Selecting Second-Line Therapy After ICI Progression in Metastatic ccRCC

Metastatic clear cell renal cell carcinoma (ccRCC) remains a therapeutic challenge after progression on first-line immune checkpoint inhibitor (ICI)–based combinations, with treatment selection often guided by balancing efficacy, tolerability, patient preferences, and prior therapy exposure. As the number of available second-line options continues to grow, clinicians face important questions regarding optimal sequencing strategies and the role of immunotherapy rechallenge.

In a virtual Case-Based Roundtable event, Dillon Cockrell, MD, of Duke Cancer Institute, and Raji Shameem, MD, of Orlando Health Cancer Institute, moderated a discussion among oncologists from the South Atlantic and Southeast regions on treatment goals, regimen selection, immunotherapy rechallenge, and unmet needs in the second-line management of metastatic ccRCC following progression.

Register today to join a Case-Based Roundtable near you.

CASE SUMMARY

• A 61-year-old man with an active lifestyle (daily walks, golfs regularly)
• Medical history: low-volume, indolent metastatic ccRCC, status post‒left nephrectomy and adrenalectomy
  • Based on low-volume, indolent disease and patient preference – observation only
• 1.5 years post-nephrectomy CT-Scan showed new paratracheal lymph nodes (2.0 x 1.5 cm) and >10 pulmonary nodules on CT
• Lung biopsy confirms metastatic ccRCC
• ECOG performance status: 0
• The patient received first-line cabozantinib (Cabometyx) + nivolumab (Opdivo)
• Decrease or stabilization in metastatic lesions noted on follow up imaging
• Tolerated therapy well, with 1 interruption due to hypothyroidism on routine labs (treated with levothyroxine)
• 14 months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain
• Imaging confirms disease progression: growth of paratracheal lymph node (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions
• ECOG performance status: 1

EVENT RECAP

Before reviewing any trial data, most participants favored lenvatinib (Lenvima) plus everolimus (Afinitor) as their preferred second-line option, selected by 43.8% of the group. Other responses were more varied, with 25% choosing tivozanib (Fotivda), 18.8% opting for belzutifan (Welireg), and 12.5% favoring an ICI rechallenge. No participants selected cabozantinib (Cabometyx) or another single-agent tyrosine kinase inhibitor (TKI), highlighting the group's preference for newer agents and combination strategies in the post–ICI setting.

DISCUSSION QUESTIONS

• What are the goals of therapy going into the second line?
• What do you find most challenging about disease management in the second-line setting for patients who have received a prior ICI?
• What are the evidence/knowledge gaps and unmet needs? How do the following factors influence your second-line regimen selection? For example, tolerability, efficacy, prior therapy, performance status, patient preference, NCCN guidelines, mechanism of action?
• Have you ever tried continuing/rechallenging with an ICI in a patient who had received a prior ICI?

Raji Shameem, MD: These patients, I would say that they have aggressive biology by requiring second-line treatment, right? Longevity, how they can tolerate treatment, tolerability—I think that's a very important feature. Is there anything else you consider about goals of therapy—tolerability, efficacy, or maybe a combination of both?

Alaa Muslimani, MD: I think most of these patients were not curing, so quality of life and toxicity is very important. This patient is unusual to progress that fast—but most patients in my experience at least, they stay on the treatment for a long time, and you don't want to make their life miserable with the treatment.

Shameem: Sometimes the treatment is worse than the disease. Thank you, Dr Muslimani. I have to ask, what did you pick as your second-line option?

Muslimani: Lenvatinib plus everolimus.

Shameem: And how is the tolerability for that? Do you have to make some dose adjustments?

Muslimani: We usually start with a lower dose, and most of the time they tolerate it well. We have to monitor their blood pressure very closely. Some of them get high blood pressure, and…we have pathways in our system and protocols for visits, so as soon as we start them, it's triggered multiple visits with the pharmacist, and they monitor the blood pressure, and most of them tolerate it well with a lower dose, in my experience.

Shameem: I think a few of you chose ICI rechallenge.

Eiran Warner, MD: I chose it. I find it interesting; I really like, unless you need a very quick response, giving nivolumab and ipilimumab [Yervoy] in the front line, but there are definitely data out there that patients who have not been exposed to ipilimumab can get a response in the second-line setting.

Shameem: That's a very good point, and I think I should emphasize that too. A CTLA-4 inhibitor, that is a different mechanism than nivolumab. Dr Warner, have you ever given—for example, a patient got nivolumab and cabozantinib—do you ever continue the nivolumab as a second-line therapy with another TKI?

Warner: If they progressed? I haven’t done that.

Shameem: I think performance status kind of resonates with tolerability. If someone is frail at baseline, you don't want the treatment to hurt them more than the disease. Do any of your patients tell you what they want, or you tell them what you recommend? Some of my patients are savvy; they do their research,

Muslimani: Some of them come, and they want something that's on television.

Shameem: I could see that happening as well. And what about the type of response? Durability, we mentioned that; what about depth of response? What if you can get even more than 30% reduction, maybe 50% reduction? Is that something you care about?

Muslimani: That's important, I think, in the first line, because we are still, at least in our system, advising for debulking if they have great response. So. I think it's more important in the first line.

Shameem: Okay, that's a good point—different goals of care in the later-line setting. And how about NCCN guidelines? Do you refer to NCCN guidelines? Does that help dictate what you recommend for your patients, or it's just an addition? I'll tell you, I use NCCN for peer-to-peer [recommendations.] Whenever I have to do a peer-to-peer [recommendation], I use that as scripture.

Muslimani: We do use the NCCN. Again, we do have our own guidelines here. Of course, it's mainly from the NCCN, but it's less complicated, to put it this way. And most of these patients, we do present them in the tumor board, so if they have low-burden disease again after the first line, they all see urologists, for future debulking refractory.

Dillon Cockrell, MD: I was going to ask, Dr Muslimani, is that a pathway that you all use? It’s built into the electronic medical record?

Muslimani: Exactly. It's like the NCCN, and then you click whatever regimen you're using, you click on it, and it triggers another link, and then you enter the data and information there, you sign it, and it goes from there. Also…I'm a general oncologist, so we have in that pathway all the clinical trials, so it helps us to explore any clinical trial for the patient, because I cannot remember how many clinical trials we have in each disease. It's actually very helpful. It's like the NCCN guidelines with the only difference [being that] when you click on it, it triggers another pathway, and you enter [the data].

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Cockrell and Shameem have not previously disclosed any conflicts of interest.