RCC Monthly Rewind: Key News and Expert Insights You May Have Missed in September 2025

September delivered several developments in renal cell carcinoma (RCC). Highlights included real-world findings on belzutifan (Welireg)–related adverse effects across tumor types, insights from the phase 1 STELLAR-002 trial (NCT05176483) evaluating zanzalintinib-based combinations, and continued discussion of pivotal studies such as IMmotion010 (NCT03024996), TiNivo-2 (NCT04987203), TRAVERSE (NCT04696731), and KEYNOTE-564 (NCT03142334). Leading investigators shared perspectives on trial design, safety, and efficacy with these different approaches, as the field looks ahead to additional updates expected at the upcoming 2025 ESMO Congress.

Check out this month-in-review recap of OncLive®’s coverage of the top news and expert insights in renal cell carcinoma (RCC):

Trial Updates

Timing of Real-World Belzutifan-Related AEs Varies Between VHL-Associated Tumors and Sporadic RCC

Findings from a single-center retrospective analysis showed that the onset and severity of belzutifan-related anemia and hypoxia differed between patients with von Hippel-Lindau (VHL)–associated tumors and those with sporadic, metastatic clear cell renal cell carcinoma (spRCC).¹ Any-grade anemia and hypoxia occurred earlier and were more severe in the spRCC cohort, whereas both events developed later and were generally less severe in the VHL cohort.

Expert Insights: QA Spotlight

In an exclusive interview, Jad Chahoud, MD, MPH, of Moffitt Cancer Center, discussed the background and impetus for examining zanzalintinib plus nivolumab (Opdivo) with or without relatlimab (Opdualag) as part of the phase 1 STELLAR-002 trial.² “In our dose-escalation cohort, we identified the dose and the safety, and we also saw some signals [in] patients with [ccRCC],” Chahoud said. “Patients with prostate cancer and those with colorectal cancer [CRC] had some initial responses, even on the dose-escalation cohort, and that helped us to move forward with the dose-expansion cohorts.”

Some key data highlights shared during the 2025 ASCO Annual Meeting³ in the doublet (n = 40) and triplet (n = 40) arms included:

• 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%)

Top Expert Insights of the Month: OncLive TV Highlights

Sumanta K. Pal, MD, FASCO, of City of Hope, spoke about the design of the phase 3 IMmotion010 trial, which examined atezolizumab (Tecentriq) vs placebo as adjuvant treatment in patients with high-risk localized RCC.⁴ “In this particular trial, there weren’t any improvements seen in disease-free survival [DFS] with atezolizumab,” he said. However, he added that the data were valuable, particularly those stemming from the specimens that were collected.

Alexander Chehrazi-Raffle, MD, of City of Hope, unpacked the clinical rationale for a subgroup analysis of the phase 3 TiNivo-2 trial examining tivozanib (Fotivda) with or without nivolumab (Opdivo) in patients with metastatic RCC.⁵ This trial did not meet is primary end point of PFS. He noted that “Of the 343 patients in the phase 3 trial, there were a substantial amount that received the medications in unconventional settings, [including] post-adjuvant [therapy] or in a clinical trial that preceded treatment.” The subgroup analysis was of those who received tivozanib plus nivolumab after nivolumab plus ipilimumab or after treatment with a VEGF inhibitor plus immune checkpoint inhibition; the data aligned with the parent trial in that no benefit was observed with the addition of nivolumab to tivozanib in this context.

In another interview, Jad Chahoud, MD, MPH, of Moffitt Cancer Center, spotlighted the safety data with ALLO-316 in patients with advanced clear cell RCC enrolled to the phase 1 TRAVERSE study.⁶ “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 said. He added that immune effector cell–associated hemophagocytic lymphohistiocytosis represented a more clinically significant toxicity, and as such, a structured approach was developed to effectively manage this complication which allowed for continued treatment.

Naomi B. Haas, MD, of the Hospital of the University of Pennsylvania and Abramson Cancer Center, discussed the rationale for examining adjuvant pembrolizumab (Keytruda) in patients with clear cell RCC in the phase 3 KEYNOTE-564 trial.⁷ “In [this trial], [approximately] 1000 patients were enrolled, with [DFS per] investigator assessment being the primary end point. Overall survival and safety were considered key secondary end points,” she said. She further unpacked the design of the study and how it compares with others in the space, such as the phase 3 PROSPER EA8143 trial (NCT03055013).

Looking Ahead to ESMO

As the countdown to the 2025 ESMO Congress continues, anticipation continues to build across the filed of oncology. To gauge expert interest ahead of the meeting, OncLive conducted polls on X and LinkedIn to determine which genitourinary cancer abstracts and disease areas oncologists were most eager to learn more about. Check out those insights.

Stay on top of the latest updates in genitourinary cancers. Sign up to get these updates sent straight to your inbox.

References

1. Winer AJ, do Amaral PS, Ryan EG, et al. The safety profile of belzutifan in renal tumors: real-world data from a tertiary academic center. Oncologist. Published online September 8, 2025. doi:10.1093/oncolo/oyaf274
2. Chan A. Zanzalintinib plus nivolumab generates early antitumor activity in untreated advanced ccRCC. OncLive.com. September 3, 2025. Accessed October 10, 2025. https://www.onclive.com/view/zanzalintinib-plus-nivolumab-generates-early-antitumor-activity-in-untreated-advanced-ccrcc
3. Chahoud J, McGregor BA, Torras OR, et al. Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with previously untreated clear cell renal cell carcinoma (ccRCC): Results form an expansion cohort of the phase 1b STELLAR-002 study. J Clin Oncol. 2025;43(suppl 16):4515. doi:10.1200/JCO.2025.43.16_suppl.4515
4. Pal SK. Dr Pal on the rationale for evaluating atezolizumab in high-risk localized RCC. OncLive.com. September 18, 2025. Accessed October 10, 2025. https://www.onclive.com/view/dr-pal-on-the-rationale-for-evaluating-atezolizumab-in-high-risk-localized-rcc
5. Chehrazi-Raffle A. Dr Chehrazi-Raffle on the TiNivo-2 study of tivozanib with/without nivolumab in mRCC. OncLive.com. September 16, 2025. Accessed October 10, 2025. https://www.onclive.com/view/dr-chehrazi-raffle-on-the-tinivo-2-study-of-tivozanib-with-without-nivolumab-in-mrcc
6. Chahoud J. Dr Chahoud on the safety of ALLO-316 in advanced ccRCC. OncLive.com. September 16, 2025. Accessed October 10, 2025. https://www.onclive.com/view/dr-chahoud-on-the-safety-of-allo-316-in-advanced-ccrcc
7. Haas NB. Dr Haas on the rationale for evaluating adjuvant pembrolizumab in clear cell RCC. OncLive.com. September 2, 2025. Accessed October 10, 2025. https://www.onclive.com/view/dr-haas-on-the-rationale-for-evaluating-adjuvant-pembrolizumab-in-clear-cell-rcc