Considering the Impact of Sequencing in Frontline RCC Therapy

The variation in frontline regimens to treat metastatic renal cell carcinoma (RCC) leads to an open-ended selection process for second-line therapy and beyond. In a virtual Case-Based Roundtable event for oncologists in Oklahoma and Texas, the reasons for selecting dual immunotherapy (IO) or IO plus tyrosine kinase inhibitor (TKI) regimens were discussed by moderator Nizar M. Tannir, MD, professor of genitourinary medical oncology, at The University of Texas MD Anderson Cancer Center in Houston, and the participants. There were differing opinions on whether leaving options for sequencing later lines should play a role in first-line therapy. As oncologists are now familiar with using various agents to treat RCC, individualizing care to patients based on their treatment goals and risk factors is feasible in this setting.

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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 immune checkpoint inhibitor? ​
• What factors affect your second-line regimen selection?

Nizar M. Tannir, MD: What do you give for first-line therapy, and what are the goals for the second line? I have given all 4 regimens that are FDA approved in the first line, nivolumab [Opdivo] plus ipilimumab [Yervoy] and the 3 IO/TKIs: pembrolizumab [Keytruda] plus axitinib [Inlyta], nivolumab plus cabozantinib [Cabozantinib], and then lenvatinib [Lenvima] plus pembrolizumab. Do you focus on the risk [status] the patient has, or do you treat everybody regardless of the risk?

Priya Ramshesh, MD: My biggest worry is that if I use cabozantinib upfront, I feel like I’m exhausting a very good second-line option. I try to use something which is not cabozantinib/nivolumab in the first line, and I have a partiality toward the IO/IO combination based on the CheckMate 214 [NCT02231749] data. That way I feel I still have the optionality to use TKIs in the second line. My preference is either to use IO/IO combination or to use pembrolizumab with lenvatinib or axitinib. That way I still have cabozantinib as the second line, and then I can go to my third-line options with either tivozanib [Fotivda] or belzutifan [Welireg]. That way I feel I have more sequencing options. When I think of what I’m doing as first line, I’m always thinking, what am I going to do as my second line? What am I going to do as my third line?

Tannir: That’s a good point you’re making, although I would say I want to give the best regimen upfront because the goal is to try to induce a complete response for the patient that’s durable if possible and give them a chance of durable remission for many years and potentially cure. But in addition to the goal of achieving a durable response and potentially cure, you’re thinking about how we’re going to sequence these other lines.

Ahn Nguyen, MD: Over the years, I’ve used the combinations of ipilimumab/nivolumab, pembrolizumab/axitinib, and nivolumab/cabozantinib…. I find that nivolumab/cabozantinib is more well tolerated compared with the others, but I don’t have a preference. It depends on comorbidities and adverse events [AEs]. I am one of those who believe in the first line, I don’t think about sequencing. If it has the best data, then I use it up front and then the second line is whatever is not used in the first line.

Tannir: So what you use in the second line is what you haven’t used. If you have decided that cabozantinib/nivolumab is the most tolerable regimen for first line, you use cabozantinib and if there is progression on that regimen, you’re thinking of subsequent therapies that do not contain an anti–PD-1 or cabozantinib.

Obiageli Ezewuiro, MD: In younger patients with aggressive disease, I prefer ipilimumab with nivolumab.

Tannir: I think many of the community oncologists as well as academic oncologists are now. With more data on CheckMate 214, we saw at ASCO durable responses at 9 years and patients with intermediate [or poor] risk alive and progression free at 9 years, at one-quarter of those patients.¹

Jeremy Ross, MD: Regardless of risk stratification, I’m treating almost all patients with [dual] IO in the first line with what I consider curative intent, and then when I move on to the second line, and I’m no longer hoping for that potential cure, then I’m focused on toxicity equally as much as progression-free survival. I use a lot of cabozantinib in the second line, and that guides where I would go from there based on how well it’s tolerated.

Tannir: I don’t know about your practices, but I know what’s published. Unfortunately, probably only 50% of patients go from first line to second line, and when you go from second line to third line, probably just 30% of patients get a third line. With the fourth line and fifth line, there will be fewer and fewer patients. MD Anderson Cancer Center is different, because patients who come to MD Anderson may be more motivated or selected to be in good shape. Obviously in your practices you may see older patients with many comorbidities and poor performance status, and they may barely get one line and maybe a second line. We have a skewed patient population, so for some patients we are able to give them 5 or 6 lines, and there are clinical trials.

When we are going onto second line and beyond, what are the goals of care and the roles of therapy? If the patient had toxicity with the pembrolizumab/axitinib regimen, does that influence what you do when you go to a second line? If the patient had a fantastic response to an IO/TKI regimen, does that give you confidence that you go into a second line that’s also a VEGFR TKI rather than going to the HIF2α inhibitor? Does bone metastasis influence you in choosing one agent over another?

The NCCN guidelines do not give you guidance in the sense of [recommending] you choose [any particular] agent. When we talk about second line and beyond, we have several agents…. Two trials…did not show any benefit of continuing an anti–PD-1 or using an anti–PD-L1 after progression on prior IO-based therapies.^2,3 There is increased toxicity and lack of efficacy. Now there is no rationale to continue an IO/TKI strategy.

Kathryn Arrambide, MD: I find it a struggle to think about first-line therapy and metastatic disease as potentially curative intent. Even though you can get long remissions, reaching for that is tough. My population is old and frail, and I’m in a rural area where our emergency department support is [poor]. It’s hard to commit people to dual IO as much as I want to do it. I often have to reach for something that’s an IO/TKI, and cabozantinib/nivolumab has been my choice. I look at tolerability, risk factors, frailty and performance status, comorbidities, burden, and sites of disease. Bone disease is a bad prognosis, and I know there are some data that suggests that some therapies are better than others in bone, but that doesn’t really drive me. It drives me in the conversations I have with people. Those conversations are going to be very straightforward about what people are looking at.

The problem with dual IO, at least in my population, is that it is the devil you don’t know, because you can’t tell people they’re going to have this or they’re going to have that. You’re going to have to give them the laundry list of all the [AEs] that can happen, recognizing that some of it is going to happen. It’s probably more doable in an urban area where you have good supportive care and a better patient population in terms of performance status and age than I have. But, in the end, it comes down to what’s the best possible therapy that patients can do?

Tannir: I agree with you. You have to look at what’s available in your community, the support you can get. We’re privileged here in Houston, at MD Anderson where I have all the specialists. If a patient developed an immune-mediated toxicity with myocarditis or myasthenia gravis, hepatitis, pneumonitis, etc, I have all the support.

Arrambide: My next available liver appointment is 3 months off. My next available pulmonary appointment is 3 months off. Even if you make a phone call, you’re not getting people in quickly, so it’s [send] them to the city or they can’t do it.

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DISCLOSURES: Tannir previously reported research funding from Bristol-Myers Squibb Company (BMS), Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Arrowhead Pharmaceuticals, Mirati Therapeutics, Takeda, Epizyme, and Eisai Medical Research; consulting, advisory, travel accommodations, and expenses from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical, and Oncorena; and honoraria from BMS, Exelixis, Nektar Therapeutics, Calithera Biosciences, Eisai Medical Research, ONO Pharmaceutical, Eli Lilly, Oncorena, Ipsen, and Surface Oncology.

REFERENCES:

1. Choueiri TK, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: Final analysis from the phase 3 CheckMate 214 trial. J Clin Oncol. 2025;43(suppl 16):4505. doi:10.1200/JCO.2025.43.16_suppl.4505

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

3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4