https://doi.org/10.52733/KCJ23n2-e

Editorial Perspective:

The Future of RCC Treatment: A Deep Dive into ASCO 2025 Highlights

Thomas E. Hutson, DO, PharmD

Texas Tech University Health Science Center School of Medicine Lubbock, Texas 79415

Correspondence to: Thomas Hutson, DO, PharmD

Dear colleagues,

As the dust settles on another illuminating Ame- rican Society of Clinical Oncology (ASCO) Annual Meeting, held from May 30 to June 3 in Chicago, Illinois, the kidney cancer community reflects on a truly transformative year. ASCO 2025 has once again served as a pivotal platform, showca- sing groundbreaking research that promises to res- hape our understanding and management of renal cell carcinoma (RCC). The presentations highlighted below, drawn from the robust program of over 5,000 abstracts, represent significant steps toward impro- ving outcomes for patients with renal cell carcinoma (RCC) and addressing unmet needs in the field.

Novel Therapeutic Combinations:

Casdatifan and Cabozantinib

A key highlight in the kidney cancer space was Abstract 4506, presented during the Oral Abstract Session on Genitourinary Cancer—Kidney and Bladder on June 1, 2025. This phase 1 ARC-20 trial (NCT05536141) evaluated casdatifan, an orally bioavailable hypoxia-inducible factor 2-alpha (HIF- 2α) inhibitor, in combination with cabozantinib, a VEGFR-TKI, in previously treated patients with clear cell RCC (ccRCC). The study enrolled 27 patients with a median follow-up of 2.9 months, most of whom had received prior immunotherapy alone or in combination with anti-VEGF therapies. The combination demonstrated a promising objective response rate (ORR) of 41%, including one complete response and eight partial responses among the 22 efficacy-evaluable patients. Common adverse events included anemia (59%) and fatigue (56%), with grade ≥3 anemia occurring in 26% of patients. Notably, dose reductions were required in a subset of patients, but only one discontinued treatment due to hypoxia related to casdatifan. These early results suggest that targeting HIF-2α alongside VEGFR could offer a novel

therapeutic avenue for advanced ccRCC, warranting further investigation in larger trials.

Biomarker Research: Progress and Challenges

A standout session, “Biomarkers in Kidney Cancer: Are We There Yet?” held on June 1, 2025, in the Arie Crown Theater, provided a comprehensive review of the RCC biomarker landscape. Led by experts including W. Kimryn Rathmell, MD, PhD, and David F. McDermott, MD, the session explored predictive markers such as PD-L1, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), gene expression signatures, and microbiome insights. Despite significant advances, no validated biomarkers consistently predict treatment response across RCC subtypes. The discussion emphasized the need for integrated, multimodal strategies to develop reliable predictors, a critical step for personalizing therapy. For instance, Abstract 4511 from the CheckMate 9ER trial presented integrated biomarker analyses, including ctDNA and tumor microenvironment (TME) predictors, highlighting their potential to refine patient selection for immunotherapy and tyrosine kinase inhibitor (TKI) combinations. Similarly, Abstract 4509 from the NEOAVAX study offered insights into neoadjuvant signals, while Abstract 4510 from the IMmotion010 trial identified genomic drivers of relapse in high-risk localized RCC. These presentations underscore the complexity of RCC biology and the urgent need for collaborative efforts to translate biomarker research into clinical practice.

PDIGREE Trial: Adaptive Treatment Strategies

The PDIGREE trial (Abstract 4516), presented by Tian Zhang, MD, during the Rapid Oral Abstracts session on May 31, 2025, explored an adaptive treatment approach for advanced RCC. In Step 1, patients received nivolumab plus ipilimumab, with 33% discontinuing due to adverse events (44%) or progressive disease (13%). In Step 2, patients with stable disease or partial response were randomized to nivolumab alone or nivolumab plus cabozantinib. The trial’s design reflects a growing interest in tailoring therapy based on early treatment response, aiming to optimize outcomes while minimizing toxicity. Although 67% of patients progressed to Step 2, the presentation highlighted challenges in managing adverse events and disease progression, underscoring the need for better predictive tools to guide treatment escalation or de-escalation.

