Retrospective Analysis Explores Cabozantinib/Nivolumab vs Lenvatinib/Pembrolizumab in Frontline Advanced RCC

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Treatment with cabozantinib (Cabometyx) plus nivolumab (Opdivo) vs lenvatinib (Lenvima) plus pembrolizumab (Keytruda) as first-line therapy for advanced renal cell carcinoma (RCC) yielded modest insights into regimen selection, based on findings from a retrospective analysis presented at the 2025 American Urological Association Annual Meeting.

In the study’s efficacy population (n = 92), 42 (79.3%) of 53 patients who received C+N achieved a response to treatment compared with 17 (43.6%) of 39 patients treated with L+P (P =.005). The partial response, complete response, and stable disease rates for C+N and L+P were 75.5% vs 35.9%, 3.8% vs 7.7%, and 20.8% vs 51.3%, respectively. Deferred cytoreductive nephrectomy occurred in 5.7% (n = 3) of the C+N arm vs 20.5% (n = 8) of the L+P arm.

The analysis did not show significant differences in overall survival (OS) or progression-free survival (PFS) between the 2 treatment arms. At a median follow-up of 15.6 months (range, 11.8-19.4) for L+P and 15.9 months (range, 12.3-19.4) for C+N, the median OS was not reached for L+P vs 46.7 months for C+N (P=.912). The median PFS was not reached vs 24.1 months, respectively (P =.725)

Safety was similar between the 2 treatment regimens. The safety analysis included all 102 patients initially identified for the retrospective analysis. Any-grade adverse events (AEs) occurred in 97.9% (n = 46) of the L+P arm vs 100% (n = 55) of the C+N group (P =.277). The rates for grade ≥3 AEs were 55.3% (n= 26) vs 52.7% (n = 29), respectively (P =.794).

“While overall response rate was significantly higher in the C+N group, this difference may have been influenced by deferred cytoreductive nephrectomy. No significant differences in PFS or OS were observed between the C+N and L+P regimens. Further studies are warranted to better understand the relative efficacy of these regimens in advanced RCC,” the authors wrote in their poster conclusion.

Study Background and Patient Characteristics

Discussing the rationale for their study, the researchers wrote in their poster that since there “is no direct comparative clinical trial” of immune checkpoint inhibitor/TKI combinations used for advanced RCC, improved insight is needed for “clinical decision-making regarding treatment selection” with these regimens.

Accordingly, the researchers conducted their retrospective analysis, which included 102 patients who had received L+P (n = 47) or C+N (n = 55) as frontline treatment for advanced RCC at Tokyo Women’s Medical University and affiliated facilities between April 2018 and May 2024.

In the L+P arm, over half (57.5%) of patients were aged 65 years or older and over three-fourths (76.6%) of patients were male. The Karnofsky Performance Status score was 90% to 100% for 39 patients, 70% to 80% for 7 patients, and less than 70% for 1 patient. Risk status per International Metastatic RCC Database Consortium (IMDC) was favorable for 7 patients, intermediate for 22 patients, and poor for 18 patients. Regarding histology, 28 patients had pure clear cell carcinoma (CCC), 2 had CCC with sarcomatoid features, and 17 patients had other/unknown histology. Metastatic sites included lymph nodes (n = 12), bone (n = 8), lung (n= 26), and liver (n = 7). Eight patients had locally advanced tumors (venous tumor thrombus [VTT] only). Over half (51.1%) of patients had multiple metastatic organs, and 46.8% (n = 22) had received radical surgery for their primary lesion.

Seventy-one percent (n = 39) of the patients in the C+N arm were male, and 63.6% (n = 35) were aged 65 years or older. Karnofsky Performance Status scores were 90% to 100% (n = 44), 70% to 80% (n = 9), and less than 70% (n = 2). IMDC status was favorable, intermediate, and poor, for 12, 32, and 11 patients, respectively. Thirty-seven patients had pure CCC histology, 3 had CCC with sarcomatoid features, and 15 had other/unknown histology. Sites of metastases were lymph nodes (n = 19), bone (n = 13), lung (n = 37), and liver (n = 5). There were 2 patients with locally advanced tumors (VTT only). Thirty-two (58.2%) patients had metastases in multiple organs and 29.1% (n = 16) had undergone radical surgery for their primary lesion.

Of note, the researchers explained on their poster that their “study is subject to selection bias, as the L+P group had more patients with IMDC poor risk and those undergoing deferred cytoreductive nephrectomy.”

The L+P and C+N regimens are both approved by the FDA for the first-line treatment of adult patients with advanced RCC.2,3

References:

1. Kazutaka Nakamura, Hanae Kondo, Yuki Nemoto,Comparison of clinical outcomes between cabozantinib+nivolumab and lenvatinib+pembrolizumab in advanced renal cell carcinoma. J Urol. Published online April 28, 2025. doi:10.1097/01.JU.0001110068.14710.ff.15

2. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. Posted August 10, 2021. Accessed April 28, 2025. https://tinyurl.com/37akdnpf

3. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Posted January 22, 2021. Accessed April 28, 2025. https://tinyurl.com/n44cpbn4