New breakthroughs and future trends in renal cell carcinoma therapy: Highlights from the 2025 European Society for Medical Oncology Annual Congress

Abstract

The 2025 European Society for Medical Oncology Annual Meeting unveiled pivotal advances across the therapeutic spectrum of renal cell carcinoma, marking a decisive shift towards precision medicine. In localized disease, adjuvant therapy is being refined through risk stratification, as demonstrated by the RAMPART trial, which showed significant benefit for dual immune-checkpoint inhibition specifically in high-risk patients. The Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer study further demonstrated that even a short course of neoadjuvant dual immunotherapy could induce meaningful pathological responses in locally advanced clear-cell renal cell carcinoma. For advanced stages, the treatment paradigm is rapidly evolving beyond standard immuno-tyrosine kinase inhibitor combinations. Investigational triple therapies, such as adding a hypoxia-inducible factor 2-alpha inhibitor to first-line regimens, show promise for deeper and more durable responses. A central theme of the conference was the parallel development of predictive biomarkers—including molecular classifiers, dynamic plasma markers, tumor microenvironment signatures, and AI-based histology analysis—to guide individualized treatment selection and avoid ineffective therapy. Following disease progression on first-line treatment, the management landscape is expanding with new evidence from direct comparative trials (e.g., LenCabo), novel drug combinations, and emerging modalities like stereotactic radiotherapy.

Key Words: Renal cell carcinoma; Precision medicine; European Society for Medical Oncology 2025; Immunotherapy; Biomarkers

Core Tip: This timely review synthesizes pivotal advances in renal cell carcinoma management presented at the 2025 European Society for Medical Oncology Annual Congress. It highlights the shift towards precision medicine, evidenced by risk-stratified adjuvant immune checkpoint inhibitor therapy, promising short-course neoadjuvant immune checkpoint inhibitor strategies, and the evolution towards triple-combination regimens in advanced disease. A parallel focus is the critical development of predictive biomarkers—from molecular classifiers to artificial intelligence-based pathology tools—to guide individualized treatment selection and optimize outcomes across the disease spectrum, marking a decisive move beyond a one-size-fits-all therapeutic approach.

INTRODUCTION

The 2025 European Society for Medical Oncology (ESMO) Annual Congress served as a critical platform for disseminating transformative research in oncology, with renal cell carcinoma (RCC) representing a particularly dynamic field. Numerous studies spanning the disease continuum, from localized to advanced stages, were presented, reflecting a period of accelerated therapeutic innovation. Notably, several key studies were highlighted as late-breaking abstracts, underscoring their potential to immediately influence clinical paradigms and future research directions. Furthermore, the presented advancements collectively signal a decisive evolution in RCC management, characterized by a decisive shift away from uniform strategies. A central theme emerging from the congress is the prioritization of precision medicine, where therapeutic intensity and mechanism are increasingly tailored to individual tumor biology and patient-specific risk profiles. This trend is evident across perioperative strategies, frontline metastatic treatment intensification, and the development of novel agents for resistant disease.

Consequently, this review aims to synthesize the most pivotal findings presented at the ESMO 2025 Congress that are poised to reshape clinical practice. The focus will be placed on key studies demonstrating risk-adapted therapeutic strategies, novel drug combinations with deepened efficacy, and the parallel development of sophisticated predictive biomarkers (Table 1). By contextualizing these updates, this article seeks to provide a concise overview of the current trajectory in RCC care and its implications for achieving more personalized and effective patient management.

Table 1 Summary of key studies on renal cell carcinoma at the European Society for Medical Oncology 2025 Congress.

