Navigating Second-Line RCC Treatment With Guidelines and Trial Data

Chandler H. Park, MD

Second-line treatment for clear cell renal cell carcinoma (RCC) remains challenging due to a lack of a preferred regimen and variable patient responses. During the virtual Case-Based Roundtable event, oncologists from the Southeastern United States reviewed the updated NCCN guidelines, noting the lack of category 1 recommendations and the heterogeneity of regimens patients previously received, which complicates decision-making. Led by Chandler H. Park, MD, a medical oncologist at Norton Cancer Institute and advisory dean/professor at University of Louisville in Kentucky, they also analyzed phase 3 data of tivozanib (Fotivda) monotherapy.

DISCUSSION QUESTION

• What do you think of the NCCN guideline recommendations on subsequent treatment in clear cell RCC?¹

Chandler H. Park, MD: When you see the updated NCCN guidelines for kidney cancer from March 2025, what are your thoughts?

Emmanuel A. Nidhiry, MD: Thankfully, we have a few options available. But it seems even though we have multiple options, the benefit is not as good as we get in the first line, and there is a need for newer agents or combinations that would make a difference in this setting. We talk about different options, but we know that benefit is somewhat limited compared to first-line treatment, so that is a concern.

Park: If you look at the NCCN guidelines for lung cancer, there are so many different arrows going in multiple directions. It could be confusing, even if you know oncology. When you look at the NCCN [guidelines for subsequent therapies], can you walk us through what jumps out? There's no category 1 regimen, so how would you go through the available regimens if you had a fellow in your practice?

Sajjad A. Bhatti, MD: We have many redundant first-line studies where we know that immunotherapy [IO]/IO is effective and IO/VEGF tyrosine kinase inhibition [TKI] is effective. But when you start looking at the second line, you end up getting a very heterogeneous group of patients, and you wouldn't necessarily know what the right second-line treatment is. I think that's what we are seeing in the guidelines, where you get a slew of different options that you can try. Honestly, I like to try a different mode of action, and that's why I [would try] belzutifan [Welireg].

The guidelines are basically showing us that we don't necessarily know what the best second-line treatment for a particular patient is, and we just have to go with our best guess for that circumstance. It's very good to have multiple first-line options, but I think it also makes that second-line decision much harder for us.

Park: Absolutely. It looks like they removed interleukin-2 in the guidelines, so they got rid of some [regimens].

DISCUSSION QUESTION

• What is your reaction to the efficacy data from the phase 3 TiNivo-2 study (NCT04987203)?²

Park: On the one hand, it allowed us to know that with continuation of immunotherapy, there may not be [positive] data there, and we give patients [more] toxicity. But on the other hand, we noticed this signal as a phase 3 study about the monotherapy TKI with tivozanib at the higher dose. What is your reaction to the efficacy data here?

Nidhiry: The efficacy data basically confirm the lack of benefit in continuing the immunotherapy in subsequent lines of treatment, as shown by multiple studies. My approach would be to go with single-agent tivozanib in this setting and use the maximum tolerated dose and get a benefit from that regimen.

Park: Absolutely. One of the things about the study is we know that rechallenging immunotherapy [may not be the best option], but what did you think about the monotherapy arm with the tivozanib at the effective dose and the 9.2 months median progression-free survival for second line immediately following immune checkpoint inhibitor? What are your thoughts on that?

Chris G. Theodossiou, MD: It could have been patient selection with selection bias. The other thing is, we have to make the distinction between statistically significant and clinically meaningful, because we're looking at differences of less than 2 months. Is it clinically meaningful?

Park: Outstanding points. Dr Vaena, you do a lot of research…is it clinically meaningful; is it practice changing; is it practice confirming? There are very provocative data here for tivozanib with 9.2 months. How do you sort these data out in your practice?

Daniel A. Vaena, MD: To me, it's a drug that has significant activity. I think the truth is that I have lots of third- and fourth-line patients with good performance status who get tivozanib in the third- and fourth-line space with significant activity. Many of my patients [benefit for] 9 months to a year even in the third- and fourth-line setting. So I think there's a lot of selection bias in terms of performance status as well that goes into this. But to me, the TiNivo-2 data solidified that tivozanib has a lot of activity.

DISCLOSURES: Park previously reported a consulting or advisory role with Bristol Myers Squibb/Celgene, Exelixis, Eisai, Gilead Sciences, Seagen, and Merck, and speakers' bureau role with Eisai, Seagen, Gilead Sciences, Pfizer, AstraZeneca, and Merck.

Vaena previously reported receiving honoraria from HMP, OneOncology, OncLive, and Total Health Conferencing, and a consulting or advisory role for Seagen, Bayer, Bristol Myers Squibb, EMD Serono, Sanofi, Cardinal Health, Gilead Sciences, Eisai, MJH Life Sciences, Curio/Vaniam Group, DAVA Pharmaceuticals, IntrinsiQ, Janssen, and Exelixis.

There were no other known disclosures.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 3.2025. Accessed June 16, 2025. https://tinyurl.com/yc2my5ya

2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6