Renal cell carcinoma (RCC) treatment has evolved significantly with the introduction of targeted therapies and immunotherapy combinations. Nataliya Mar, MD, associate clinical professor in the Division of Hematology/Oncology, Medicine at UC Irvine Chao Comprehensive Cancer Center, reviewed trial data appropriate for a patient with non–clear cell RCC in a virtual event with oncologists from California. Mar covered first-line treatment options for non-clear cell RCC, highlighting the KEYNOTE-B61 trial (NCT04704219) results with lenvatinib (Lenvima) plus pembrolizumab (Keytruda).
Register today to join a Case-Based Roundtable near you.
CASE SUMMARY
- A 57-year-old man presented to the emergency department with new onset gross hematuria, right flank pain, and weight loss.
Past medical history
- Hypertension, well controlled on angiotensin-converting enzyme inhibitor taken once daily
- No prior history of malignancy
Social history
- Employed as a bank teller
- Non-smoker
Family history
- Father died of colon cancer at 60, mother underwent hysterectomy for uterine fibroids at age 37, no other family history of malignancy
Diagnostic workup
- Abdominal CT: 7-cm solid mass in right kidney; liver and lung metastases detected
- Laboratory test results: normal complete blood cell counts, differential, and comprehensive metabolic panel
- Histopathology: core needle biopsy – papillary architecture consistent with non–clear cell RCC
- Molecular testing results: awaiting results
Targeted Oncology: What are the treatment options for a patient with non–clear cell RCC such as this?
Nataliya Mar, MD: The NCCN guidelines have the systemic therapy options for previously untreated, non–clear cell RCC. As preferred regimens, there is lenvatinib and pembrolizumab, as well as cabozantinib [Cabometyx] and nivolumab [Opdivo]; these are our 2 doublets. You still have the single-agent cabozantinib in there, and then you have [the option of a] clinical trial.1
Clinical trials are always my preferred choice for any patient with non–clear cell RCC, because these are diverse diseases with different drivers. We need to develop new regimens and new drugs. So if I have a chance, I always try to put these patients on the trial, but trials are hard to come by sometimes. In terms of standard-of-care options, I would probably lean towards some kind of doublet.
Can you discuss the trial behind using lenvatinib plus pembrolizumab for this patient?
In the non–clear cell RCC space, the most recent and largest one that was reported out was KEYNOTE-B61. It’s a phase 2 study of patients with non–clear cell RCC or various histologies. These patients had locally advanced or metastatic disease, no prior therapies, and Karnofsky performance status here was 70% or higher. This was a single-arm trial that enrolled 158 patients. If patients were eligible, they received a combination of pembrolizumab at a dose of 400 mg every 6 weeks, up to 2 years, plus lenvatinib at 20 mg daily. They were assessed at baseline, and then every 12 weeks for response. The primary end point here was objective response rate [ORR].2
The majority of patients on this study had papillary RCC, with 59%, and 18% had chromophobe RCC, so that’s a pretty decent chunk of patients with chromophobe [histology]. Thirteen percent had unclassified RCC, 4% had translocation RCC, and then 6% had other.
What was the result for the primary end point in KEYNOTE-B61?
In the entire study population, the ORR was 50.6%. Complete responses [CRs] were noted in 8.2%, partial responses [PRs] were noted in 42.4%, and stable disease in 31.6%. The disease control rate, which is a composite end point where you add CR, PR, and stable disease together, was 82.3% in the overall study population. Then there’s another end point called clinical benefit rate, which is very similar to disease control rate, except you have to stay in response for at least 6 months; the clinical benefit rate was 71.5%. Antitumor activity was observed across various subgroups, including all International Metastatic Renal Cell Carcinoma Database Consortium risk categories, sarcomatoid features, and regardless of PD-L1 status.2
There was a breakdown based on the various subtypes of RCC histology. For papillary RCC, the ORR was just a bit higher than in the overall population, at 53.8%. For chromophobe RCC, the ORR drops to 34.5%. Unclassified RCC was similar to the overall population, at 50%. Translocation RCC was 66.7% and the ‘other’ category was 60%. Most of these subgroups did very similarly to the overall population.
The median duration of response on this trial was 19.5 months, and over 50% of patients had a response for 18 months or higher.
In the overall study population, it was 17.9 months for median progression-free survival. The median overall survival was not reached in any of these in the total population and subgroups because the data were immature, but I’m sure we’ll see follow-up results in future meetings.
How did patients do in terms of toxicity with lenvatinib and pembrolizumab?
Most of the treatment-related adverse events were grade 1 or 2, or mild or moderate. When you get to severe, the only significant severe one was hypertension in 23% of patients. The rest of them are 4% and under. When you’re talking about grade 4 or very severe events, there was 5% [and it was not any of the treatment-related adverse events in 20% or more of patients].3
Register today to join a Case-Based Roundtable near you.
DISCLOSURES: Mar previously reported a consulting or advisory role with Exelixis, EMD Serono, Pfizer, Aveo, a part of the speakers’ bureau with Eisai and Merck, and research funding from Gilead Sciences.
References:
1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 1.2026. Accessed August 13, 2025. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
2. 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; abstr 2). doi:10.1200/JCO.2024.42.4_suppl.2
3. 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