Ref.	Study name	Study design	Main findings
Burgers et al[3], 2025	NESCIO	Phase II randomized controlled trial	The ipilimumab plus nivolumab group and the relatlimab plus nivolumab group both met the prespecified primary endpoint of pathologic response, demonstrating clear antitumor activity, with the short-course (6-week) therapy being well-tolerated
Haake et al[6], 2025	OPTIC RCC	Prospective phase II multicenter study	Targeted immunotherapy based on molecular subtypes achieved a higher ORR in the selected population compared to historical controls (nivolumab plus cabozantinib) (75% vs 55%)
Hahn et al[20], 2025	LenCabo	Multicenter phase II randomized controlled trial	Lenvatinib plus everolimus vs cabozantinib monotherapy: Superior median PFS (15.7 months vs 10.2 months), reducing disease progression risk by 49% (HR = 0.51); higher ORR (52.6% vs 38.6%); but higher incidence of grade ≥ 3 adverse events (67.5% vs 50.0%)
Huang et al[25], 2025	Dynamic ctDNA-MRD Monitoring	Cohort study	ctDNA levels decreased significantly after treatment; patients with persistently negative MRD had a lower risk of disease progression, and their median PFS was significantly longer than that of MRD-positive patients (not reached vs 14 months)
Huang et al[23], 2025	CLEAR-IT	Phase II study	Cadonilimab plus lenvatinib in patients progressing on prior immunotherapy: ORR was 29%, DCR was 96%, median PFS was 16.8 months, with a low incidence of grade ≥ 3 TRAEs (12.5%)
Kim et al[10], 2025	AI-based Immune Phenotype Analysis Model	Cohort study	Patients with an “inflammatory” phenotype had significantly better PFS, OS, and ORR with dual immunotherapy (nivolumab plus ipilimumab) than with sunitinib, while no significant difference in efficacy was observed between the two treatments in patients with a “non-inflammatory” phenotype
Larkin et al[2], 2025	RAMPART	Phase III randomized controlled trial	Durvalumab plus tremelimumab vs active surveillance significantly improved DFS in the overall population (2-year DFS rate: 81% vs 73%); the significant benefit was entirely driven by the high-risk recurrence population (HR = 0.52), with no clear benefit observed in the intermediate-risk group
Machaalani et al[9], 2025	Soluble MAdCAM-1 Translational Study	Cohort study	Higher baseline plasma soluble MAdCAM-1 (sMAdCAM-1) levels were independently associated with longer PFS and OS
Seront et al[24], 2025	RENALUT	Multicenter, open-label phase II trial	First exploration of 177Lu-PSMA-617 radioligand therapy in RCC resistant to both TKIs and ICIs; the study is ongoing, and results are pending
Simsek et al[8], 2025	COSMIC-313	Randomized controlled trial	Density of a specific CD8+ T-cell subset (CD8+ PD-1 + TIM-3-LAG-3 TILs) significantly correlated with efficacy: The high-density group had an ORR of 60.4% and median PFS was not reached; the low-density group had an ORR of 37.9% and median PFS was only 9.3 months
Ye et al[26], 2025	FRUSICA-2	Phase III randomized controlled trial	Compared to standard second-line monotherapy (axitinib or everolimus), the combination regimen significantly extended median PFS to 22.21 months (vs 6.90 months) and increased ORR to 60.5% (vs 24.3%), without increasing treatment-related death risk

NESCIO: Neoadjuvant Immuno-Oncology Trial in Localized Renal Cell Carcinoma; OPTIC RCC: OPtimal Treatment by Invoking biologic Clusters in Renal Cell Carcinoma; ORR: Overall response rate; PFS: Progression-free survival; HR: Hazard ratio; ctDNA-MRD: Circulating tumor DNA-minimal residual disease; CLEAR-IT: Clear Cell Renal Cell Carcinoma Immunotherapy Trial; DCR: Disease control rate; TRAEs: Treatment-related adverse events; OS: Overall survival; RAMPART: Durvalumab Plus Tremelimumab Versus Placebo in the Adjuvant Treatment of High-Risk Renal Cell Carcinoma; DFS: Disease-Free Survival; MAdCAM-1: Mucosal addressin cell adhesion molecule-1; RENALUT: Renal Cell Carcinoma PSMA-Targeted Therapy Trial; TKIs: Tyrosine kinase inhibitors; ICIs: Immune checkpoint inhibitors; COSMIC-313: Cabozantinib, Nivolumab, and Ipilimumab Versus Cabozantinib and Nivolumab in Advanced Renal Cell Carcinoma; FRUSICA-2: Fruquintinib Plus Sintilimab in Previously Treated Advanced Renal Cell Carcinoma.

