The Evolving Landscape of Refractory Renal Cell Carcinoma
May 14, 2026
Key Points
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Immune checkpoint inhibitor rechallenge does not improve progression-free survival (PFS) or overall survival (OS) in refractory clear cell renal cell carcinoma and should not be routinely used after frontline IO-based therapy.
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VEGF TKIs remain the backbone of second-line treatment, offering meaningful antitumor activity and durability despite limitations related to resistance and toxicity.
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Combination regimens improve response rates and PFS but increase toxicity and have not demonstrated an OS benefit.
First-line treatment for clear cell renal cell carcinoma (ccRCC) typically incorporates combination anti–PD-1 therapy with either ipilimumab (IO/IO) or vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (IO/TKIs) that have markedly improved response rates, progression-free survival (PFS), and overall survival (OS) compared with VEGF TKIs alone.1,2,3,4 Although some patients experience sustained antitumor responses, resistance is common, highlighting the need for effective subsequent therapies. Refractory ccRCC treatment has historically relied on single-agent VEGF TKIs that have demonstrated antitumor shrinkage benefits but are limited by resistance and chronic toxicities. More recent clinical trials for patients with refractory ccRCC have investigated the role of combination VEGF TKIs with anti–PD-1/PD-L1, hypoxia-inducible factor-2α (HIF-2α), and mechanistic target of rapamycin (mTOR) inhibition.
Combination VEGF TKI and Anti–PD-1/PD-Lin Refractory RCC
CONTACT-03 was a phase 3 trial that randomized patients with RCC who had received prior immune checkpoint inhibitor (ICI) therapy as their most recent therapy to cabozantinib 60 mg plus atezolizumab 1200 mg every 3 weeks or cabozantinib 60 mg.5
There was no improvement in PFS or OS, and higher rates of serious adverse events (AEs) were observed in the combination arm. Cabozantinib monotherapy demonstrated robust antitumor activity with an overall response rate (ORR) of 41% and progressive disease (PD) in 5% of patients, with durability of median PFS of 10.8 months, and duration of response (DOR) of 14.8 months. Although there were grade 3-4 treatment-related adverse events (TRAEs, 47%), a majority were managed with dose reductions, and the discontinuation rate was 4%.
Ti-Nivo2 was a phase 3 trial that randomized patients with RCC who had progressed following 1 to 2 lines of therapy in the post-ICI setting to tivozanib 0.89 mg plus nivolumab 480 mg every 4 weeks (Tivo/Nivo) or tivozanib 1.34 mg.6 There was no improvement in PFS or OS between treatment arms, and similar rates of serious AEs were observed despite different doses of tivozanib between arms. Tivozanib monotherapy demonstrated modest antitumor activity with an ORR of 20% and PD in 25% of patients with durability of mPFS 7.4 months. Although there were grade 3-4 TRAEs (35%), a majority were managed with dose reductions and a low rate of discontinuation at 19%. Among patients treated in the second-line setting, mPFS was 7.3 months with Tivo/Nivo and 9.2 months with tivozanib (HR, 1·15; 95% CI, 0·82–1·62).
Taken together, the results of CONTACT-03 and TiNivo2 demonstrate that patients with ccRCC who experience disease progression on first-line IO/IO or IO/TKI regimens should not routinely receive subsequent ICI therapy. These studies reinforce the role of VEGF TKIs for the management of refractory ccRCC with antitumor benefit that must be balanced with TRAEs, which often require dose modification.
HIF-2α Inhibition in Refractory ccRCC
LITESPARK-005 was a phase 3 trial that randomized patients with ccRCC with 1 to 3 prior therapies, including anti–PD-1/PD-L1 and VEGF TKI therapy, to belzutifan 120 mg or everolimus 10 mg.7 Belzutifan was associated with improvements in ORR (22.7% vs 3.9%), PFS (HR, 0.75; 95% CI, 0.63-0.88), and DOR (19.3 months vs 13.7 months) but not OS (HR, 0.92; 95% CI, 0.77-1.10) relative to everolimus. However, belzutifan showed a high rate of PD (34%) and grade 3-4 anemia (33%) and hypoxia (10.5%) requiring dose reduction, erythropoiesis-stimulating agents or supplemental oxygen. There are no biomarkers to select which patients optimally benefit from belzutifan. However, caution should be exercised in patients with refractory ccRCC who have symptomatic disease and those with underlying anemia or hypoxia.
