Comparing Long-Term Data for IO/IO and IO/TKI in Favorable-Risk mRCC

Commentary
Article

During a Case-Based Roundtable® event, Rana McKay, MD, discussed the updated favorable-risk group data for 4 frontline combination trials in renal cell carcinoma in the first article of a 2-part series.

McKay headshot

Rana McKay, MD

Associate Professor of Medicine

University of California San Diego​

San Diego, CA​

Targeted Oncology: What efficacy outcomes were observed in frontline combination trials for patients with favorable-risk metastatic renal cell carcinoma (mRCC)?

McKay: Across the studies, the percentage of patients who [were in each risk group] differed. In the pembrolizumab [Keytruda]-based studies, it was approximately one-third of patients who had favorable risk mRCC; at 32% and 31% from KEYNOTE-426 [NCT02853331] and CLEAR [NCT02811861], respectively, and fewer patients [23% in each study] with favorable risk from CheckMate 9ER [NCT03141177] and CheckMate 214 [NCT02231749].1-4 When we're looking at overall survival [OS] data for the immune-oncology [IO]/VEGF combinations in favorable-risk disease…there have been multiple cuts of this data.

At the most recent update, the median follow-up was 67.2 months [for KEYNOTE-426] and almost 100 months’ follow-up from CheckMate 214. But the HR was above 1.0 for KEYNOTE-426 and CheckMate 9ER. For CLEAR, these data aren’t as mature as the other 2 trials. CLEAR was a much later study, [but the HR for OS] was 0.74.2 Looking at that HR for OS for the favorable-risk patients from CheckMate 214 over time, this number has been getting better over time.3

How does dual IO/IO compare with IO plus VEGF-TKI (tyrosine kinase inhibitor) in the favorable-risk setting?

[Based on CheckMate 214], there seems to be long-term benefit to nivolumab [Opdivo] plus ipilimumab [Yervoy] in this population. So why are we not using nivolumab/ipilimumab in patients with favorable risk? I think these are the patients who are coasting once they get through the ipilimumab and they're on maintenance nivolumab. But then when they have to be on a TKI for [long term], favorable-risk patients could be on therapy for several years before they progress. They feel [poorly on treatment]. At baseline, they tend to not have a lot of symptoms because they have favorable risk. But I think it's something to think about when the initial thought was to not give these patients nivolumab/ipilimumab. But as we've seen the data mature over time, a lot of people are beginning to think maybe we should be utilizing it.

With regards to short-term gain, the numbers are all better for the IO/VEGF-TKI agents. Progression-free survival [PFS] was dramatically better for IO/VEGF-TKI vs sunitinib: median PFS of 21 months vs 18 months in KEYNOTE-426, 21 months vs 13 months with CheckMate 9ER, and then 22 months vs 6 months with CLEAR.1,2,4 Response rate data were all better, over 60% objective response rate [in all 3 studies with the experimental arm], and clinical benefit rate with IO/VEGF-TKI agents was over 90%. They do work tremendously well in the short term. When you pit them against CheckMate 214, the numbers [for nivolumab/ipilimumab] don't look as great. This is why the Kaplan-Meier curves crossed early on [in CheckMate 214, with median PFS of] 12 months vs 29 months with sunitinib, and an ORR of 30% vs 52% with sunitinib.3 But the complete response [CR] rate is on par in some of the other studies [13% vs 6%, respectively]. There's a doubling of the CR rate.

Can sequential IO be used, particularly in the frontline mRCC setting following adjuvant pembrolizumab?

This is a highly relevant question. I don't think we know the right answer. There have been a series of studies that looked at sequential IO, like CONTACT-03 [NCT04338269], which reported as a negative study.5 That was looking at atezolizumab [Tecentriq] plus cabozantinib [Cabomety] vs cabozantinib alone in the post-IO setting. Some may argue that atezolizumab may not have been the right partner, but that was what was done. There was also a series of adaptive-based studies that looked at starting patients with nivolumab and if they didn't have a response, layering in the ipilimumab. Those studies in aggregate demonstrated that approach did not generate the same level of response rates and CR rates, as doing the combination upfront.6

In clinical practice, a lot of people want to believe that the kinetics of how patients relapse matters. We don't have data on this, but patients who are relapsing on treatment, or within 6 months of treatment, are being labeled as IO refractory, and maybe they should not necessarily be rechallenged with an IO combination when they recur in that short time. For patients who that fall outside of that, I may [be able to] treat them like a traditional frontline patient [with metastatic disease] and give them doublet therapy. But there are no data to say that that's the right thing to do. I think this is a question that's going to come up as we're using more adjuvant pembrolizumab.

REFERENCES:
1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma. J Clin Oncol. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl.LBA4501
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. 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. Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42(suppl_4):362. doi:10.1200/JCO.2024.42.4_suppl.362
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
6. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). J Clin Oncol. 2022;40(25):2913-2923. doi:10.1200/JCO.21.02938
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