PRECISION STRATEGIES IN PERIOPERATIVE MANAGEMENT

The management of localized RCC is undergoing a significant transformation, moving decisively away from uniform postoperative strategies towards a more nuanced, stage-specific, and biologically informed approach[1]. This evolution is characterized by two key developments presented at the ESMO 2025 Congress: The validation of risk-adapted adjuvant therapy to prevent overtreatment and the exploration of short-course neoadjuvant immunotherapy as a strategy for in vivo sensitivity assessment and tumor downstaging.

The paradigm for adjuvant therapy in resected RCC was rigorously refined by the results of the RAMPART trial, a large international phase III study[2]. This investigation evaluated adjuvant durvalumab, both as monotherapy and in combination with tremelimumab, compared to active surveillance in patients with resected primary RCC at increased risk of recurrence. For the overall study population, a statistically significant improvement in disease-free survival (DFS) was observed with the dual immune checkpoint inhibitor (ICI) strategy[2]. However, the most critical and practice-changing insight was derived from a pre-specified subgroup analysis, which demonstrated that the clinical benefit was exclusively driven by patients classified as having a very high risk of recurrence (Leibovich score 6-11), while those with intermediate-risk disease (Leibovich score 3-5) derived no significant disease-free survival advantage[2]. Consequently, this finding establishes a new, risk-adapted standard for adjuvant decision-making, strongly advocating for the selective use of intensive dual ICI therapy specifically in the highest-risk subgroup. This approach directly addresses longstanding clinical debates regarding patient selection, economic burden, and the generalizability of earlier trial results, thereby minimizing overtreatment and associated toxicities in patients unlikely to benefit.

Simultaneously, interest has grown in the potential of systemic therapy administered before surgery. The feasibility and biological activity of an ultra-short course neoadjuvant approach were compellingly demonstrated by the randomized phase II Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer (NESCIO) trial in locally advanced clear-cell RCC (ccRCC)[3]. In this study, patients were randomized to receive only six weeks of preoperative immunotherapy with either nivolumab monotherapy, nivolumab combined with ipilimumab, or nivolumab combined with relatlimab. The primary endpoint of pathological response was successfully met in the dual ICI combination arms, confirming that even a brief preoperative exposure can induce measurable tumor regression[3]. This strategy offers a critical in vivo “window” to assess intrinsic tumor sensitivity to specific immunologic agents, information that could potentially guide postoperative adjuvant therapy decisions. Furthermore, the superior activity observed with dual ICI regimens over monotherapy suggests that a more potent immunologic activation can be achieved preoperatively[3]. While these initial results are promising and support the feasibility of this short-course model, they also underscore the necessity for subsequent larger phase III trials. Future research must confirm clinical efficacy endpoints such as recurrence-free survival, refine optimal patient selection through predictive biomarkers, and determine the best integration of this neoadjuvant strategy into comprehensive, multimodal treatment plans for high-risk localized RCC.

Collectively, the data from the RAMPART and NESCIO trials signify a maturation of perioperative RCC management. The field is now firmly oriented towards precision intervention, where the intensity and timing of therapy—whether adjuvant or neoadjuvant—are increasingly tailored to individual tumor biology and refined risk estimates, aiming to maximize therapeutic benefit while minimizing unnecessary treatment exposure.

INTENSIFICATION AND PERSONALIZATION IN ADVANCED FIRST-LINE THERAPY

Following the refinement of perioperative strategies, the evolution of first-line treatment for advanced ccRCC is being shaped by two interdependent trends: The escalation towards triple-combination regimens and the parallel development of sophisticated biomarkers for treatment personalization. This dual progression aims to deepen therapeutic efficacy while ensuring that intensified therapies are directed towards the patients most likely to benefit from them.

Efforts to build upon the established standard of ICI plus tyrosine kinase inhibitor (TKI) combinations have led to the exploration of adding a third agent with a complementary mechanism. This strategy was notably evaluated in the phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With Renal Cell Carcinoma (KEYMAKER-U03) substudy, which investigated several pembrolizumab-based triple combinations in systemic therapy-naïve patients with advanced ccRCC meeting protocol-defined criteria, including adequate organ function and controlled blood pressure[4]. The regimen incorporating the hypoxia-inducible factor 2-alpha inhibitor belzutifan with pembrolizumab and lenvatinib delivered compelling results, demonstrating a similar objective response rate to historical dual therapies but with a doubled complete response rate and a substantially prolonged median progression-free survival[4]. This regimen was associated with grade 3 or higher treatment-related adverse events in 70% of patients, an incidence comparable to that of the reference dual-therapy arm[4]. This provides preliminary high-grade evidence that first-line triple-combination therapy can yield deeper and more durable disease control. This effectively propels the treatment paradigm towards a more intensive three-drug era, pending confirmation from ongoing phase III trials[5].

