Ornstein Assesses Treatment Decision Process in Metastatic RCC

Moshe Ornstein, MD, MA

Genitourinary Medical Oncologist

Cleveland Clinic Main Campus

Cleveland, OH

At a live virtual event, Moshe Ornstein, MD, looked at the latest data behind the 4 main combination therapies available for patients with metastatic renal cell carcinoma (RCC). He discussed the updated data from the trials that initially led to the FDA approvals of these therapies and what data make the most sense to follow and help decide a patient’s treatment. He also walked through his overall decision-making process for selecting treatment in this patient population.

Where to Start

ORNSTEIN: The reality is that we do [reference] the National Comprehensive Cancer Network [NCCN] guidelines, but... you can turn to these NCCN guidelines, and when you look at the preferred regimens, there are 4 preferred regimens in the patient population [with] poor-and intermediate-risk [disease] that are all category 1 recommendations: axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivo-lumab [Opdivo], ipilimumab [Yervoy] plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab.¹

It comes down to when we see the patient in front of us, and we know we’re going to have another patient with kidney cancer [coming into the clinic whom we’ll also have to treat]. Ultimately, how are we going to decide between these regimens for the individual patients?

At the end of the day, the medicines work only if we can get them to the patients. When you give them their medicine and they walk out of the clinic doing OK, then you know they’ve been medicated [and are on track, hopefully].

Assessing the Next Steps

For patients with kidney cancer, I incorporate next-generation sequencing [NGS] testing much later in the [treatment of their] disease. I have yet to strike gold with NGS in patients with RCC in terms of finding something [that would make me consider a different targeted approach such as in] therapy for patients with lung cancer or how it’s done for patients with breast cancer.

It’s a totally different phenotype when it comes to its sequencing. The same thing can be seen with the use of circulating tumor DNA. RCC just doesn’t shed a ton of tumor to do tests [such as] Signatera that we would do for patients with bladder cancer, for example. So I haven’t seen anything remarkable pop up on NGS [results for these patients].

We have certain trials...where we’re doing NGS up front.² For the most part, NGS is used much later in their disease course because we now have so many options to offer them that have response rates over 20% or 30%, which is probably better than what we’re likely to find with a therapy [dictated by the] NGS results. When choosing the frontline regimen [for treating these patients], to what extent do we also take into consideration what’s going to be left to use in the second-line setting is an important question as well.

There are those who...would argue it [in] different ways, and they’ll say we’ve got to use ipilimumab/nivolumab up front because the only time to use ipilimumab is in the frontline setting, because using ipilimumab/nivolumab in the salvage setting has dreadful data.³ There are those who say cabozantinib has solidified itself as a second-line standard therapy, so [they’re] going to use axitinib/pembrolizumab, ipilimumab/ nivolumab, or lenvatinib/pembrolizumab up front. Then there are those...physicians who want to use lenvatinib/everolimus in the second or third line,⁴ so they’re going to use anything but lenvatinib/pembrolizumab up front. The nice part about this is that there’s no wrong answer; any one of these regimens is appropriate. I use any of these regimens in the favorable-risk [disease] setting as well. I tend to lean a little bit more on lenvatinib/pembrolizumab [in this setting].

The [order in which these combination therapy studies] were published and subsequently FDA approved [based on the data that followed] was the CheckMate 214 [NCT02231749], KEYNOTE-426 [NCT02853331], CheckMate 9ER [NCT03141177], and CLEAR [NCT02811861] trials.^5-8 These were all compared against sunitinib [Sutent], which was at the time the standard of care [for patients with RCC in this setting], so all [these trials] have at least the same comparator arm. [When comparing all these therapies], ipilimumab/nivolumab is always going to have the longest term of follow-up...because it was the first [combination therapy in this setting] on the market, but there are different ways to look at these data.

