A number of trials presented during the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany, provided clearer direction on treatment sequencing in renal cell carcinoma (RCC). First-line treatment for metastatic RCC focuses on immunotherapy-based approaches, such as dual immunotherapies or a combination of immunotherapy plus a tyrosine kinase inhibitor (TKI). Once the disease progresses, however, the clinical picture gets a little murkier.

“We have 4 options to choose from when patients experience disease progression on first-line treatment options,” Andrew W. Hahn, MD, said during an interview with Targeted Therapies in Oncology. “There is not a lot of clarity about what’s the right next treatment to choose.” Hahn is an assistant professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Overall, the choice of treatment is determined by such factors as the International Metastatic RCC Database Consortium (IMDC) risk score, functional status, safety profiles, sarcomatoid features, use of immunosuppressive drugs, and need for immediate response.¹

Currently, standardized second-line approaches remain unmet. TKIs, either alone or paired with everolimus, show promising benefit, whereas HIF-2α inhibitors, such as belzutifan (Welireg), have offered newer options for consideration.

LenCabo Trial

As the first head-to-head randomized trial comparing contemporary second-line treatments after progression on immune checkpoint inhibitors (ICIs), the LenCabo trial (NCT05012371) provides important data relevant to treatment sequencing that inform oncology practice.

Ninety patients with metastatic clear cell RCC (ccRCC) who were treated with a prior PD-1 or PD-L1 ICI were randomly assigned to receive either 18 mg lenvatinib (Lenvima) and 5 mg of everolimus (n = 43) or 60 mg of cabozantinib (Cabometyx; n = 47).

“We hypothesized that lenvatinib plus everolimus would outperform cabozantinib alone for progression-free survival [PFS],” said lead author Hahn, who presented the data during ESMO Congress 2025.²

Patients were stratified by IMDC risk group and prior receipt of VEGF-targeted therapy; the primary end point was PFS, and secondary end points were objective response rate (ORR), safety, and overall survival (OS).

The median age for all patients was 64 years (range, 60.0-68.0). In the lenvatinib/everolimus arm, the median age was 65 years (range, 59.7-70.0), and in the cabozantinib arm, the median age was 64 years (range, 60.2-66.0). Across the groups, the majority of patients had received 1 prior line of therapy (69.8%, 65%, and 73.9%, respectively), although the majority had not received prior VEGF-targeted therapy (56.9%, 55%, and 58.7%, respectively).

The median PFS for the lenvatinib/everolimus group was 15.7 months compared with 10.2 months for the cabozantinib group (HR, 0.51; 95% CI, 0.29-0.89; P = .02).²

A number of secondary end points were also evaluated. The ORR for the lenvatinib/everolimus arm was 53% compared with 39% for the lenvatinib arm, but this was not statistically significant or significantly different between the 2 treatment arms. After a median follow-up of 20 months (IQR, 14.9-22.5), 27.9% of patients had died, with 27.5% in the treatment arm and 28.3% in the control arm. “The OS [data] are immature and inconclusive at this point,” Hahn said.

“What’s encouraging about our findings for patients is that very few patients experienced primary disease progression when they were receiving either of these treatments,” Hahn said. “These are pretty active treatment arms.”

Regarding safety findings, 27.5% of patients in the treatment arm (n = 40) experienced serious adverse events (AEs) vs 19.6% of patients in the control arm (n = 46; OR, 1.56; 95% CI, 0.57-4.24). Just over two-thirds of patients (67.5%) in the treatment arm had grade 3/4 AEs compared with half (50%) of patients in the control arm (OR, 2.08; 95% CI, 0.86-5.02). Twenty percent of patients in the treatment arm discontinued treatment compared with 10.9% in the control arm (OR, 2.05; 95% CI, 0.61-6.91).

In the treatment arm, the top treatment-related AEs were fatigue (72.5%), diarrhea (70%), and proteinuria (65%). In the control arm, top treatment-related AEs were diarrhea (73.0%), fatigue (73.9%), and palmar-plantar erythrodysesthesia syndrome (52.2%).

“Community oncologists should see that among angiogenesis-targeted therapies, [the combination of] lenvatinib plus everolimus seems to have the most activity,” Hahn said. “If we conducted this experiment 10 times, we would consistently see lenvatinib/everolimus outperform cabozantinib. The difference is clinically meaningful.”

Highlighting other presentations focused on RCC that were presented at ESMO Congress 2025, Hahn discussed the phase 1/2 KEYMAKER-U03 trial (NCT04626479) and phase 2 OPTIC RCC trial (NCT05361720).

