RCC September 2025: News & Expert Insights

Recent Advances in Renal Cell Carcinoma Treatment Show Promise, Highlight Key Challenges

A wave of new data presented throughout September is reshaping the landscape of renal cell carcinoma (RCC) treatment, offering both encouraging advancements and highlighting areas requiring further investigation. Real-world evidence on belzutifan (Welireg), insights from the STELLAR-002 trial evaluating zanzalintinib combinations, and ongoing analysis of pivotal studies like IMmotion010, TiNivo-2, TRAVERSE, and KEYNOTE-564 are driving progress as the field anticipates further updates at the 2025 ESMO Congress.

Belzutifan: Real-World Safety Profiles Differ by RCC Subtype

A single-center retrospective analysis revealed notable differences in the onset and severity of adverse effects associated with belzutifan in patients with von Hippel-Lindau (VHL)-associated tumors versus those with sporadic, metastatic clear cell renal cell carcinoma (spRCC). The study found that anemia and hypoxia occurred earlier and were more severe in the spRCC cohort, while these events developed later and were generally less severe in patients with VHL-associated tumors. This suggests a need for tailored monitoring and management strategies based on the underlying RCC subtype.

STELLAR-002 Trial: Zanzalintinib Combinations Show Early Activity

The phase 1 STELLAR-002 trial (NCT05176483) is exploring the potential of zanzalintinib-based combinations, and early results are promising. Jad Chahoud, MD, MPH, of Moffitt Cancer Center, explained that the dose-escalation phase identified a safe and tolerable dose, with signals of activity observed in patients with clear cell RCC (ccRCC), as well as those with prostate and colorectal cancers.

Data shared during the 2025 ASCO Annual Meeting demonstrated encouraging efficacy in the doublet (n = 40) and triplet (n = 40) arms:

• Overall Response Rates: 63% (95% CI, 46%-77%) and 40% (95% CI, 25%-57%)
• Disease Control Rate: 90% (95% CI, 76%-97%) in both arms
• Median Duration of Response (DOR): Not estimable (NE) in either arm; 12-month DOR rates of 73.4% (95% CI, 50.0%-87.1%) and 74.1% (95% CI, 39.1%-90.9%)
• Median Time to Response: 2.1 months (range, 1.7-11.0) and 3.6 months (range, 1.7-12.8)
• Median Progression-Free Survival (PFS): 18.5 months (95% CI, 9.5-NE) and 13.0 months (95% CI, 7.4-NE) with 6-month rates of 83.4% (95% CI, 66.8%-92.2%) and 80.4% (95% CI, 63.1%-90.2%) and 12-month rates of 64.4% (95% CI, 45.7%-78.1%) and 58.4% (95% CI, 39.9%-73.0%)

Pivotal Trial Insights: Refining Treatment Strategies

Ongoing analysis of key trials continues to inform clinical practice. Sumanta K. Pal, MD, FASCO, of City of Hope, discussed the phase 3 IMmotion010 trial, which investigated atezolizumab (Tecentriq) versus placebo as adjuvant treatment for high-risk localized RCC. While the trial did not demonstrate improvements in disease-free survival (DFS), Dr. Pal emphasized the value of the data generated from collected specimens.

Similarly, a subgroup analysis of the phase 3 TiNivo-2 trial, examining tivozanib (Fotivda) with or without nivolumab (Opdivo) in metastatic RCC, did not meet its primary endpoint of PFS. Alexander Chehrazi-Raffle, MD, of City of Hope, noted that a substantial number of patients in the trial had received prior unconventional treatment regimens, potentially influencing the results. The subgroup analysis, focusing on patients who received tivozanib plus nivolumab after prior nivolumab plus ipilimumab or VEGF inhibitor plus immune checkpoint inhibition, mirrored the parent trial’s findings, showing no benefit from adding nivolumab to tivozanib.

Emerging Therapies: ALLO-316 Demonstrates Promising Safety Profile

The phase 1 TRAVERSE study is evaluating the safety of ALLO-316 in patients with advanced clear cell RCC. Jad Chahoud, MD, MPH, highlighted the favorable safety profile observed thus far. “We didn’t see…grade 3 cytokine release syndrome [effects], which was great. We [also] didn’t see any graft-vs-host disease, which is great for patients receiving an allogeneic CAR T-cell therapy,” he stated. However, immune effector cell–associated hemophagocytic lymphohistiocytosis emerged as a clinically significant toxicity, prompting the development of a structured management approach to facilitate continued treatment.

Adjuvant Pembrolizumab: KEYNOTE-564 Trial Design and Context

Naomi B. Haas, MD, of the Hospital of the University of Pennsylvania and Abramson Cancer Center, discussed the rationale behind the phase 3 KEYNOTE-564 trial, which is examining adjuvant pembrolizumab (Keytruda) in patients with clear cell RCC. Approximately 1000 patients were enrolled, with investigator-assessed disease-free survival (DFS) as the primary endpoint and overall survival and safety as key secondary endpoints. The study design was contextualized alongside other trials in the field, such as the phase 3 PROSPER EA8143 trial (NCT03055013).

Looking Ahead: Anticipation Builds for ESMO 2025

As the 2025 ESMO Congress approaches, oncologists are keenly anticipating new data across various genitourinary cancer subtypes. OncLive conducted polls on X and LinkedIn to gauge expert interest and identify key areas of focus for the upcoming meeting.

These recent developments underscore the dynamic nature of RCC research and treatment. Continued investigation and refinement of therapeutic strategies are crucial to improving outcomes for patients facing this challenging disease.