A population-based analysis using Surveillance, Epidemiology, and End Results (SEER) data showed that overall survival (OS) outcomes improved substantially for younger patients vs older patients with advanced renal cell carcinoma (RCC) following the introduction of immune checkpoint inhibitors (ICIs) in the treatment paradigm.1
In the pre-ICI era, no statistically significant differences in OS were observed between younger and older patients, with median OS durations of 7 months and 6 months, respectively. Multivariate analysis confirmed that age was not an independent prognostic factor during this period (HR, 1.05; 95% CI, 0.97-1.32; P = .203). In contrast, clear age-related disparities emerged in the ICI era. Younger patients experienced a median OS of 16 months compared with 13 months in older patients, and age remained an independent predictor of inferior survival after adjustment for relevant clinical variables (HR, 1.37; 95% CI, 1.24-1.51; P = .0001).
Age-Associated Survival Patterns With ICIs in Advanced RCC
- In the pre-ICI era, OS outcomes were similar by age (< 65 years vs ≥ 65 years, 7 months vs 6 months, respectively; HR, 1.05).
- In the ICI era, younger patients had a longer median OS compared with older patients (16 months vs 13 months, respectively); age was an independently adverse factor for OS (HR, 1.37; 95% CI, 1.24-1.51; P = .0001).
- OS outcomes improved overall in the ICI era; worse OS outcomes were linked to Black race, larger tumors, poor tumor grade, and no surgery.
Across the entire cohort, patients treated during the ICI era achieved a significantly longer median OS than those treated in the non-ICI period, regardless of age (P = .0001). Gains in median OS were consistently observed across demographic characteristics, metastatic status, and treatment variables during the ICI era (all P < .05), underscoring the broad population-level effect of immunotherapy in advanced RCC.
Within the ICI-treated population, several factors were associated with worse OS across age groups, including Black race, larger tumor size, poor or undifferentiated tumor grade, and lack of surgical intervention. Surgical management was associated with longer OS vs nonsurgical treatment in both younger (22 months vs 7 months, respectively) and older patients (21 months vs 6 months, respectively), although the study authors noted that these findings should be interpreted cautiously. They explained that the SEER database does not distinguish between curative nephrectomy and cytoreductive nephrectomy, and the observed surgical benefit likely reflected patient selection, consistent with findings from prior randomized studies, such as the phase 3 CARMENA (NCT00930033) and SURTIME (NCT01099423) trials.
“The ICI era has marked a significant improvement in survival outcomes for [patients with] advanced RCC, with longer median [OS] observed across most variables in both age groups compared to the pre-ICI period,” lead study investigator, Abdullah Al-Danakh, PhD, shared in the discussion of the results. “Within the ICI era, younger [patients with] RCC (< 65 years) experienced significantly better survival outcomes, with age serving as an independent prognostic factor: younger patients showed a lower HR for death than older patients (65 years). Prior studies indicate that multimodal therapies based on ICI enhance anticancer efficacy across various illnesses. [Although] some research suggests minimal age-related differences in outcomes with immunotherapy, our analyses demonstrate a clear age-associated disparity in the ICI era.”
Al-Danakh is part of the Department of Urology at the First Affiliated Hospital of Dalian Medical University in Liaoning, China; as well as the Department of Urology at Amran University in Yemen.
How was this study designed to evaluate age-related differences in outcomes with ICIs in advanced renal cell carcinoma?
To address persistent gaps in understanding how age influences outcomes with ICI therapy in advanced RCC, investigators conducted a large, population-based retrospective analysis complemented by a meta-analysis. This approach was designed to overcome the limitations of prior evidence, which has largely been derived from small case series and short observational reports that were insufficient to characterize age-related differences in immunotherapy efficacy.
The primary component of the study leveraged data from the SEER database to evaluate real-world oncologic outcomes across different age groups. Investigators identified a cohort of 21,904 patients diagnosed with advanced RCC, spanning both the pre-immunotherapy era and the contemporary ICI era. Of these, 11,814 patients were diagnosed before the widespread adoption of ICIs (non-ICI period), and 10,090 patients were diagnosed after ICIs became part of routine clinical practice. This temporal stratification allowed for comparison of outcomes before and after the introduction of immunotherapy and accounted for broader shifts in management patterns.