Combination VEGF TKI and HIF-2α or mTOR inhibition in Refractory RCC
LenCabo was an investigator-initiated phase 2 trial that randomized patients with RCC previously treated with 1 to 2 lines of therapy, including PD-1 ICI, to lenvatinib 18 mg plus everolimus 5 mg (Len/Eve) or cabozantinib 60 mg.8 The combination of Len/Eve demonstrated improvements in ORR (53% vs 39%) and PFS (14.8 months vs 10.7 months) relative to cabozantinib. Len/Eve was associated with higher rates of grade 3-4 TRAE and discontinuations whereas Cabo had higher rates of dose reductions. LenCabo was the first trial in refractory RCC to demonstrate combination VEGF TKI plus mTOR inhibition improved outcomes relative to VEGF TKI alone. Although Len/Eve was initially FDA-approved for refractory RCC in 2016 based on a PFS benefit relative to everolimus, the results of LenCab reinforce its role compared with a more modern comparator, Cabo.
LITESPARK-011 was a phase 3 trial that randomized patients with ccRCC progressing after anti–PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy to lenvatinib 20 mg plus belzutifan 120 mg or cabozantinib 60 mg.9 The combination was associated with improvements in ORR (53% vs 40%), PFS (14.8 months vs 10.7 months), and DOR (23 months vs 12.3 months) relative to Cabo. Len/Eve was associated with higher rates of grade 3-4 TRAE and similar rates of discontinuation. LITESPARK-011 was the first trial in refractory RCC to demonstrate combination VEGF TKI plus HIF-2α inhibition improved outcomes relative to VEGF TKI alone. In contrast to the high PD rate of 34% of belzutifan on LITESPARK-005, this combinationl demonstrated a low PD rate (6%), suggesting that belzutifan may be optimally paired with VEGF TKI to prevent early progression.
Taken together, the results of LenCabo and LITESPARK-011 demonstrate that lenvatinib combined with either everolimus or belzutifan improves ORR and PFS relative to cabozantinib. Despite these antitumor benefits, an OS benefit has not been observed in either study, and the combination regimens are associated with increased risk of AEs that require close monitoring and dose adjustments.
Future Directions for Refractory RCC
Over the past 5 years, the treatment of patients with refractory RCC has been shaped by several pivotal clinical trials. Despite the success of IO-based regimens in the frontline, IO rechallenge should not be routinely practiced for refractory RCC. While VEGF TKI therapies remain a critical component of refractory RCC management, there is emerging data that combination regimens with mTOR or HIF-2 inhibition are feasible and further improved outcomes albeit with higher toxicities. Several ongoing studies are investigating combination and sequential approaches using VEGF TKIs and HIF-2 inhibition. Although end points such as ORR and PFS are objective benchmarks of efficacy, these must be weighed against AE profiles and quality-of-life impact to optimize treatment selection.
References
1. Choueiri TK, Albiges, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2026;35(11):1026-1038. doi:10.1016/j.annonc.2026.02.017
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nat Med. 2025;31(10):3475-3484. doi:10.1038/s41591-025-03867-5
3. Motzer R J, Escudier B, Burotto M, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2025;37(1):33-43. doi:10.1016/j.annonc.2025.09.006
4. 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
5. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4
6. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6
7. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906
8. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear-cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2025;37(2):241-249. doi:10.1016/j.annonc.2025.10.009
9. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L) 1 therapy: Open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(7). doi:10.1200/JCO.2026.44.7_suppl.LBA417
Table 1: Selected Trials in Refractory RCC
