First-line treatments for metastatic clear cell renal cell carcinoma (ccRCC) combine PD-1 immune checkpoint inhibition (ICI) with CTLA-4 ICI or angiogenesis targeted therapy (TT). Upon progression, common options include cabozantinib or lenvatinib + everolimus, although these regimens have never been directly compared.
We hypothesized that lenvatinib + everolimus will improve progression-free survival (PFS) compared to cabozantinib after progression on PD-1 ICI.
This multicenter, randomized phase II trial enrolled patients with metastatic ccRCC previously treated with 1-2 lines including PD-1 ICI. Participants received lenvatinib 18 mg/day + everolimus 5 mg/day versus cabozantinib 60 mg/day, stratified by International Metastatic RCC Database Consortium risk group and prior TT. A Bayesian optimal phase 2 (BOP2) design was used.
90 patients were randomized; 86 patients received at least 1 dose of assigned lenvatinib + everolimus (n=40) or cabozantinib (n=46). Median time from randomization to data cut-off date (August 1, 2025) was 20 months (IQR 14.9, 22.5). A total of 60 PFS events were observed. Median PFS was 15.7 months with lenvatinib + everolimus and 10.2 months with cabozantinib (hazard ratio 0.51, 95% CI 0.29 - 0.89, p = 0.02). The objective response rate was 52.6% with lenvatinib + everolimus and 38.6% with cabozantinib. Overall survival (OS) data were immature and inconclusive due to a low number of events (n=24/86; 1-y OS probability 87.0% vs. 84.6% [95% CI 0.47-2.38] with lenvatinib + everolimus vs. cabozantinib, respectively. Discontinuation rates due to toxicity were 20% with lenvatinib + everolimus and 10.9% with cabozantinib.
In this randomized phase II trial in metastatic ccRCC that progressed on prior PD-1 ICIs, lenvatinib + everolimus significantly prolonged PFS over cabozantinib. As the first head-to-head comparison of contemporary second-line or later treatments after ICI, these results are relevant to treatment sequencing and inform oncology practice.
Annals of oncology : official journal of the European Society for Medical Oncology. 2025 Oct 18 [Epub ahead of print]
A W Hahn, J Chahoud, W P Skelton, Y Yuan, A J Zurita, C Kovitz, O Alhalabi, M T Campbell, E Jonasch, J Lin, M Desai, M J M N Santos, H Hwang, P G Corn, P Msaouel, N M Tannir
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA. Electronic address: ., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41115467
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