Patients were categorized by age to specifically evaluate differences between younger patients (< 65 years) and older patients (≥ 65 years). The primary end point of interest was OS among patients receiving ICI therapy, with age serving as the key stratification variable. In addition to survival outcomes, the study explored associations between age and immune-related biomarkers in patients with clear cell RCC, aiming to generate hypotheses regarding the biological underpinnings of observed differences.
Baseline demographic and clinical characteristics were assessed across both ICI eras. The cohort was predominantly composed of White, married male patients with tumors that were poorly differentiated or undifferentiated; had larger primary tumor volumes; and had no evidence of bone, brain, or liver metastases at diagnosis. Comparative analyses between the non-ICI and ICI eras were performed using chi-square testing to assess differences in baseline variables across age groups. Most variables differed significantly between eras (P < 0.05), reflecting evolving diagnostic and treatment practices, whereas sex and marital status did not show statistically significant variation.
Do first-line immunotherapy combinations deliver comparable benefit across patient age groups in advanced RCC?
Age-stratified analyses of first-line regimens indicated that the magnitude of benefit associated with ICI-based combinations varied by age across several pivotal phase 3 trials. In CheckMate 9ER (NCT03141177), nivolumab (Opdivo) plus cabozantinib (Cabometyx) significantly reduced the risk of death by 46% in younger patients (< 65 years; HR, 0.54; 95% CI, 0.39-0.74).1,2 In contrast, no OS benefit was observed among patients aged 65 years or older (HR, 1.03; 95% CI, 0.71-1.51). Progression-free survival (PFS) outcomes followed a similar pattern, with a more pronounced benefit in younger patients (HR, 0.50; 95% CI, 0.39-0.63) compared with older patients (HR, 0.70; 95% CI, 0.51-0.96).
Avelumab (Bavencio) plus axitinib (Inlyta) in JAVELIN Renal 101 (NCT02684006) also demonstrated greater efficacy in younger patients, with a 24% reduction in mortality (HR, 0.76; 95% CI, 0.58-0.98) and a 40% reduction in progression risk (HR, 0.60; 95% CI, 0.49-0.74) compared with sunitinib (Sutent).1,3 Although numerical improvements were observed with the investigational combination vs sunitinib in older patients, these did not reach statistical significance for OS (HR, 0.86; 95% CI, 0.62-1.19) or PFS (HR, 0.84; 95% CI, 0.65-1.09).
Findings from KEYNOTE-426 (NCT02853331) showed that pembrolizumab (Keytruda) plus axitinib reduced the risk of death by 34% (HR 0.66; 95% CI 0.51-0.85) vs sunitinib in younger patients, with a less pronounced and non–statistically significant OS benefit in older patients (HR 0.78; 95% CI 0.57-1.1).1,4 PFS improvements were again more robust in the younger cohort.
In CheckMate 214 (NCT02231749), nivolumab plus ipilimumab (Yervoy) demonstrated clear age-dependent efficacy.1 Younger patients experienced a 43% reduction in the risk of death with the ICI combination vs sunitinib (HR 0.57; 95% CI 0.44-0.76), whereas no significant OS benefit was seen in patients ages 65 years or older (HR 0.99; 95% CI 0.72-1.37). PFS benefit with this regimen was limited across both age groups.
In contrast, findings from the CLEAR trial (NCT02811861) suggested more consistent efficacy across age strata. Pembrolizumab plus lenvatinib (Lenvima) was associated with comparable reductions in mortality in both younger and older patients, and PFS benefits were similarly robust regardless of age.
“Our meta-analysis of major randomized controlled trials in advanced RCC demonstrated that ICI-based therapies significantly improved OS in patients [younger than] 65 years [of age] compared [with] those 65 years [of age or older], with a striking 29% reduction in mortality risk. Importantly, conventional non-ICI therapies showed no significant age-dependent treatment effects. This distinct pattern suggests that age-related factors specifically influence responses to immunotherapy,” The authors concluded.
References
- Al-Danakh A, Jian Y, Yang L, et al. Age-related survival disparities in advanced renal carcinoma in the immune checkpoint inhibitor era using the SEER database and meta-analysis. Sci Rep. 2025;15(1):43501. doi:10.1038/s41598-025-06297-y
- Motzer RJ, Escudier B, Burotto M, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2026;37(1):33-43. doi:10.1016/j.annonc.2025.09.006
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/nejmoa1816047
