The PD-1 inhibitor nivolumab plus the tyrosine kinase inhibitor cabozantinib continues to demonstrate a significant survival advantage over sunitinib alone in patients with previously untreated advanced renal cell carcinoma, according to data presented at the 2025 ASCO Genitourinary Cancers Symposium.1
With a median follow-up of 67.6 months, final results from the phase III CheckMate 9ER trial showed a median overall survival of 46.5 months for patients randomly assigned to receive nivolumab plus cabozantinib vs 35.5 months for those given sunitinib. In addition to significantly longer progression-free survival, the combination therapy also doubled the objective response rate compared with sunitinib (55.7% vs 27.4%), with 13.9% of patients achieving a complete response.
Authors of the study emphasized that these findings confirm the durable and superior clinical benefits of nivolumab plus cabozantinib over sunitinib as a first-line treatment for advanced renal cell carcinoma. “With a median follow-up of over 5.5 years, these results highlight the sustained efficacy and manageable safety profile of nivolumab plus cabozantinib, further supporting its use as a first-line standard of care for patients with advanced renal cell carcinoma,” said Robert J. Motzer, MD, a genitourinary oncologist and Kidney Cancer Section Head at Memorial Sloan Kettering Cancer Center, New York.
Study Methods
The CheckMate 9ER trial is a global, randomized phase III study evaluating the efficacy and safety of nivolumab plus cabozantinib vs sunitinib alone in patients with advanced renal cell carcinoma. A total of 651 patients were randomly assigned 1:1 to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg daily) or sunitinib (50 mg daily, 4 weeks on/2 weeks off). The primary endpoint was progression-free survival, assessed per Response Evaluation Criteria in Solid Tumors v1.1 by blinded independent central review. Secondary endpoints included overall survival, objective response rate, and safety.
Survival Outcomes
With extended follow-up, nivolumab plus cabozantinib maintained its significant efficacy advantage over sunitinib alone. The median progression-free survival was 16.4 months with nivolumab plus cabozantinib vs 8.3 months with sunitinib (hazard ratio [HR] = 0.58), and the median overall survival was 46.5 months for nivolumab plus cabozantinib vs 35.5 months for sunitinib (HR = 0.79).
The confirmed objective response rate was 55.7% with nivolumab plus cabozantinib vs 27.4% with sunitinib, with a complete response rate of 13.9% vs 4.6%, respectively. The duration of response at 60 months was 22.0% with nivolumab plus cabozantinib vs 10.0% with sunitinib.
As Dr. Motzer reported, the combination therapy also demonstrated efficacy across risk subgroups. In the intermediate- and poor-risk groups, nivolumab plus cabozantinib was superior to sunitinib in progression-free survival, overall survival, and response rates. Among patients with bone, liver, and lung metastases, response rates also favored nivolumab plus cabozantinib.
Safety and Tolerability
The safety profile of nivolumab plus cabozantinib remained consistent with previous reports, with no new safety signals emerging. Grade 3 or higher treatment-related adverse events occurred in 67.8% of patients receiving nivolumab plus cabozantinib compared with 55.3% of those receiving sunitinib. The most common adverse events were diarrhea, skin toxicity, and hypertension, which were primarily attributed to cabozantinib. The rate of severe immune-related adverse events was relatively low at 14%.
Dose reductions of cabozantinib were required in 60% of patients. However, Dr. Motzer noted that only a modest number of patients discontinued therapy because of toxicity, indicating dose adjustments and supportive care measures were effective in managing adverse effects.
EXPERT POINT OF VIEW
Invited discussant of CheckMate 9ER, Tian Zhang, MD, MHS, Associate Professor, Hematology and Oncology, Internal Medicine, and Associate Director of Clinical Research at Harold C. Simmons Comprehensive Cancer Center, UT Southwestern University, highlighted the broader implications of this trial’s results, emphasizing that although immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations have transformed metastatic renal cell carcinoma treatment, further refinement is needed.
“The CheckMate 9ER trial has demonstrated that patients are living longer with metastatic disease, with median survival now approaching 4 years,1” said Dr. Zhang. “However, kidney cancer remains a highly heterogeneous disease, and future strategies should aim to personalize therapy based on biologic markers.”
Dr. Zhang noted that although clear cell kidney cancer has historically been treated as a single entity, the disease is far more complex than previously understood. Advances in molecular profiling have revealed distinct subpopulations of tumors with unique genomic and transcriptomic alterations, including BAP1 loss, PBRM1 mutations, and angiogenic vs inflammatory tumor microenvironment.
“Kidney cancer is not a monolithic disease,” said Dr. Zhang. “It comprises multiple biologic subsets, each with different treatment susceptibilities. Our current clinical models, such as the International Metastatic Renal Cell Carcinoma Database Consortium criteria, provide a useful framework for stratification, but we need to integrate biologic markers to better guide therapy selection.”
Tumor Biology
One of the emerging areas of interest in renal cell carcinoma research is the role of macrophage-driven tumor biology. Dr. Zhang highlighted the recent findings on M2-high tumors, which appear to have distinct immunosuppressive properties that may influence treatment response. In the CheckMate 9ER study, patients with M2-high tumors seemed to derive enhanced benefit from cabozantinib-containing regimens, said Dr. Zhang.
“There is a growing appreciation for the impact of the tumor microenvironment on response to therapy,” Dr. Zhang added. “M2-high macrophage signatures may serve as a predictor of response to certain therapies, and leveraging this knowledge could help us refine patient selection for IO-TKI combinations.”
What Next?
Looking ahead, Dr. Zhang noted that front-line triplet regimens are under investigation, but lessons from previous trials suggest that increased toxicity and treatment discontinuation remain challenges. Future research should focus on adaptive and sequential treatment strategies rather than simply adding more agents to current regimens.
“We must move beyond the mindset that adding more drugs upfront is always the answer,” Dr. Zhang said. “Instead, we should consider adaptive and sequential strategies based on real-time tumor biology, leveraging biomarkers to determine when to escalate or de-escalate therapy.”
Additionally, novel therapeutic approaches are currently being explored in clinical trials. These next-generation therapies aim to address mechanisms of immune resistance and tumor adaptation.
“We are just beginning to scratch the surface of what is possible in renal cell carcinoma treatment,” Dr. Zhang concluded. “Our goal should be to tailor therapies more precisely, maximize efficacy while minimizing toxicity, and ultimately extend survival in a meaningful way for our patients.”
DISCLOSURE: Research funding for the study was provided by Bristol Myers Squibb. Dr. Motzer reported financial relationships with Aveo Oncology, EMD Serono, Exelixis, Incyte, Merck, and Takeda. Dr. Zhang reported financial relationships with Archimmune Therapeutics, Capio BioSciences, Nanorobotics, Aptitude Health, Clinical Care Options, Curio Science, MJH Life Sciences, PeerView, Aravive Biologics, AstraZeneca, Aveo Oncology, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Gilead Sciences, Janssen, Lilly, Loxo/Lilly, Merck, Novartis, Pfizer, Sanofi/Aventis, Seagen, and Xencor.
REFERENCE
1. Motzer R, Escudier B, Burotto M, et al: Nivolumab plus cabozantinib vs sunitinib for previously untreated advanced renal cell carcinoma: Final follow-up results from the CheckMate 9ER trial. 2025 ASCO Genitourinary Cancers Symposium. Abstract 439. Presented February 15, 2025.
