Long-Term Data Prompt Shifting Approaches to Frontline RCC Therapy

Chandler Park, MD

Medical Oncologist

Norton Cancer Institute

Advisory Dean/Clinical Professor

University of Louisville Medical School

Louisville, KY

DISCUSSION QUESTION

• What drives your selection of first-line therapy for favorable-risk, metastatic clear cell renal cell carcinoma (RCC)?

Chandler Park, MD: There are lot of different camps in terms of what you hold important in your practice. We all say overall survival [OS], but if you look at the OS, the trial outcomes don’t show [significant benefit vs sunitinib in favorable-risk patients]. So what do you consider in your practice?

Anand Patel, MD: I like the treatment that allows me to get the highest chance of a complete response [CR], because these patients are looking at a palliative diagnosis, but [in roughly] 10%, depending on which trial you‘re looking at, [combination therapy] can afford them a CR and an opportunity to get off treatment.

Park: Yes, great point. What about progression-free survival [PFS]? And in terms of OS…do you look at how mature the data is, for example 99 months vs 50 months? What do you do when you look at new studies coming out for any cancer?

Isoken Koko, MD: Yes, I do look at the duration. Fifty months is good enough to me, but if the study has been on for only 12 months, that makes a big difference. I look at that, but I tend to look at overall response rate and PFS as well.

Park: What about performance status? In some of these patients who have liver, lung, or bone metastases, it‘s the cancer that‘s causing the performance status to be [poor]. You can have patients who get better with the treatment. Has anybody [with patients] on first-line therapy with high-volume disease said, “I‘m not going to give treatment because they have ECOG performance status of 3?”

Melhem Jabbour, MD: No. You have to fight. If it‘s a young patient in their 60s, for example, it doesn‘t matter what their performance status is…. I had a patient who had brain metastases, and I know he‘s going to die in the end, but I want to give him as much time with his family I can withoutmaking him sick. But you sometimes have to fight those adverse events and try to have some response. I try to be very aggressive if they‘re young. I‘m not saying [to always do this] if they‘re 80 years or older. [However, one of my patients] is 80 years old, and I gave him cabozantinib [Cabometyx] plus nivolumab [Opdivo], and he‘s doing well now. I think we should be a little bit aggressive in those cases, especially with young patients.

Park: I‘m the same way in my practice. If they‘re young, give them a chance. Maybe give them a strong TKI [tyrosine kinase inhibitor] like cabozantinib. Now, what about brain metastases? Does that help you go through one of the lines in terms of certain treatments. If it‘s asymptomatic vs symptomatic, what do you do with patients with RCC with brain metastases?

Jabbour: I think [you could use] cabozantinib. There are some data with cabozantinib and brain metastases.¹ Of course you will irradiate [them]; maybe, if solitary, we can try if they are surgically removable, but [we give] radiation, and I tend to give cabozantinib/nivolumab.

Mohamad K. Khasawneh, MD: For brain metastases, I try to address them before I start systemic therapy. If there are a few, and the radiation oncologist can do stereotactic radiotherapy for those, I will go with that, start steroids, and try to taper them fast and start systemic therapy. I think the ipilimumab [Yervoy] plus nivolumab data for brain metastases are pretty impressive.² So in patients with [brain metastasis and] and bulky visceral disease,understanding that TKIs also have good activity in the brain with immunotherapy, ipilimumab/nivolumab would be my to go-to regimen, especially if they have bulky disease or high-risk disease.

DISCUSSION QUESTIONS

• How often do you have to modify/interrupt/discontinue these regimens for toxicity?
• What influences your decision to initiate therapy at a dose lower than the protocol dose?
• Do your patients still experience toxicity even with the lower dose?

Park: What is your strategy in terms of lowering the dose [of the TKI]? Do you do that rapid drop? If you have lenvatinib [Lenvima] plus pembrolizumab [Keytruda], you go from 20 mg to 14 mg.

Patel: I have run into hand-foot syndrome with cabozantinib, and I have to stop it entirely. Then I start it slowly at 20 mg every other day, and then I‘ll get up to 20 mg daily, and stop there. I don‘t rechallenge at the same dose. I‘ve given some of these people topical [diclofenac], and it‘s helped, but I don‘t rechallenge them. It‘s an excruciating hand-foot syndrome that some of these patients run into.

Park: I know the patients may have 40 mg [tablets], and when we‘re waiting for the 20 mg [tablets], sometimes, if it‘s not that severe, I do 40 mg every other day until the 20 mg [tablets] arrive.

Khasawneh: Initially, with the approval of lenvatinib, I started with the FDA package insert dose, but I‘ve noticed that a lot of patients had to stop the drug permanently because of the adverse events, so I adjusted my approach, and I‘ve been using lower doses, starting around 12 mg, and making my way slowly up to the highest tolerable dose. Axitinib [Inlyta] continues to be 5 mg orally twice daily which seems to be the most tolerated dose for the vast majority of patients.

Jabbour: In general, [I believe] ipilimumab/nivolumab is going to be a category 1 in the National Comprehensive Cancer Network guidelines in favorable risk, and change the whole plan with treatment. [I would] just look into that, because how the 2 curves still stay separate is an impressive [result].

Park: Yes, it‘s a great point [that we have] 99-month data for the favorable risk, because you want to have that tail of the curve, and so there‘s separation there.³

Koko: When we‘re using the CheckMate 9ER [NCT03141177] regimen, and when the patient [experiences progression], what‘s your second line?

Park: The data are for lenvatinib/everolimus there [whereas tivozanib is indicated for the third line]. Then the question is third line [where you could use] belzutifan [Welireg]. But I think for me, I can‘t continue with the immunotherapy. The TiNivo-2 study [NCT04987203] read out and it’s negative, so now [with this and CONTACT-03 (NCT04338269)] you have 2 immunotherapy studies that are negative to continue with immunotherapy, so you can‘t do immunotherapy after the first line fails [to show benefit].^4,5 If you do cabozantinib/nivolumab, what would you do for second line?

Bilal Siddiqui, MD: [I would use] lenvatinib/everolimus and then belzutifan as you said, and tivozanib as the fourth line.

_References:

_{1. Hirsch L, Martinez Chanza N, Farah S, et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. 2021;7(12):1815-1823. doi:10.1001/jamaoncol.2021.4544}

_{2. Emamekhoo H, Olsen MR, Carthon BC, et al. Safety and efficacy of nivolumab plus ipilimumab in patients with advanced renal cell carcinoma with brain metastases: CheckMate 920. Cancer. 2022;128(5):966-974. doi:10.1002/cncr.34016}

_{3. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO + IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl 4):363. doi:10.1200/JCO.2024.42.4_suppl.363}

_{4. 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}

_{5. 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}