Ensuring Response and Tolerable Dose Are Crucial in RCC

Daniel M. Geynisman, MD

Chief, Division of Genitourinary Medical Oncology

Associate Professor, Department of Hematology/Oncology

Fox Chase Medical Center – Temple Health

Philadelphia, PA

DISCUSSION QUESTION

What efficacy end points are the most important to you when treating a patient with metastatic clear cell renal cell carcinoma?

Daniel Geynisman, MD: Out of median overall survival [OS], median progression-free survival [PFS], overall response rate, and complete response [CR] rate, what's the most important for you as you're thinking about the patient in front of you?

Rana Bilbeisi, MD: For me, it's OS, because that's usually the first question the patients have is, in general, how long do they have to live?

Wajahat Khan, MD: I would say response rate is also very important, because a lot of these patients are very symptomatic, and if they have bulky disease, the first and most important thing is they want to feel better, so that their symptoms improve. I think response rates, in my opinion is also important.

Pallavi Jasti, MD: I agree with that. Response rate is important, and the percentage of patients who have progressive disease is also, because if they don't respond, then there's no talking about OS or any second or third line of treatment. Their performance status may go downhill quickly.

Magdalena Flejsierowicz, MD: I agree. It’s response if [the patient has] a lot of disease and they are symptomatic. The first thing they care about is, can I get better? Then when they get better, they see the light. They can ask about [if] they’re going to now live longer.

Geynisman: I'm hearing that the response rate, at least from those of you spoken, is almost coming up to the top, even maybe more important than the median OS, because you have to get control of the disease. For the symptomatic patients, the response rate is important. Which one is the least important out of OS, PFS, response rate, CR, and primary progressive disease rates?

Khan: Historically, with most of the combination therapies that we have seen, the CR has not been very high in RCC. I think if you get a good partial response and you have good symptom relief, I'm good with that, as long as there's improvement in [PFS] and OS.

Geynisman: I would agree. CR is nice, and we love to see it, but it's relatively rare, and probably the least important to me. At least in the beginning, that's for sure.

DISCUSSION QUESTIONS

Do the discontinuation rates of the combination regimens align with your own clinical experience?

If you dose modify for tolerability, do you believe it is affecting efficacy?

Geynisman: The discontinuation rates due to adverse events are broken down by different categories. Do you just stop one drug [or] both drugs? Some of this is dependent on how the trial was designed. In some trials, you had to continue both.

I would say cabozantinib [Cabometyx] plus nivolumab [Opdivo] has probably the lowest discontinuation rate in general.^1-5 If you look at the high-dose steroid use for immune-related adverse events, the highest is for ipilimumab [Yervoy] plus nivolumab [29%], the dual immunotherapy [IO], although it's pretty close for IO plus TKI [tyrosine kinase inhibitor] for axitinib [Inlyta] plus pembrolizumab [Keytruda] as well [27%], which is a little surprising, because that is not what I see in practice. I think the rate is probably closer to 15% in practice with having to give high-dose corticosteroids with pembrolizumab, but that's the number in the trial.

Do these rates align with what you see? Are you discontinuing or modifying whatever combination you're using? If you're doing axitinib/pembrolizumab or lenvatinib [Lenvima] plus pembrolizumab, what are you finding in terms of stopping the drug?

Khan: Both lenvatinib and axitinib have the flexibility of dialing it down to a lower dose. Especially with lenvatinib, you have so many dose levels that you could use. With axitinib, unfortunately, after 5 mg, you go down to 3 mg, and I don't know if you can go down any further, so you are limited in terms of decreasing the dose in axitinib.

Geynisman: We have all sorts of different doses. We do 4 mg [axitinib]; we go down to 3 mg, and we do have some patients at 2 mg. I think once you start getting down to 2 mg, you're wondering if you're doing any good, but you can, and I have some frail patients who are able to stay on that dose and do OK.

Jasti: I agree. I don't use axitinib/pembrolizumab as much anymore. The TKI combinations of cabozantinib/nivolumab and in some cases lenvatinib/pembrolizumab are the ones I've been choosing. With 40 mg of cabozantinib with nivolumab, I think it's manageable. There are older patients for whom I have dose reduce to 20 mg, but most people, I'm able to keep them on the 40 mg. With lenvatinib/pembrolizumab, I never start at 20 mg [lenvatinib]. I usually do 14 mg or 18 mg as a starting dose and try to ramp up to the full dose if I can.

With the ipilimumab/nivolumab combination, I have used it in younger patients without a lot of disease burden. I had patients for whom I was able to complete all the 4 [ipilimumab doses], but with a recent younger patient I had to use high-dose steroids after 3 treatments. In the fourth [cycle], I'm contemplating doing nivolumab alone. He was admitted with severe headaches, almost meningitis-like symptoms, but we never found any infectious etiology. I felt like this is immunotherapy associated encephalopathy-like symptoms. I was not able to continue the dual ipilimumab/nivolumab combination for the full 4 cycles. That's my general experience with the combination.

Geynisman: For the dual IO/IO, you feel OK sometimes stopping the CTLA-4, the ipilimumab, and continuing the PD-1 inhibitor, rather than stopping both. In the CheckMate 214 trial [NCT02231749], you had to stop both. It was all or nothing; that's the way it was designed. It's a little bit of a relic of that. It doesn't mean that's what you have to do.

DISCLOSURES: Geynisman previously reported consulting or advisory roles for Pfizer, Exelixis, AstraZeneca, Seattle Genetics/Astellas, Merck, and Bristol Myers Squibb.

REFERENCES:

1. 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

2. Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023;24(3):228-238. doi:10.1016/S1470-2045(23)00049-9

3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

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