Phase 2 Trials Support NCCN’s Inclusion of Combinations for nccRCC

Limited randomized trial data are available for regimens to treat non–clear cell renal cell carcinoma (nccRCC). However, in light of experience in the clear cell setting and favorable outcomes in phase 2 trials, lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and cabozantinib (Cabometyx) plus nivolumab (Opdivo) are now included as preferred regimens. In a virtual Case-Based Roundtable, Moshe C. Ornstein, MD, MA, a genitourinary oncologist at the Cleveland Clinic, reviewed the trial data that supported the use of these 2 combination regimens. He discussed the differences in trial design such as how they enrolled patients with different disease histologies.

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Targeted Oncology: What is the background for the NCCN’s current recommendations for systemic therapy for stage IV nccRCC?¹

Moshe C. Ornstein, MD, MA: Historically…the only preferred agents for nccRCC in the NCCN guidelines were either a clinical trial or cabozantinib. The data for cabozantinib were the PAPMET study [NCT02761057] that compared patients with papillary RCC. It randomly assigned them to [cabozantinib] vs 1 of 3 other tyrosine kinase inhibitors [TKIs]. Ultimately it came down to cabozantinib vs sunitinib [Sutent] and cabozantinib was superior with a PFS of about 10 to 11 months.² These were not any remarkable data, but at the end of the day, they were randomized data. Recently, there were nonrandomized single-arm phase 2 data for both cabozantinib and nivolumab, as well as lenvatinib and pembrolizumab. Interestingly, the data for lenvatinib and pembrolizumab have been added to the lenvatinib/pembrolizumab package inserts and the FDA approved having the clinical trial data added into the label.

Could you describe the study of lenvatinib plus pembrolizumab in greater detail?

This was the KEYNOTE-B61 study [NCT01130519]. Even though it was published a couple of years ago, the median overall survival [OS] data were not mature. These data are relatively new, from a meeting that occurred in July. This study was, importantly, a frontline study. It included all histologies of nccRCC. Not surprisingly, papillary and chromophobe are going to make up about 80% and the rest are unclassified, translocation, etc.³ Patients were treated with pembrolizumab and lenvatinib at the usual doses and schedules that we have in the clear cell RCC setting. This was a large international study. It included almost 160 patients and patients were treated until disease progression or unacceptable toxicity.

Regardless of histology, I tend to quote the number 50% where I tell patients the [overall] response rate. The trial had over 90 patients with papillary RCC. This is the largest group of patients with papillary RCC ever studied in a combination trial. Across the board, you see similar response rates and complete response rates. In the chromophobe population, the response rates are about 35%, a little lower than the other subtypes. Some would call chromophobe histology not as immune responsive, but [there was] still good activity relative to historical controls, and most patients had either a response or stable disease across histologies.

The response rates are nice, but it's great to see the waterfall plots and seeing the tumor burden decrease in papillary, unclassified, chromophobe, translocation, and other histologies. Almost all patients in the study, even if they did not achieve a RECIST response, had at least some tumor burden reduction.⁴ Many of these responses occur pretty early. The responses tend to occur at about 3 months, and many of these patients [have] ongoing responses, with 50% of patients having a response of greater than 18 months.³

What were the survival outcomes in this trial?

[According to] the older data, the progression-free survival [PFS] was about 18 months regardless of histology.⁴ At a median follow up of 41.6 months, this was presented at the Kidney Cancer Research Summit in July of this year.⁵ The median OS, in this mixed bag of papillary, translocation, chromophobe etc, was 41.5 months. [These are] great data for a rare subtype of what many would call an orphan disease. The 24-month OS rate was 66.5% and 36-month OS rate was 53.7%. The median OS in the CLEAR study [NCT02811861] for lenvatinib/pembrolizumab in clear cell RCC is 53 months.⁶ It's obviously shorter in nccRCC, but longer than anything we’ve seen in other trials.

These were the treatment-related adverse events seen in more than 20% of patients.⁴ I don't see any major surprises. You see hypertension, which we're used to seeing with lenvatinib, [plus] diarrhea, hand-foot syndrome, and some proteinuria. …I don't think it shows anything concerning relative to what we're used to seeing in the clear cell population.

What differences were there in the design of the B61 study vs the other combination trial?

The differences that jump out are that with the cabozantinib/nivolumab data, there were 2 cohorts, papillary, unclassified, and translocation at 40 patients, and the chromophobe cohort [which] did have 7 patients, but it closed early because there were no responses with cabozantinib/nivolumab.⁷ Right away, there's going to be a little bit of a difference in the studies. There were no patients with chromophobe RCC with cabozantinib/nivolumab compared with the lenvatinib/pembrolizumab study. The cabozantinib/nivolumab study included patients who were both treatment naive as well as patients who had received 1 prior line of therapy.

It's a smaller study. KEYNOTE-B61, the lenvatinib/pembrolizumab study, had almost 160 patients. Here you have 26 patients in the first line and 14 patients in the second line. Response rates for patients in the first line were about 50%; that's the number I quote across the board, regardless of histology and which combination therapy is used.

[There were] very few patients with primary disease progression, like with lenvatinib/pembrolizumab, so the response rates are impressive in both studies. [There was] a general tumor burden reduction seen in most patients with cabozantinib/nivolumab as we saw with lenvatinib/pembrolizumab, and some ongoing responses on the swimmers’ plot.

Here is where we begin to see some of the differences between the studies. The cabozantinib/nivolumab study was a smaller study. It didn't really have patients with chromophobe RCC, but [there were] response rates [of] about 50% in both combinations. But the PFS for cabozantinib/nivolumab was 13 months and it was about 18 months with lenvatinib/pembrolizumab.^5,7 The median OS was 28 months with cabozantinib/nivolumab and about 41 months with lenvatinib/pembrolizumab. This study included some patients who were [treated in the] second line as well, so that might be another reason why the median OS is lower. We’re not directly comparing the 2 trials, just trying to highlight some of the major differences and nuances between these 2 regimens and the way that they've been studied in the nccRCC setting.

Toxicity profiles for cabozantinib/nivolumab were what you would expect having a TKI and immunotherapy, similar to what we're used to seeing in the clear cell setting as well.⁷

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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. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2026. Accessed November 18, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf}

_{2. Barata P, Tangen C, Plets M, et al. Final overall survival analysis of S1500: a randomized, phase II study comparing sunitinib with cabozantinib, crizotinib, and savolitinib in advanced papillary renal cell carcinoma. J Clin Oncol. 2024;42(33):3911-3916. doi:10.1200/JCO.24.00767}

_{3. 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}

_{4. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-891. doi:10.1016/S1470-2045(23)00276-0}

_{5. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for advanced non-clear-cell renal cell carcinoma: updated results from the phase 2 KEYNOTE-B61 trial. Eur Urol. 2025;88(6):614-624. doi:10.1016/j.eururo.2025.05.019}

_{6. 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}

_{7. 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}