Abstract
Aging causes gradual and significant declines in immune functions and responses. However, the impact of aging on the immunotherapy outcomes in advanced renal cell carcinoma is largely unknown. Here, we conducted a pooled analysis of individual participant data from two regulatory-approved randomized controlled trials: CheckMate 214 and JAVELIN Renal 101. The overall population (n=1926) included 964 individuals treated with immune checkpoint inhibitors (ICIs) and 962 subjects treated with sunitinib. The optimal age to separate young from old was found to be 60. For young patients, immunotherapy was associated with favorable overall survival (OS; HR=0.70, 95% CI 0.56 to 0.87, p<0.001). For individuals over 60 years old, the OS benefits were marginal (HR=0.82, 95% CI 0.67 to 1.00, p=0.05). Notably, patients with Memorial Sloan Kettering Cancer Center poor risk demonstrated clear benefits from ICIs in this population. Immunotherapy failed to improve OS in patients aged 75 and above (HR=1.05, 95% CI 0.62 to 1.79, p=0.85). Further investigations indicated that young patients exhibited increased infiltration of immune cells, enhanced tumor immunogenicity, and improved immune responses. In summary, the advantage of immunotherapy diminished progressively with age. ICIs were associated with favorable outcomes in young patients. However, for patients over 60 years old, clinicians need to carefully balance efficacy, safety, and patient preferences to deliver individualized treatment.
Keywords: Immunotherapy, Kidney Cancer, Survivorship
Introduction
Renal cell carcinoma (RCC) is a commonly diagnosed cancer with an estimated 400 000 new cases annually.1 Globally, the incidence rates of RCC rise consistently with age, peaking at approximately 75 years.1 The management of elderly patients presents a constant challenge for clinicians since their poor physical conditions can greatly affect treatment success. Indeed, previous studies have demonstrated that patients with cancer of advanced age usually have decreased response rates and tolerance to chemotherapy, radiation therapy, and targeted therapy.2 Hence, despite elderly individuals constituting a large share of new cancer diagnoses, they are frequently under-represented in clinical studies.
Currently, immunotherapy has become a standard-of-care therapeutic option in RCC. It is widely recognized that aging causes immunosenescence, a phenomenon marked by diminished immune function and response,3 raising doubts about the effectiveness of immunotherapy in elderly patients. Here, with individual participant data (IPD) from two high-profile randomized controlled trials (RCTs), CheckMate 214 (CM-214)4 and JAVELIN Renal 101 (JAV-101),5 we systematically evaluated the association between aging and outcomes of immunotherapy in advanced RCC (online supplemental methods).
Results
Baseline characteristics of included trials and patients
Both CM-2144 and JAV-1015 were multicenter phase III RCTs, and their applications as first-line treatments in advanced RCC have been approved internationally. Generally, the risks of bias were relatively low. The main issue affecting quality was the lack of blinding, as both studies were open labeled.
Totally, 1926 patients with RCC with identified age (1054 from CM-214 and 872 from JAV-101) were included here. The median age was 62 years (range: 21–88). Overall, 1426 (74.04%) were male, and 500 (25.96%) were female. Based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model, 385 (19.99%), 1101 (57.17%), and 315 (16.36%) patients showed favorable, intermediate, and poor risk, respectively. Additionally, 410 (21.29%), 1171 (60.80%), and 199 (10.33%) patients were Memorial Sloan Kettering Cancer Center (MSKCC) favorable, intermediate, and poor risk. In 1764 patients with programmed cell death-ligand 1 (PD-L1) expression recorded, PD-L1+ was identified in 804 (45.58%) patients, while 960 (54.42%) had PD-L1 tumors. Sarcomatoid features were examined in 858 patients, and 105 (12.24%) were established as sarcomatoid histology. 964 (50.05%) patients were included in the experimental arm, and the remaining 962 (49.95%) subjects were treated with sunitinib. Immune checkpoint inhibitors (ICIs) were associated with significantly longer overall survival (OS; HR=0.76, 95% CI 0.65 to 0.88, p<0.001) and progression-free survival (PFS; HR=0.79, 95% CI 0.70 to 0.89, p<0.001; online supplemental figure S1).
Aging and immunotherapy outcomes in RCC
Considering the best age cut-off for old patients was unclear, we first determined the optimal age by assessing the clinical significance of every age value as a threshold. Following extensive data analysis, we discovered that the age of 60 could serve as the ideal point to distinguish between young and old. The categorization of patients into different chronological age subgroups and their detailed characteristics are illustrated (table 1 and online supplemental table S1). In all five categories (≤60 years, >60 years, >65 years, ≥70 years, and ≥75 years), the numbers of patients were generally balanced. Generally, patients with key clinicopathological features, including sex, IMDC risk, MSKCC risk, sarcomatoid RCC, tumor location, and PD-L1 expression, were also evenly distributed across these categories.