Concurrently, significant advances were reported in the realm of predictive biomarkers, which are essential for guiding individualized regimen selection. This pursuit spans multiple analytical levels. Molecular classifiers, such as the RNA sequencing-based model used in the OPtimal Treatment by Invoking biologic Clusters in Renal Cell Carcinoma trial to assign therapy, aim to align treatment with intrinsic tumor biology[6]. Dynamic plasma biomarkers offer another dimension; for example, an early decline in kidney injury molecule-1 levels was shown to predict improved outcomes specifically for dual ICI therapy but not for a triple-combination regimen, highlighting its context-dependent utility[7,8]. Furthermore, the baseline level of soluble mucosal addressin cell adhesion molecule-1 was validated as an independent prognostic factor across multiple trial cohorts, reflecting the influence of the gut-immune axis[9]. At the tissue level, the density of specific, less-exhausted CD8+ T-cell subsets within the tumor microenvironment (TME) was identified as a powerful predictor of response to dual ICI[8]. Finally, the application of artificial intelligence (AI) to routine histopathology presents a scalable tool, as demonstrated by a model that accurately categorized tumors from hematoxylin and eosin-stained slides into “inflamed” and “non-inflamed” phenotypes, with the former predicting superior benefit from dual ICI over sunitinib[10]. Collectively, these developments in molecular subtyping, liquid biopsy, tissue immunophenotyping, and computational pathology are constructing a multi-dimensional framework[11-13]. The convergent goal is to precisely match patients with the specific therapeutic mechanism, whether dual ICI, immuno-TKI, or triple therapy is most likely to induce a durable response, thereby optimizing the risk-benefit ratio of increasingly potent frontline options.

It must be acknowledged that the direct, cross-trial comparison of the efficacy, optimal patient populations, and cost-effectiveness of different advanced first-line regimens (e.g., dual immuno-TKI vs triple therapy) remains challenging based on the current congress data. The studies presented, such as KEYMAKER-U03, provide pivotal evidence within their own contexts but were not designed for head-to-head comparisons. Definitive conclusions regarding superior efficacy in biomarker-defined subgroups or economic evaluations await the final publication of mature trial results. Future research priorities should include dedicated randomized comparisons and comprehensive meta-analyses once more complete datasets are available. This review serves to synthesize these emerging, practice-informing signals from the ESMO 2025 Congress, highlighting the expanding arsenal and the imperative for biomarker-guided selection, while recognizing that the framework for definitive regimen comparison is still under construction.

EVOLVING LANDSCAPE FOR FIRST-LINE THERAPY RESISTANT RCC

An understanding of the core biological mechanisms driving resistance to first-line regimens provides the essential rationale for developing subsequent therapeutic strategies. Resistance to ICI-based therapy is broadly categorized into mechanisms intrinsic to tumor cells (e.g., alterations in antigen presentation machinery) and extrinsic mechanisms mediated by the TME, such as the recruitment of immunosuppressive cells or the upregulation of alternative immune checkpoints[14]. A pivotal TME-mediated pathway involves SPP1-CD44 signaling, which disrupts antigen presentation in effector cells and exacerbates CD8+ T-cell exhaustion through mitogen-activated protein kinase pathway activation, thereby driving primary ICI resistance[15]. Additionally, the programmed death-ligand 1 protein itself can initiate intrinsic signaling; antibody-mediated crosslinking can activate a SOX10-MITF-GPNMB cascade, promoting an immunosuppressive and angiogenic TME that facilitates acquired resistance[16].

