide the selection of first-line treatment. Personally, I tend to focus on how the patient is presenting, whether they have symptoms, or whether I need to look for a rapid response. To be completely honest, if I had to pick one regimen, I personally tend to use the NIVO-IPI combination more often because I like having cabozantinib available as a backup once disease progression occurs. However, I do not have data suggesting that you should avoid NIVO-CABO or LEN-PEMBRO, or any combination you prefer. It is more of a personal preference. One thing we learned last year from Dr. Tannir’s update on the NIVO-IPI data is that, even though the initial trial was not designed to assess the signal in the favorable-risk population, in the long term, we are seeing the curves separate with this regimen. I believe it is also appropriate for favorable-risk patients.

Dr. Tawagi: What does the rest of the group think about IO-IO for favorable-risk patients?

Dr. Maughan: Someone asked me earlier about my approach to favorable-risk patients, and the most succinct answer I could give is “haphazard,” because I find this population particularly challenging to treat when I am trying to find the optimal therapy for each specific patient. The population is so heterogeneous. We have patients who do well with surveillance, while others could benefit from a cure. Even though they have favorable-risk disease, some are still relatively young, and their cancer grows at a faster pace than would be predicted based on the IMDC score. It is a really tricky population to treat, and identifying the optimal therapy is challenging. Since this group of patients does so well for so long, regardless of what you treat them with, I am concerned about long-term toxicities, especially with IPI-NIVO.

I am always tempted by the possibility of curing people with IPI-NIVO, but I have also seen patients who are now on dialysis or who have developed type 1 diabetes. If your patient population is likely to live a really long time, it becomes difficult to decide how to treat them. So many factors come into play that I cannot honestly say I have a clear approach to treating this complex patient population. However, the data Dr. Tannir presented, with long follow-up in the favorable-risk population, has shifted my thinking a bit. Now, I consider and entertain IPI-NIVO along with other options for this group as well. It is still a particularly challenging population for me. What about the rest of you?

Dr. McDermott: It is not as much of a challenge for me. I have a discussion with patients. I agree that when you add CTLA-4, you double the risk of severe toxicity compared to just using PD-1. However, if the patient’s goal is remission or potentially a cure, and they are willing to accept the risks, then we have been treating people with NIVO-IPI for years. We have never strictly followed the guidelines, and we were not forced to follow them. Now, as Regina mentioned, the guidelines have expanded, allowing the use of NIVO-IPI in this setting. Of course, there are trade-offs, but to me, it is not just about long-term benefits; it is about the chance of being off-drug for the long term, which is what patients want most.

The concept of treatment-free survival is meaningful. It would be interesting to conduct a treatment-free survival analysis in the context of the COSMIC-313 trial, as I am pretty sure it would show something valuable, but we would need to be able to do the analysis. The main point is that it is not only about long-term benefits, but also about long-term benefits off-drug. You have to educate your patients, and they must understand what they are signing up for.

Dr. Maughan: I definitely agree with that, particularly in this patient population. What makes it somewhat challenging for me is that I can often achieve a treatment-free interval by using intermittent TKI therapy for some of them. So, there are many potential right answers for this patient population. I think the best approach is, as you described, to have a good discussion with the patient about what they want to accomplish and what they are willing to accept.

Dr. Tawagi: Absolutely. When it comes to deciding on frontline IO-TKI, does anyone have a preference? Does the second-line choice influence your decision for frontline treatment?

Dr. Maughan: For me, no. Fortunately, kidney cancer is becoming more complex as we get better treatments. However, the principle I usually follow is to decide on the best treatment for today because studies have consistently shown that the greatest impact on a patient’s cancer experience comes from the first treatment. The second treatment has a significant impact, but typically less so than the first. So, I usually do not base the first-line treatment decision on optimizing second- and third-line options. Instead, I focus on what is best for this line of therapy for the patient.

Dr. Tawagi: Along those lines, do you have a preference for IO-TKI combinations? Do you stick to what you are used to, managing dose reductions and toxicities?

Dr. Maughan: Yes, I do, and for full disclosure, I often use IPI-NIVO as my first-line therapy. This allows me to use whatever TKI I want for the second-line therapy and beyond. However, for patients with very symptomatic or particularly aggressive disease, I tend to prioritize a TKI-IO combination. Based on my experience in treating patients with these therapies, and the data from trials like CLEAR and CheckMate 9ER, they seem to perform well in terms of achieving good short-term disease control, which is my primary concern at the moment. I need to address hypoxia or progressing liver injury, for example.

For me, incorporating a TKI works well when needed. When I speak with community oncologists who do not see many kidney cancer cases, I often recommend that they familiarize themselves with one of these combinations and use it. I believe that will be much more successful than trying to select different combinations for different patients.

Dr. Tawagi: That is very true. Does anyone else have input?

Dr. Barragan-Carrillo: I personally tend to favor nivolumab with cabozantinib, primarily because of the 40 mg dosing we use. I think it improves quality of life, and the data from CheckMate 9ER show that patients actually experience better quality of life with this combination. That is why I tend to favor it, but of course, it is a personal preference. I would not be opposed to someone starting with LEN-PEMBRO or AXI-PEMBRO.