Second-Line RCC Therapy Depends on Mechanism of Action and Toxicity

In metastatic renal cell carcinoma (RCC), second-line therapy focuses on extending survival while preserving quality of life after progression on first-line therapies. Chandler H. Park, MD, a medical oncologist at Norton Cancer Institute and advisory dean/professor at University of Louisville in Kentucky, and participants at a virtual Case-Based Roundtable event explored challenges in managing metastatic RCC after first-line immune checkpoint inhibition. The group emphasized balancing survival benefits with toxicity and selecting therapies with distinct mechanisms of action instead of rechallenging patients with similar therapies.

DISCUSSION QUESTIONS

• What are the goals of therapy going into the second line for metastatic RCC?
• What do you find most challenging about disease management in the second-line setting for patients who have received a prior immune checkpoint inhibition?
• What are the evidence/knowledge gaps and unmet needs? How do the following factors influence your second-line regimen selection?

Chandler H. Park, MD: Once the patient goes through first-line therapy, we start [thinking about] the goals of therapy going into second line. In your practice, what are your goals for second-line therapy for metastatic RCC?

Emmanuel A. Nidhiry, MD: Trying to maximize the survival and keep their quality of life as much as possible. The idea is to build upon whatever benefit they got from the first-line treatment and keep them going. Generally, they respond well to first-line treatment and have a meaningful time where they are able to go on with their life and hopefully build upon that time period.

Park: Absolutely, that quality of life starts to become even more important. Dr Vaena, I know you do a lot of clinical studies in RCC and genitourinary disease. What do you find most challenging about patient cases that progress in terms of disease management for a second-line setting?

Daniel A. Vaena, MD: I think it's the issue about the tolerability. I take into account how well they tolerated the prior VEGF TKI [tyrosine kinase inhibitor] and what their goals are. But I agree that the goals are the same as was discussed, but quality of life is increasingly the question. If a patient has a ECOG performance status of 2, I would favor tivozanib [Fotivda] rather than lenvatinib [Lenvima] because of performance status. On the other hand, if a patient had very poor tolerance of cabozantinib [Cabometyx] before, meaning severe hypertension, lots of dose reductions, mucositis, then I would gravitate towards belzutifan [Welireg]. I can clearly see the tolerability playing a bigger and bigger role in in my practice.

Rajasree Pia Chowdry, MD: The one that jumps out to me most is mechanism of action. One of the biggest challenges in sequencing RCC treatment is now that [combination] therapy is approved as first line, what do you do thereafter? We give [everything] up front, and that is true for multiple different cancers, including prostate. but once someone fails both immune checkpoint inhibitor and TKI, how do you justify going moving on to a drug with a similar mechanism of action, which is so hard in kidney cancer as opposed to other solid tumors where you have different cytotoxic chemotherapy drugs that work in different ways. So that's why my choice for a clear cell patient would be belzutifan, because it would offer a different mechanism of action.

Park: Dr Myint, you're one of the leaders for RCC in Kentucky, and you get a lot of second opinions. Is there any guidance that you provide on things that influence your second-line regimen?

Zin W. Myint, MD: The mechanism of action and also prior tolerability, because a lot of the second line [therapies] are TKIs, so they have similar adverse events.... My preferred second line is tivozanib or belzutifan. But with single-agent belzutifan, the response takes time. It's a little slow because of its mechanism of action. I feel like you need to have a quick response. Combining another TKI with belzutifan [is preferred], if they can tolerate it. However, it's still in early phase trials. Lenvatinib/everolimus is also great, but the adverse events are pretty toxic, so I feel like a lot of patients are not doing well on the combination. So single-agent TKI or belzutifan is great for the second line.

Park: I agree with everything you said. Sometimes we get [swayed] into giving immunotherapy because when you look at the immune checkpoint inhibitor studies, especially with the nivolumab [Opdivo]/ipilimumab [Yervoy], when they have the tail at the end of the Kaplan-Meier curve, and that durable response, I think most people are guilty of this. Have you ever, before the [negative rechallenge] studies came out, rechallenged with immunotherapy? Or maybe if the patient received adjuvant immunotherapy in a metastatic setting, and you rechallenged with immunotherapy?

Mark Vellek, MD: Certainly, if they've had adjuvant therapy, giving them immunotherapy if it's been more than 6 to 12 months, you can get a good response. I haven't personally done it, but I've unfortunately, been on the receiving end of patients who've been rechallenged, so they've had nivolumab, and added ipilimumab on top, and I have not been impressed. I've been impressed by the amount of toxicity and the lack of benefit.

Park: This is very controversial, because we don't have prospective studies here. We hear anecdotal stories like yourself, Dr Vellek, and patients say that they respond, and other oncologists say they respond. Then the question is, where do you draw that line? Let's say, for instance, if a patient received adjuvant pembrolizumab [Keytruda] for 3 months, but then they experience progression, some people say maybe they have microscopic disease while they receive immunotherapy, and now it's showing up. Other people say at the other end of the extreme, based on the melanoma studies, that if patients receive immune checkpoint inhibitor up to 2 years—so they say after 1 year, when they finish treatment, an additional 12 months, that they would consider a CTLA-4 [inhibitor], but we don't have any kind of prospective studies on that. What are your thoughts about this? I know this is a tricky situation. It's going to be hard to do a clinical study in this arena.

Kevin M. Gallagher, MD: It's nice to have these other options available. Before, I think I was more concerned about recycling immunotherapy, but now that we have these others, I don't know what the best sequence will be. With some of the toxicities with belzutifan [including] anemia and hypoxia, it's been difficult, and so tivozanib is my answer for certain cases [of metastatic RCC]. I've had better tolerability, and it seems to carry the patient a little further too.

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.