Redefining First-Line Strategies: The Evolving Landscape of Combination Therapies

A dominant theme at ASCO 2025 was the continued evolution and refinement of combination therapies in the first-line setting for advanced RCC. Updates from pivotal trials reinforced the sustained efficacy of immunotherapy (ICI) plus tyrosine kinase inhibitor (TKI) regimens. Long-term follow-up data from studies like CheckMate-9ER (nivolumab plus cabozantinib) continued to demonstrate impressive overall survival benefits and durable responses, solidifying their role as cornerstone treatments.

Perhaps even more compelling were the emerging insights into triplet therapies. The COSMIC-313 trial, combining cabozantinib, nivolumab, and ipilimumab, presented further data highlighting the potential for deeper and more sustained responses in specific patient populations. While acknowledging the increased complexity and potential for toxicity with such regimens, the discussions emphasized careful patient selection and proactive toxicity management as crucial for maximizing their benefit. The nuanced presentations provided invaluable guidance on identifying patients most likely to derive significant advantage from these intensified approaches.

CheckMate 214: Final Analysis

The final analysis of the CheckMate 214 trial (Abstract 4505), presented on June 1, 2025, provided long-term data on nivolumab plus ipilimumab versus sunitinib in patients with advanced ccRCC. This phase 3 study, discussed by Robert J. Motzer, MD, reinforced the sustained efficacy of the immunotherapy combination, demonstrating superior overall survival and durable responses compared to sunitinib. The presentation highlighted the depth of response, with patients achieving complete or near-complete responses showing significantly improved progression-free survival rates. These findings solidify nivolumab plus ipilimumab as a cornerstone of first-line treatment for intermediate- and poor-risk ccRCC, offering clinicians robust evidence to guide treatment decisions.

Non-Clear Cell RCC: Addressing an Unmet Need

Non-clear cell RCC, which accounts for 20-25% of kidney cancer diagnoses, remains challenging area due to poorer a survival outcomes compared to ccRCC. Insights from ASCO 2023, reiterated in 2025 discussions, emphasized the efficacy of lenvatinib plus pembrolizumab in this subtype. The KEYNOTE-B61 study, previously presented, reported an ORR of 50% and disease control in 82% of patients with non-clear cell RCC, with responses across papillary, chromophobe, and translocation subtypes. While no new non-clear cell RCC trials were highlighted in the 2025 program, the continued focus on this subgroup in biomarker and combination therapy discussions signals a commitment to addressing this unmet need.

Optimizing Adjuvant Care and Beyond

The discussions around adjuvant therapy continued to mature, with a focus on refining patient selection for pembrolizumab based on long- term data from KEYNOTE-564. Experts debated the optimal duration of therapy and strategies to mitigate toxicity while preserving efficacy. Furthermore, early-phase investigations into novel immune- based strategies, such as cytokine- induced memory-like (CIML) natural killer (NK) cells and personalized vaccine approaches, hinted at future directions for both localized and advanced disease settings, pushing the boundaries of immunotherapy.

Looking Ahead

The 2025 ASCO Annual Meeting has reinforced the dynamic evolution of kidney cancer research, with significant strides in biomarker development, novel therapeutic combinations, and adaptive treatment strategies. The presentations on casdatifan plus cabozantinib, the final CheckMate 214 analysis, and the PDIGREE trial highlight the field’s progress toward personalized, effective therapies. However, challenges remain, particularly in identifying validated biomarkers and optimizing treatments for non-clear cell RCC. As editor of the Kidney Cancer Journal, I, along with other members of the editorial board, am inspired by the dedication of researchers and clinicians worldwide. The insights gleaned from this meeting will undoubtedly catalyze further research, ultimately translating into tangible benefits for our patients. The future of kidney cancer treatment is indeed brighter than ever. As we move forward, the Kidney Cancer Journal encourages researchers, clinicians, and patient advocates to engage with these findings, available on the ASCO Meeting Library website, and to collaborate on translating these advances into meaningful clinical impact. The path to improving outcomes for kidney cancer patients is clearer, but there is still work to be done.

In this issue, you'll find an insightful roundtable discussion I had the privilege to chair, featuring prominent genitourinary oncologists. This expert dialogue dives into the multifaceted role of cabozantinib in advanced and metastatic renal cell carcinoma (RCC), offering valuable clinical perspectives on its broad applicability, established efficacy, synergistic potential with immune checkpoint inhibitors, and practical guidance for optimizing its use and managing its toxicity.