Regarding resistance to TKIs, mechanisms extend beyond vascular endothelial growth factor signaling pathway reactivation to include the activation of alternative pro-angiogenic or proliferative signaling pathways[14]. For instance, resistance to cabozantinib can be driven by the secretion of non-vascular endothelial growth factor factors like platelet-derived growth factor-BB, interleukin-8, and chemokine (C-C motif) ligand 2[14,17,18]. Similarly, lenvatinib resistance is associated with the activation of bypass pathways such as epidermal growth factor receptor-p21-activated kinase 2-extracellular signal-regulated kinase[14]. Targetable mutations and epigenetic alterations also play a critical role, as evidenced by increased expression of nuclear protein 1 in axitinib-resistant cells[14]. These multifaceted mechanisms collectively underscore the complexity of overcoming treatment resistance and inform the design of the novel agents and combinations discussed in the following sections.

Despite significant advancements in first-line treatment, disease progression remains a common challenge, necessitating the development of effective subsequent therapies. The management of advanced ccRCC after progression on frontline ICI-based regimens is therefore an area of intense research and evolution, focusing on both optimizing existing drug classes and introducing novel agents with distinct mechanisms of action[19].

High-quality comparative evidence to guide treatment selection after ICI failure has been historically scarce. This gap was directly addressed by the LenCabo trial, a randomized multicenter phase II study that provided the first head-to-head comparison between the combination of lenvatinib plus everolimus and cabozantinib monotherapy in this specific patient population[20]. The combination arm demonstrated a statistically significant improvement in median progression-free survival and a higher objective response rate compared to monotherapy[20]. This finding provides pivotal level II evidence supporting the use of a lenvatinib-based combination as a potentially more effective strategy than cabozantinib alone following ICI progression. However, this enhanced efficacy was accompanied by a higher incidence of grade 3 or higher adverse events, underscoring the critical need for meticulous toxicity management when employing this regimen[20]. This trade-off highlights the importance of personalized decision-making, balancing anticipated efficacy against individual patient tolerance and comorbidities.

Concurrently, novel therapeutic mechanisms are being explored to overcome resistance. Promising activity has been reported with innovative immuno-oncology constructs, such as the programmed death-ligand 1/cytotoxic T-lymphocyte-associated protein 4 bispecific antibody cadonilimab[21,22]. When combined with lenvatinib in the phase II CLEAR-IT study involving patients whose disease had progressed on prior immunotherapy, this regimen demonstrated encouraging antitumor activity and a manageable safety profile, suggesting a potential to re-sensitize tumors to immune attack[23]. Furthermore, entirely new treatment modalities are entering clinical investigation. Targeted radioligand therapy represents a paradigm shift by leveraging specific tumor antigens for precise radiation delivery. The pioneering EORTC-2361-GUCG RENALUT trial is evaluating the efficacy and safety of ¹⁷⁷Lu-PSMA-617 in patients with metastatic ccRCC resistant to both TKIs and ICIs, who are selected based on prostate-specific membrane antigen positron emission tomography/computed tomography imaging[24]. Although final results are pending, the initiation of this trial formally introduces a mechanistically distinct option into the later-line treatment arsenal for RCC[24].

Collectively, the landscape for managing therapy-resistant RCC is expanding beyond sequential TKI monotherapy. It is now characterized by a dual approach: The optimization of combination strategies using existing agents, guided by emerging comparative evidence, and the introduction of novel drug classes and treatment modalities that operate through fundamentally different mechanisms. This evolution offers renewed hope for extending survival and maintaining disease control in patients who have exhausted standard frontline options.

FUTURE PERSPECTIVES: INTEGRATION AND IMPLEMENTATION

As the therapeutic arsenal for RCC expands across all disease stages, including novel options for resistant disease, the central challenge now evolves from drug development to the precise and effective implementation of these strategies. The collective evidence presented at the ESMO 2025 Congress converges on a clear future direction, characterized by three dominant and interconnected trends: A shift towards earlier intervention, the intensification of treatment regimens, and a paramount focus on precision matching. The move towards earlier intervention is exemplified by the risk-stratified adjuvant approach validated in the RAMPART trial for very high-risk patients and the exploratory short-course neoadjuvant model tested in the NESCIO study[2,3]. In advanced disease, intensification is vividly illustrated by the progression from doublet to triplet combinations, as seen in the KEYMAKER-U03 substudy, where adding a hypoxia-inducible factor 2-alpha inhibitor to a standard backbone yielded deeper and more durable responses[4]. Most critically, the trend of precision matching is underscored by a plethora of biomarker studies, ranging from molecular classifiers and dynamic plasma markers to AI-based histopathology models, all aimed at aligning therapy with individual tumor biology[6,8-10].