Key Data

Some people will look at [findings from these studies] and say all [they] care about is the median overall survival [OS], which for ipilimumab/nivolumab was 52.7 months, about 46 months for axitinib/pembrolizumab and cabozantinib/nivolumab, and 53.7 months with lenvatinib/pembrolizumab [Figure^5-8]. Some people will say what they care about the most is how long [they] can keep a patient on their frontline therapy, meaning they want to know what the progression-free survival [PFS] was. And for that, the PFS is certainly longest in the CLEAR study [findings] with lenvatinib/pembrolizumab [at 23.9 months compared with 9.2 months in the sunitinib arm (HR, 0.39; 95% CI, 0.32-0.49; P < .001)].⁸ I never know what to make of complete responses, but if you’re [receiving] cabozantinib/nivolumab or lenvatinib/ pembrolizumab, you’ll look at that and that’ll help sway your decision. But sometimes we see responses that are 95%, and I’m not convinced there’s a significant difference.

As we go from one year to the next, we have better options as part of the subsequent therapies. So if you look at the median survival in the sunitinib arm for ipilimumab/nivolumab, the median OS in the sunitinib arm was 38 months, which is dreadful.⁵ You compare that with the CLEAR study [findings], it was 54 months,⁸ and part of that has to do with the ipilimumab/ nivolumab arm [of the CheckMate 214 study. For] those patients who got sunitinib, many of them did not have the ability to get nivolumab as a salvage therapy.⁵ What we’re seeing now is that there are opportunities in the second-line setting for these patients to get immunotherapy-based therapies. So the sunitinib arm with each passing trial is overall trending to do better than it was in the first trial [findings] based on subsequent therapies and availability of these agents across the world, which is where a lot of these studies are done.

What I would point out...is the primary disease progression in the experimental arm [of these 4 studies], because the best response to therapy was disease progression. For ipilimumab/ nivolumab, it’s 18%; for axitinib/pembrolizumab, it’s 11%; and then [it’s] 6.5% and 5.4% for cabozantinib/nivolumab and lenvatinib/pembrolizumab, respectively.^5-8

What that translates to is when a patient’s sitting in front of me, I tell them with ipilimumab/nivolumab, there’s close to a 20% chance that there’s going to be disease progression as the best response and we won’t have disease control, whereas with cabozantinib/nivolumab and lenvatinib/pembrolizumab, there’s...about a 95% chance that at the very least, there’s going to be disease control. I find it soul crushing when on the first set of scans there’s disease progression, and there’s something nice about having that option with cabozantinib/nivolumab and lenvatinib/pembrolizumab that at the very least...the disease should be controlled.

Response rates are always going to be higher for the immunotherapy and tyrosine kinase inhibitor combinations vs immunotherapy combined with immunotherapy. The highest response is with lenvatinib/pembrolizumab at 71.3%, and the axitinib- and nivolumab-based combinations are at about 56%. So they all have survival benefits compared with the prior standards of care. They’re all category 1–preferred recommendations within the NCCN guidelines. I lean much more on lenvatinib/pembrolizumab because of the higher response rates, longer PFS, and the very low rate of primary progression, but you can use all these regimens in different settings.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2024. Accessed May 14, 2024. https://tinyurl.com/h2y8hfef

2. Elias R, Sharma A, Singla N, Brugarolas J. Next generation sequencing in renal cell carcinoma: towards precision medicine. Kidney Cancer J. 2019;17(4):94-104.

3. McKay RR, Leucht K, Xie W, et al. A pooled analysis of 3 phase II trials of salvage nivolumab/ipilimumab after nivolumab in renal cell carcinoma. Oncologist. 2024;29(4):324-331. doi:10.1093/oncolo/oyad298

4. Hamieh L, Beck RL, Le VH, Hsieh JJ. The efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front-line targeted therapy or immunotherapy. Clin Genitourin Cancer. 2020;18(4):252-257.e2. doi:10.1016/j.clgc.2020.03.003

5. 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

6. Plimack ER, Powles T, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 KEYNOTE-426 study. Eur Urol. 2023;84(5):449-454. doi:10.1016/j. eururo.2023.06.006
7. 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

8. Motzer RJ, Porta C, Eto M, et al; CLEAR Trial Investigators. 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