NCCN Guidelines in nccRCC Weigh New Data for Combinations

Immunotherapy (IO) and tyrosine kinase inhibitor (TKI) are now listed in the NCCN guidelines for advanced non–clear cell renal cell carcinoma (nccRCC).¹ This change comes based on the efficacy seen with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and cabozantinib (Cabometyx) plus nivolumab (Opdivo) despite these results coming from a pair of single-arm trials. In a virtual Case-Based Roundtable, Moshe C. Ornstein, MD, MA, a genitourinary oncologist at the Cleveland Clinic, discussed why these regimens can be used. He also looked back at the older regimen of lenvatinib/everolimus before considering how to interpret the results of another recent trial for the dual IO regimen of ipilimumab (Yervoy)/nivolumab in this setting.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What features of the design and outcomes of the studies of lenvatinib/pembrolizumab and cabozantinib/nivolumab stand out?

Moshe C. Ornstein, MD, MA: The lenvatinib/pembrolizumab study was a larger study. The primary end points were the overall response rates [ORRs] which are similar across both studies [and are] in the low 50% [range].^2,3 The response rates are similar by histology, acknowledging that patients with chromophobe [histology] were included in KEYNOTE-B61 [NCT01130519] and not included in the cabozantinib/nivolumab study [CA209-9KU; NCT03635892].

The median overall survival [OS] was longer in the lenvatinib/pembrolizumab study, acknowledging the limitation that there were second-line patients included in the cabozantinib/nivolumab study as well, which may have dampened the OS signal there as well. The median progression-free survival [PFS] for frontline patients was about 18 months in lenvatinib/pembrolizumab and 11 months in cabozantinib/nivolumab.^2,3

What are the most important takeaways on safety of the combinations?

For me at least, the more important data are treatment-related adverse events that lead to the discontinuation of either study drug. It’s actually reversed from the clear cell setting where in the nccRCC setting, with lenvatinib/pembrolizumab, 22% of patients had to discontinue either lenvatinib or pembrolizumab, and half the patients had to discontinue either cabozantinib or nivolumab, and with both study drugs, a smaller percentage of patients receiving lenvatinib/pembrolizumab [discontinued both].^2,3

What other combination regimen is recommended by the NCCN?

There still are physicians using lenvatinib plus everolimus for patients with nccRCC, more specifically for chromophobe RCC. Those data came from a fairly small study of lenvatinib and everolimus in non–clear cell RCC.⁴ There were a grand total of 9 patients with chromophobe histology. Four of those patients had a response, so the response rate was 44%. It led to a lot of excitement about lenvatinib/everolimus for chromophobe RCC. There are some scientific data to support it in terms of mTOR mutations or TSC mutations, and that there might be a role for mTOR inhibition in chromophobe. It’s falling a little bit out of favor. But I find that when you’re dealing with these patients…knowing about the role of everolimus in at least some patients with chromophobe is helpful.

How did the phase 2 studies become incorporated into the NCCN guidelines?

There were questions in the community whether you could include single-arm phase 2 trials and…whether those could be incorporated into the NCCN guidelines, especially because cabozantinib had a randomized study that led to its inclusion. But when we started seeing data showing PFS of 18 months, and median OS that was not reached at follow-ups of 34 or 36 months, there was a strong belief that even though they were single-arm phase 2 trials, there were enough data to support their inclusion in the NCCN guidelines. I haven’t had any issues with insurance companies covering them. There is a question as we move forward, how do we design further clinical trials? Can we do clinical trials that have cabozantinib as a control arm, or do we need to have IO/TKI as a control arm now that we have these response, PFS, and overall survival data?

What other regimen has supporting data in this setting?

One thing that we did not see in the NCCN guidelines is ipilimumab plus nivolumab. Data were presented at the European Society of Medical Oncology Congress [in 2024], and these were the phase 2 SUNNIFORECAST [NCT03075423] data for ipilimumab/nivolumab in non–clear cell RCC.⁴ There are 2 different ways to look at the results here.

These were patients with metastatic or locally advanced nccRCC, included papillary, chromophobe, collecting duct, unclassified, sarcomatoid, etc. Patients were randomly assigned to ipilimumab/nivolumab followed by nivolumab maintenance vs standard-of-care [SOC] agents with 85% of the patients receiving TKI monotherapy either with sunitinib [Sutent] or cabozantinib.

The primary end point of the study was not PFS; it was OS at a landmark of 12 months. The arms were fairly well balanced based on International Metastatic RCC Database Consortium risk groups, prior therapies, and sites of metastatic disease. In this study, 80% the patients had either papillary or chromophobe [histology].

The primary end point in the study was met in that the 12-month OS rate was almost 87% for ipilimumab/nivolumab and about 77% for the SOC arm [HR, 0.83; 95% CI, 0.59-1.17; P = .2922]. Patients who had a higher PD-L1 status had a greater benefit with ipilimumab/nivolumab. Patients who had lymph node metastases, patients with chromophobe [subtype], regardless of what you gave, it was unclear which one was favored, but the primary end point of the study was met. So…if the primary end point of the study was met, how come it’s not included in the NCCN guidelines yet, and how come there hasn’t been more excitement around this combination? That is because of the [response data].

[Looking at all patients with] nccRCC, the response rates were fairly low, relatively speaking. The ORR for ipilimumab/nivolumab was only about 25% and the response rates [for] cabozantinib/nivolumab or lenvatinib/pembrolizumab were about 50%. More than one-third of patients with nccRCC who received ipilimumab/nivolumab had primary disease progression. On top of that, there was a very short PFS with ipilimumab/nivolumab of only 5.5 months.

So even though it met its primary end point, the overall efficacy [included] a relatively low response rate and a relatively short PFS, [whereas] we were talking about anywhere between 10 and 18 months with lenvatinib/pembrolizumab and cabozantinib/nivolumab. It dampened the enthusiasm for the ipilimumab/nivolumab in the setting. …You’re going to see generally favorable survival with ipilimumab/nivolumab, but still a much lower PFS and ORR, given that it’s a pure IO regimen that doesn’t have the same degree of efficacy in the nccRCC setting.

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DISCLOSURES: Ornstein previously reported consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, Seattle Genetics, and Bristol Myers Squibb; served on speakers bureaus for Bristol Myers Squibb; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, Astra-Zeneca, HiberCell, Arcus.

REFERENCES

1. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl 4):2. doi: 10.1200/JCO.2024.42.4_suppl.2

2. Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. Eur Urol. 2024;86(2):90-94. doi:10.1016/j.eururo.2024.04.025

3. Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80(2):162-170. doi:10.1016/j.eururo.2021.03.015

4. Bergmann L, Albiges L, Ahrens M, et al. Prospective randomized phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial. Ann Oncol. 2025;36(7):796-806. doi:10.1016/j.annonc.2025.03.016