KEYMAKER-U03 trial

In this trial, the triplet regimen of belzutifan, pembrolizumab (Keytruda), and lenvatinib demonstrated promising efficacy in patients with advanced ccRCC, outperforming 4 other regimens to determine the role of different belzutifan and pembrolizumab combinations in the first-line setting.³

The current standard is pembrolizumab plus lenvatinib, but when belzutifan was added, “it produced a dramatic median PFS of 31.8 months [95% CI, 26.3-not reached] compared with 20.8 months [95% CI, 12.4-29.0] for the reference arm,” Hahn said. “OS was not reached for either arm.”

A total of 5 regimens were evaluated. Following a safety lead-in phase, patients were randomly assigned in a 2:1 fashion. Arm 1 included coformulated favezelimab/pembrolizumab 800 mg/200 mg intravenously every 3 weeks and lenvatinib 20 mg orally once daily.

Arm 2 included coformulated vibostolimab/pembrolizumab 200 mg/200 mg intravenously (IV) every 3 weeks plus belzutifan 120 mg orally once daily.

Arm 3 included coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV every 6 weeks plus lenvatinib 20 mg orally once daily.

Arm 4 included belzutifan 120 mg orally once daily plus pembrolizumab 400 mg IV every 6 weeks plus lenvatinib 20 mg orally once daily. A concurrent reference arm included pembrolizumab 400 mg IV every 6 weeks plus lenvatinib 20 mg orally once daily.

“Some of these regimens were disappointing and some were neutral,” Hahn said. “Although the cohorts were relatively small, arm 4 experienced a 55% reduction in the hazard for disease progression compared with standard care.”

Hahn noted that giving triplet regimens can be challenging and that questions about toxicity will need to be addressed, but these were promising findings from an efficacy perspective.

The phase 3 LITESPARK-012 study (NCT04736706) will evaluate the combination of pembrolizumab plus lenvatinib and the combination of quavonlimab/pembrolizumab plus lenvatinib. “We are eagerly awaiting the results of this study,” Hahn said.

OPTIC-RCC

The OPTIC-RCC trial revealed promising outcomes in patients with angiogenic tumors who were treated with cabozantinib and nivolumab (Opdivo).

The trial determined whether the use of RNA sequencing (RNAseq)–defined clusters could be effectively used to select the best treatment for patients with metastatic ccRCC because primary and metastatic tumors can exhibit different gene expression signatures.⁴

The investigators hypothesized that selecting patients who exhibit an angiogenic gene expression signature enriches the clinical outcome for cabozantinib plus nivolumab. RNAseq-defined clusters were defined using a machine learning model from data collected from the IMmotion151 trial (NCT0242082).⁵

Patients in cluster 1/2, which demonstrated an angiogenic tumor, were treated with the combination of cabozantinib and nivolumab (n = 26). Cluster 4/5 remained open for accrual, whereas cluster 3/6/7 was excluded from the trial.

“Patients in this cluster saw improved objective response rates compared with historical controls, with an ORR of 71% and no patients experiencing progressive disease as their best response to treatment,” Hahn said. “That is great news for patients.”

Hahn was quick to emphasize that the findings by themselves would not be considered practice changing.

“Kidney cancer does not traditionally use genomic biomarkers to define treatment parameters,” Hahn said. “But it’s not from a lack of trying; it just hasn’t been successful.”

Patients were eligible for the OPTIC RCC trial if they had an ECOG performance score (PS) of 0 or 1, metastatic ccRCC without prior systemic therapy in any setting, and available tissue for RNA sequencing or cluster prediction.

ORR served as the primary end point, and secondary end points included PFS, a depth of response of 80% or more at 6 months, and immune-related AEs.

Of the 27 patients included in the analysis, patients had a median age of 68 years (range, 52-86) and the majority were men (56%), were White (89%), and had an ECOG PS of 0 (70%). Of note, 41% of patients were in the favorable-risk IMDC prognostic group.

“We shouldn’t be recommending that everyone get bulk RNAseq for patients with RCC at this point,” Hahn said. “But we are taking steps toward becoming biomarker informed and identifying biologically driven treatments.”

REFERENCES

1. Barragan-Carrillo R, Saad E, Saliby RM, et al. First and second-line treatments in metastatic renal cell carcinoma. Eur Urol. 2025;87(2):143-154. doi:10.1016/j.eururo.2024.10.019

2. Hahn AW, Chahoud J, Skelton W, et al. LenCabo: a randomized phase II multicenter trial of lenvatinib plus everolimus (len/eve) versus (vs) cabozantinib (cabo) in patients (pts) with metastatic clear cell RCC (ccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI). Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA94.

3. Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA96.

4. Haake SM, Beckermann K, Barata P, et al. Efficacy of cabozantinib and nivolumab in cluster 1/2 metastatic clear cell renal cell carcinoma: results from OPTIC RCC, a phase II trial of a novel RNAseq-based biomarker. Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 2591O.

5. Motzer RJ, Powles T, Atkins MB, et al. Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol. 2022;8(2):275-280. doi:10.1001/jamaoncol.2021.5981