Key Takeaways From QOL and Use of Steroids With IO-Based RCC Regimens

Ulka Vaishampayan, MBBS

Professor of Internal Medicine

Director of the Phase I program

Rogel Cancer Center, University of Michigan

Ann Arbor MI

Targeted Oncology: What concerns are there with immune-related adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) who received ipilimumab (Yervoy) plus nivolumab (Opdivo) in the CheckMate 214 trial (NCT02231749)?

VAISHAMPAYAN: The immune-related AEs are a big deal here. The incidence is small [later in duration of treatment], but the treatment-related AEs can occur at any time during the treatment. There is unpredictable timing, and 94% had some AE or another with ipilimumab/nivolumab, as compared with sunitinib, where it was 98%.¹ The tyrosine kinase inhibitor [TKI] and ipilimumab/nivolumab both had some kind of toxicity in almost everyone. The severe AEs, though, were seen in 48% with ipilimumab/nivolumab and 64% with sunitinib, so there was a slightly higher risk of toxicity with the severe toxicities with the VEGF TKI. There were 8 patient deaths in the ipilimumab/nivolumab arm and 5 in the sunitinib arm from some kind of toxicity. The discontinuation [rate] was 24% with ipilimumab/nivolumab and 13% in the sunitinib [arm].

Ipilimumab/nivolumab has the longest follow-up [of the frontline RCC studies]. We have a longer duration to monitor patients for toxicity, patients are still in follow-up at all the sites, and we are still keeping this study open, because the long-term follow-up is ongoing.

Does steroid use impact the treatment efficacy with immune checkpoint inhibitor (ICI)-based therapy?

My perception is that doesn’t happen much. I feel our typical thinking about steroid use is with cytokine therapies, such as interleukin-2 therapy [where] we did not want them getting steroids. No matter how sick patients were, we wanted to weather the storm, and not to give them steroids. But I feel like cytokines had a quick peak and dropped, so you only had that time to create the impact on the immune system. With ICI therapies, I don’t think that’s true; these medications tend to last in the system for much longer and they create the immune activation over a longer period. Because of that, I feel like the steroids don’t make as much of an impact. But clearly if they need it, it’s better to use the steroids and otherwise, the AEs are too life-threatening to have to deal with.

[Using steroids] for the longer term is not a great idea, [or using] continuous steroids. Typically, we would use them in spurts, unless they got adrenal insufficiency, which is a common AE of ICI therapy. Then you’re giving them replacement steroids, which technically shouldn’t count as steroid therapy. But I feel like immunosuppressive therapy gets withheld too often, and then patients end up getting way too sick.

I see this in our hospital when I’m doing rounds—that a patient has colitis and [providers] are waiting for a colonoscopy and stool studies when I know this is immune colitis, and we can turn around that patient within a day with steroids. That is somewhat unfortunate with a lot of our medicine colleagues. It is the same thing for pneumonitis. I’ve had so many patients who have been in the intensive care unit and they just don’t want them to get steroids until they have done a bronchoscopy, and in reality, that doesn’t give you any diagnosis unless it’s rip-roaring pneumonia, which you should be able to find out. But you shouldn’t need a bronchoscopy for that. It’s the same thing for skin rashes; I’ve seen skin rashes progress so rapidly that there is no time for doing skin biopsies. It is important to put them on steroids if there is concern that there is a toxicity.

High-dose steroid use was pretty similar in all of the studies except for lenvatinib [Lenvima] plus pembrolizumab [Keytruda]; for some reason it is much lower at 15%.² But the bottom line, is that the efficacy [on CheckMate 214] has been seen with [almost] one-third of the patients getting steroids.³

How did the frontline RCC studies differ by quality-of-life (QOL) measures?

The different measures that were used were FKSI-19, FACT-G, and the European [EORTC-QLQ-C30]. [In all] 4 studies, they did the QOL patient-reported outcomes. One of the things that has come out about the patient-reported outcomes is that physicians underplay the toxicities, which shouldn’t come as a surprise but now there are multiple randomized trials where that has become more and more evident.[We can] just ask the patient.

The interesting thing was CheckMate 214 and CheckMate 9ER [NCT03141177], so cabozantinib [Cabometyx] nivolumab and ipilimumab/nivolumab, showed an improvement in the patient’s QOL.All of the QOL questionnaires are limited by the fact that the sick patients are in the hospital and they’re not filling out any questionnaires. But within those caveats for all these studies, axitinib [Inlyta] plus pembrolizumab and lenvatinib/pembrolizumab, the amount of QOL drop was similar with sunitinib, whereas with ipilimumab/nivolumab and cabozantinib/nivolumab, the patient’s QOL went higher than the baseline.^4-7 Their QOL improved while they were on the study. That is an added parameter, since we see similar progression-free survival, response rates, overall survival, etc. This is an added [data point] that you can use to make a decision about how patients are going to feel during treatment.

With ICI therapy, even the patients who were without treatment got prolonged treatment-free intervals, because if these patients were in remission, at 42 months [median follow-up], patients who are free of any further treatment and never needed any other treatment is 31% [vs 9% with sunitinib].⁸ That is pretty similar to the 30% number we saw in long-term survival. The probability of being treatment free if they had been randomized is 18% [with ipilimumab/nivolumab vs 4.9% with sunitinib]. This is an older study from when we did not have a limited time interval [of nivolumab], so 18% of the patients were treatment-free.

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. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569

3. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079

4. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):292-303. doi:10.1016/S1470-2045(21)00693-8

5. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780. doi:10.1016/S1470-2045(22)00212-1

6. Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life analysis from KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82(4):427-439. doi:10.1016/j.eururo.2022.06.009

7. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl_15):4553. doi:10.1200/JCO.2021.39.15_suppl.4553

8. Regan MM, Jegede OA, Mantia CM, et al. Treatment-free survival after immune checkpoint inhibitor therapy versus targeted therapy for advanced renal cell carcinoma: 42-month results of the CheckMate 214 Trial. Clin Cancer Res. 2021;27(24):6687-6695. doi:10.1158/1078-0432.CCR-21-2283