Table 1. Baseline characteristics of patients with RCC in CheckMate 214 and JAVELIN Renal 101.
| ≤60 years | >60 years | ≥75 years | ||||
|---|---|---|---|---|---|---|
| Immunotherapy | Control | Immunotherapy | Control | Immunotherapy | Control | |
| Patients, n | 435 | 448 | 529 | 514 | 77 | 78 |
| Sex | ||||||
| Male (%) | 326 (74.94) | 337 (75.22) | 383 (72.4) | 380 (73.93) | 58 (75.32) | 58 (74.36) |
| Female (%) | 109 (25.06) | 111 (24.78) | 146 (27.6) | 134 (26.07) | 19 (24.68) | 20 (25.64) |
| IMDC risk model | ||||||
| Favorable (%) | 82 (18.85) | 80 (17.86) | 113 (21.36) | 110 (21.4) | 13 (16.88) | 17 (21.79) |
| Intermediate (%) | 247 (56.78) | 265 (59.15) | 298 (56.33) | 291 (56.61) | 47 (61.04) | 46 (58.97) |
| Poor (%) | 78 (17.93) | 71 (15.85) | 83 (15.69) | 83 (16.15) | 11 (14.29) | 13 (16.67) |
| Not available (%) | 28 (6.44) | 32 (7.14) | 35 (6.62) | 30 (5.84) | 6 (7.79) | 2 (2.56) |
| MSKCC risk model | ||||||
| Favorable (%) | 91 (20.92) | 84 (18.75) | 116 (21.93) | 119 (23.15) | 13 (16.88) | 17 (21.79) |
| Intermediate (%) | 263 (60.46) | 284 (63.39) | 311 (58.79) | 313 (60.89) | 45 (58.44) | 54 (69.23) |
| Poor (%) | 51 (11.72) | 43 (9.6) | 55 (10.4) | 50 (9.73) | 11 (14.29) | 4 (5.13) |
| Not available (%) | 30 (6.9) | 37 (8.26) | 47 (8.88) | 32 (6.23) | 8 (10.39) | 3 (3.85) |
| Sarcomatoid features | ||||||
| Yes (%) | 23 (5.29) | 36 (8.04) | 22 (4.16) | 24 (4.67) | NA | 2 (2.56) |
| No (%) | 169 (38.85) | 174 (38.84) | 211 (39.89) | 199 (38.72) | 33 (42.86) | 38 (48.72) |
| Not available (%) | 243 (55.86) | 238 (53.12) | 296 (55.95) | 291 (56.61) | 44 (57.14) | 38 (48.72) |
| Tumor location | ||||||
| Primary (%) | 292 (67.13) | 301 (67.19) | 339 (64.08) | 347 (67.51) | 48 (62.34) | 47 (60.26) |
| Metastasis (%) | 92 (21.15) | 105 (23.44) | 132 (24.95) | 119 (23.15) | 19 (24.68) | 19 (24.36) |
| Not available (%) | 51 (11.72) | 42 (9.38) | 58 (10.96) | 48 (9.34) | 10 (12.99) | 12 (15.38) |
| PD-L1 expression | ||||||
| Positive (%) | 178 (40.92) | 213 (47.54) | 207 (39.13) | 206 (40.08) | 26 (33.77) | 30 (38.46) |
| Negative (%) | 215 (49.43) | 201 (44.87) | 277 (52.36) | 267 (51.95) | 40 (51.95) | 37 (47.44) |
| Not available (%) | 42 (9.66) | 34 (7.59) | 45 (8.51) | 41 (7.98) | 11 (14.29) | 11 (14.1) |
| TMB (mean±SE) | 52.01±1.51 | 48.39±1.33 | 63.07±1.41 | 63.04±1.65 | 79.16±5.43 | 62.95±2.39 |
IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; PD-L1, programmed death-ligand 1; RCC, renal cell carcinoma; TMB, tumor mutation burden.
In 883 young patients (≤60 years; 476 from CM-214 and 407 from JAV-101), 435 (49.26%) received ICIs, and 448 (50.74%) served as controls. Immunotherapy was associated with favorable OS (HR=0.70, 95% CI 0.56 to 0.87, p<0.001) and PFS (HR=0.78, 95% CI 0.65 to 0.93, p=0.006; figure 1A).
