Submitted - October 18, 2022 | Revised December 4, 2022 Accepted - December 7, 2022 | | ePublished - December 31, 2022
https://doi.org/10.52733/ASCO25Summary
Kidney Cancer Summary from ASCO 2025:
Therapies, Biomarkers, and Beyond
ABSTRACT
BACKGROUND: The 2025 ASCO Annual Meeting provided significant updates in kidney cancer management, emphasizing durable immunotherapy outcomes and promising novel targeted therapies. The 9-year update of CheckMate-214 solidified nivolumab plus ipilimumab as a superior first-line treatment, demonstrating sustained overall survival and durable responses. Adjuvant pembrolizumab's long- term benefit in high-risk RCC was also reinforced by the 5-year KEYNOTE-564 update. While initial immune checkpoint blockade showed tolerability challenges in the PDIGREE analysis, next-generation agents like zanzalintinib combinations and HIF-2α,$ inhibitors (belzutifan, casdatifan) presented encouraging early-phase results, alongside the novel off-the-shelf CAR-T cell therapy ALLO-316. Further sessions highlighted the importance of personalized approaches. Immune profiling in the NEOAVAX study provided insights into neoadjuvant therapy responses, while CONTACT-03 clarified optimal treatment sequencing by suggesting limited benefit from PD-(L)1 re-challenge. Although the IMmotion010 trial for adjuvant atezolizumab was negative for DFS, it showcased the potential of integrative genomics and serum KIM-1 for patient stratification. These diverse findings collectively underscore a growing emphasis on individualized, biology-driven care in kidney cancer, leveraging long-term immunotherapy efficacy and exploring new targeted and cellular therapies.
INTRODUCTION
The 2025 ASCO Annual Meeting, held from May 30 to June 3 in the vibrant hub of Chicago, Illinois, delivered a whirlwind of breakthroughs in kidney cancer research that left oncologists buzzing with excitement. With over 5,000 abstracts presented, the spotlight shone brightly on renal cell carcinoma (RCC), unveiling transformative insights into novel therapies, cutting-edge biomarkers, and game-changing clinical strategies. This summary dives into the most electrifying updates from ASCO 2025, offering fellow oncologists a front-row seat to the future of RCC management.
COMBINATION THERAPIES: POWERHOUSE REGIMENS STEAL THE SHOW
CheckMate-9ER: A Five-Year Victory Lap The phase 3 CheckMate-9ER trial (Abstract #4511) stole the stage with its five-year follow-up data on nivolumab (anti-PD-1 immunotherapy) paired with cabozantinib (a tyrosine kinase inhibitor, TKI) versus sunitinib in untreated advanced clear cell RCC (ccRCC). This long-term data cements nivolumab plus cabozantinib as a cornerstone of first-line therapy for advancedccRCC, especially for intermediate- or poor- risk patients. It’s a powerful reminder of how immune/ TKI combos can rewrite the story for our patients.Key Takeaways: The nivolumab-cabozantinib combo extended median OS to an impressive 46.5 months, outpacing sunitinib’s 35.5 months by nearly a year (HR, 0.77; 95% CI, 0.63-0.94). Talk about a survival win! The combination delivered deeper responses, with 13.6% of patients achieving complete response (CR) compared to a mere 4.6% with sunitinib. Tumor shrinkage was sustained in 56% of patients versus 28% in the sunitinib arm. <
COSMIC-313: Triplet Therapy Turns Heads
The COSMIC-313 trial (Abstract #438, ASCO GU 2025) brought the heat with its exploration of a triplet regimen—nivolumab, ipilimumab (anti-CTLA-4), and cabozantinib—in untreated advanced RCC. Dr. Laurence Albiges dropped a bombshell: patients with high M2 macrophage levels saw a striking OS boost with the triplet compared to the nivolumab/ipilimumab doublet. This regimen is a bold step forward, hinting at M2 macrophages as a potential biomarker to pinpoint ideal candidates. While toxicity needs taming, this triplet could be a game-changer for personalized RCC care. •Key Takeaways: The triplet sparked higher tumor response rates in M2 macrophage-high patients, but toxicity was a hurdle, with 33% of patients stopping treatment due to adverse events (AEs).
Lenvatinib and Belzutifan: A Second-Line Sensation
Abstract #440 (ASCO GU 2025) showcased the dynamic duo of lenvatinib (VEGFR-TKI) and belzutifan (HIF-2α inhibitor) in heavily pre-treated advanced RCC patients. The results? A clinical benefit rate of 63.0% and an ORR of 22.2%—numbers that had the audience buzzing. For those battling progression after first-line therapies, lenvatinib plus belzutifan is a beacon of possibility. It underscores the critical role of clinical trials in unlocking innovative treatments.
Key Takeaways: This combo offers hope for patients running out of options, proving its worth in the second-line setting.