However, the translation of these promising trends into routine clinical practice is accompanied by significant and multifaceted challenges. A primary hurdle is the effective integration of complex, multi-dimensional data. While distinct biomarkers from various sources, including genomic, transcriptomic, proteomic, and histologic data, have shown individual promise, a unified framework for synthesizing these multi-omics datasets into a clinically actionable algorithm is still lacking[6,8,9]. Furthermore, the validation and standardization of novel tools are imperative. Dynamic biomarkers, such as circulating tumor DNA for minimal residual disease monitoring, require rigorous analytical and clinical validation across platforms and prospective confirmation of their utility in guiding real-time therapy adjustments[25]. Similarly, AI-based diagnostic tools necessitate extensive external validation and standardization to ensure reproducibility, generalizability, and equitable access across diverse healthcare settings[10]. The translation of these biomarkers into reliable clinical tools faces additional practical challenges. For molecular classifiers and dynamic plasma markers, key hurdles include the establishment of standardized, cross-platform assay protocols and the definition of validated clinical cut-off values. The clinical application of AI-based pathology models is further complicated by requirements for standardized digital slide acquisition, computational infrastructure, and consistent model training across institutions. These technical and procedural barriers contribute to significant accessibility differences between well-resourced and community medical centers, potentially limiting equitable patient access to precision guidance. Additionally, the economic implications and systemic logistics of deploying advanced molecular profiling and complex treatment regimens must be addressed to ensure broad and equitable patient access.

Therefore, the overarching goal for the next era of RCC management is the realization of a truly adaptive and individualized therapy paradigm, where treatment decisions are continuously optimized to maximize long-term efficacy while preserving quality of life. Achieving this goal requires a concerted, parallel effort on several fronts. Research must focus on refining predictive models by integrating clinical risk factors with dynamic multi-omics data streams. Therapeutic development should strategically explore novel combinations and sequencing to overcome resistance while improving tolerability profiles[4,20,23]. Crucially, the oncology community must prioritize the development of robust clinical utility frameworks for novel biomarkers and invest in the infrastructure needed for their standardized application. The incorporation of real-world evidence will also be vital to understanding long-term outcomes and optimal sequencing in broader populations. By successfully navigating these challenges of integration, validation, and implementation, the field can translate the exciting research presented at the ESMO 2025 Congress into a more nuanced, effective, and patient-centric standard of care for all individuals with RCC.

Ultimately, the most defining theme of the conference was the synergistic convergence of therapeutic innovation and biomarker development. The introduction of more effective and mechanistically diverse treatments provides the tools for improved outcomes, while advances in molecular classification, dynamic monitoring, and AI-enabled diagnostics offer the essential roadmap for their precise application. This interdependent progress underscores that the future of RCC care lies not in a single breakthrough but in the integrated implementation of complementary advances. The continued parallel development and clinical integration of novel therapeutics with validated predictive tools will be fundamental to realizing the goal of truly individualized therapy, optimizing efficacy and tolerability for each patient throughout their disease course.

CONCLUSION

In summary, the ESMO 2025 Congress has highlighted decisive shifts in the management of RCC, collectively steering the field toward a more proactive, potent, and personalized paradigm. The evolution is evident across the entire disease continuum. In localized disease, therapeutic intervention is being refined and strategically timed, with adjuvant therapy guided by robust risk stratification to avoid overtreatment and neoadjuvant strategies explored for biological insight and tumor downstaging[2,3]. For advanced stages, the treatment landscape is being reshaped by the intensification of frontline regimens, including promising triple-drug combinations, and is increasingly guided by a sophisticated array of predictive biomarkers derived from molecular, tissue, and imaging data[4,6,8-10]. Furthermore, the therapeutic options for resistant disease are expanding beyond sequential monotherapy to include optimized targeted combinations and novel mechanism-based approaches, offering new avenues after progression on standard agents[20,23,24,26].