BIOMARKERS: UNLOCKING PRECISION MEDICINE’S POTENTIAL
CheckMate-9ER’s Biomarker Breakthroughs
Dr. David McDermott’s riveting presentation on Abstract #4511 dove into biomarker discoveries from CheckMate-9ER, spotlighting Kidney Injury Molecule-1 (KIM-1) as a rising star. KIM-1 could revolutionize adjuvant therapy selection, identifying high-risk patients for treatments like atezolizumab while sparing others unnecessary interventions. However, the search for a single, definitive biomarker (PD-L1, TMB, or ctDNA) continues, pushing us toward integrated, multimodal approaches. This blood-based biomarker stole the show with its ability to predict RCC outcomes:
KIM-1’s Power: Elevated pre-nephrectomy
KIM-1 levels flagged higher RCC risk, worse metastasis-free survival, and poorer OS. It even distinguished benign from malignant tumors and was elevated up to five years before diagnosis. More Biomarker Buzz Beyond KIM-1, other studies kept the biomarker momentum going. The NEOAVAX Trial (Abstract 4509) hinted at promising biomarkers for response to neoadjuvant nivolumab plus vaccine in high-risk localized RCC. From IMmotion010 (Abstract 4510), researchers identified genomic drivers of relapse, offering crucial clues for more intelligent adjuvant therapy decisions. Additionally, the role of the gut microbiome in immunotherapy response sparked intrigue (Abstract 4512), though definitive predictors remain elusive. Dr. W. Kimryn Rathmell's compelling review (Abstract #4505) underscored the urgent need for integrated biomarker models to truly realize the potential of precision medicine.
NON-CLEAR CELL RCC: A NEW HOPE EMERGES
Lenvatinib Plus Pembrolizumab Shines The KEYNOTE-B61 study (Abstract 4518, updated from ASCO 2023) lit up the stage with lenvatinib plus pembrolizumab as a first-line option for advanced non-clear cell RCC (nccRCC), a subtype that accounts for 20-25% of cases and faces grim survival odds. This combo is a lifeline for nccRCC patients, offering robust responses across subtypes. It’s a major step toward closing the treatment gap for this underserved population. In 158 patients (mostly papillary or chromophobe subtypes): •Key Takeaways: An ORR of 50% and disease control in 82% of patients, with a median PFS of 18 months. Three-quarters of responders held strong for at least a year.
ADJUVANT THERAPY AND EARLY DETECTION
KIM-1’s Adjuvant Edge Abstract 4506 (revisited from ASCO 2024) spotlighted KIM-1’s potential to identify patients at high risk of RCC recurrence post-nephrectomy. Elevated KIM-1 correlated with worse DFS and OS in trials like ASSURE and IMmotion010, making it a prime candidate for guiding adjuvant therapy. KIM-1 could transform how we approach adjuvant therapy, ensuring high-risk patients get the treatment they need while sparing others. Validation studies are the next frontier.CA-62: A Glimpse at Early Detection
Abstract 4526 (ASCO 2024, discussed at ASCO 2025) explored CA-62 for early kidney cancer detection. While promising, its lack of specificity calls for a multi-biomarker approach. Combining CA-62
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. with other markers could pave the way for earlier RCC detection, especially in high-risk groups, but we’re not there yet.EMERGING THERAPIES: THE NEXT FRONTIER
PDIGREE Trial: Smart, Adaptive Strategies Dr. Tianster Zhang’s PDIGREE trial (Abstract 4516) wowed the crowd with its adaptive approach. Patients started with nivolumab plus ipilimumab, then moved to nivolumab maintenance (for stable disease/ partial response) or nivolumab plus cabozantinib (for progression). This flexible strategy tailors therapy to patient needs, balancing efficacy and toxicity in a real- world setting. •Key Takeaways: 33% of patients dropped out due to AEs or progression, but 67% moved to maintenance or escalated treatment based on response.
Belzutifan: A Rising Star
The LITESPARK-015 trial’s success in pheochromocytoma and paraganglioma fueled excitement about belzutifan’s role in RCC. Its synergy with lenvatinib in advanced RCC is sparking hope for VHL-associated tumors and beyond. Belzutifan’s targeted HIF-2α inhibition is a fresh weapon in our arsenal, with combination regimens poised to reshape treatment landscapes. Practical Considerations for Oncologists The ASCO 2025 Annual Meeting provided actionable insights for kidney cancer management: • First-Line Therapy: Nivolumab plus cabozantinib remains a cornerstone for advanced ccRCC, with long-term data from CheckMate-9ER (Abstract #4511) confirming its superiority over sunitinib. Lenvatinib plus pembrolizumab, evaluated in KEYNOTE-B61 (Abstract #4518), is a viable option for nccRCC, expanding treatment options for this challenging subtype. • Second-Line and Beyond: Lenvatinib plus belzutifan, explored in Abstract #440, offers promise for pre-treated patients, emphasizing the role of clinical trials in accessing novel therapies. • Biomarker-Driven Care: While KIM-1, highlighted in Abstracts #4506 and #4511, shows potential as a prognostic and predictive biomarker, integrated models combining ctDNA, TME, and other markers (Abstracts #4509–4512) are critical for precision medicine. Oncologists should stay informed about ongoing biomarker validation studies. • Adjuvant Therapy: KIM-1, as discussed in Abstract #4506, could guide patient selection for adjuvant therapies, reducing overtreatment and improving outcomes in high-risk localized RCC. • Patient Counseling: The high rate of AEs in triplet regimens, such as in COSMIC-313 (Abstract #438), underscores the need for robust patient education and toxicity management strategies.CONCLUDING REMARKS
ASCO 2025 was an electrifying leap forward for kidney cancer, blending durable therapies, biomarker breakthroughs, and innovative trial designs. From the unstoppable nivolumab-cabozantinib combo to lenvatinib-pembrolizumab’s nccRCC triumph, these advances are turning vision into reality. KIM-1 and adaptive trials like PDIGREE are lighting the way to personalized care. Let’s keep the momentum going by enrolling patients in trials and leveraging ASCO’s tools (like the ASCO Meetings Mobile App) to stay ahead. Aligned with ASCO’s 2025 theme, “Driving Knowledge to Action: Building a Better Future,” the path to better RCC outcomes is brighter than ever.
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