Figure 1. Association between aging and the outcomes of immunotherapy in patients with advanced renal cell carcinoma. (A) Immunotherapy was associated with favorable OS (left panel) and PFS (right panel) in young patients (<60 years). (B) In patients aged 60 years or older, the benefit of immunotherapy was marginal. (C) Immunotherapy and control showed comparable OS in patients over 65 years old (left panel) or over 70 years old (right panel). (D) In patients with MSKCC poor risk score, OS benefits were achieved in populations aged 60 and above (left panel), 65 and above (middle panel), and 70 and above (right panel). (E) Old patients (≥75 years) cannot benefit from immunotherapy in terms of OS and PFS. (F) Comparisons of the expression levels for 17 MHC-related antigen-presenting molecules, along with 11 coinhibitors and 25 costimulators, among patients over 65 years old and patients aged 55 or younger. (G) Comparisons of 38 chemokines and their receptors between patients >65 years old and patients <55 years old. (H) 35 ILs and their receptors in patients >65 years old versus patients <55 years old. (I) Comparison of eight immune and two stromal cell populations estimated by the MCP-counter method. Blue denotes patients aged over 65 years; red denotes patients aged 55 or younger. HLA, human leukocyte antigen; IL, interleukin; MCP, Microenvironment Cell Populations; MHC, major histocompatibility complex; MSKCC, Memorial Sloan Kettering Cancer Center; NK, natural killer; ns, not significant; OS, overall survival; PFS, progression-free survival. *P<0.05; **p<0.01.
Of 1043 individuals over 60 years old (578 from CM-214, 465 from JAV-101), 529 (50.72%) were in the experimental arm and 514 (49.28%) were controls. The OS benefit from immunotherapy was marginal (HR=0.82, 95% CI 0.67 to 1.00, p=0.05; figure 1B). ICIs and sunitinib showed comparable OS in 654 patients aged over 65 years (363 from CM-214, 291 from JAV-101; HR=0.91, 95% CI 0.71 to 1.18, p=0.50) and 340 patients aged over 70 years (190 from CM-214, 150 from JAV-101; HR=0.92, 95% CI 0.63 to 1.32, p=0.63; figure 1C). Even so, further subgroup analysis revealed that patients with MSKCC poor risk (figure 1D) or IMDC poor risk (online supplemental figure S2) could still benefit from ICIs.
Among 155 participants aged 75 and above (82 from CM-214, 73 from JAV-101), immunotherapy failed to show superiority over controls in terms of OS (HR=1.05, 95% CI 0.62 to 1.79, p=0.85) and PFS (HR=0.94, 95% CI 0.61 to 1.45, p=0.77; figure 1E). These associations remained consistent across all MSKCC or IMDC risk scores (online supplemental figure S3).
The underlying mechanism between aging and immunotherapy
To explore the potential molecular mechanisms, we investigated the tumor immune landscapes with RNA information extracted from JAV-101.6 Compared with elder patients (>65 years), the expression levels of many major histocompatibility complex-related antigen-presenting molecules, coinhibitors, and costimulators (figure 1F); chemokines and their receptors (figure 1G); and interleukins and their receptors (figure 1H) were notably increased in individuals aged 55 or younger. Moreover, the abundance of tissue infiltration of several immune cell populations, estimated by the Microenvironment Cell Populations-counter approach,7 was also enriched in young patients (figure 1I).
Discussion
The diminished immune response with advancing age is a well-known phenomenon.3 Nonetheless, the age thresholds separating young from old differed across various studies. In 2022, one meta-analysis on advanced solid tumors showed there was no significant relationship between age and immunotherapy outcomes like PFS and OS, with a cut-off age of 65 years.8 On the other hand, Nie et al showed that patients aged 75 and above did not experience benefits from immunotherapy.9 These analyses, however, were compromised by disease heterogeneity as they included various cancer types. In RCC, a trial-level meta-analysis including three RCTs (JAV-101, KEYNOTE-426, and CheckMate 9ER) also indicated that OS was unaffected by age, with 65 years as the dividing point.10 In contrast, a recent study conducted on multicenters in Japan demonstrated that, in patients with RCC treated with nivolumab+ipilimumab, being 75 years or older was a significant independent predictor of poorer OS.11 Of note, only 33 individuals aged over 75 were enrolled in this retrospective study. With approximately 2000 IPD available, here we determine the optimal age by evaluating the clinical significance of every age value as a threshold, and age 60 emerged as the best threshold to distinguish between young and old. Notably, this study is the first to establish the age criteria for young and old in RCC immunotherapy. While young subjects benefited from ICIs, for most seniors, clinicians need to carefully balance efficacy, safety, and patient preferences to deliver individualized treatment.
Although the exact mechanisms behind immunosenescence were not completely comprehended, there was substantial evidence showing its significant effect on both innate and adaptive immune systems.12 Indeed, Alpert et al identified distinctions in the immune systems of young versus old people, showing a more stable immune cell environment in young individuals.3 Moreover, this study highlighted the notion of immunological aging as the continuous restructuring of the immune system over time. Here, by examining the expression levels of 126 immune-related molecules, our findings, consistent with previous research,3 suggested that being young was associated with increased infiltration of immune cells, enhanced tumor immunogenicity, and improved immune responses. Additionally, as time passed, the efficacy of immunotherapy was observed to decline gradually. Among patients aged 75 years and older, immunotherapy was even associated with slightly poor OS. It is recommended that the application of immunotherapy in this population should be carefully evaluated, taking into account the expected lifespan of these patients.
Significantly, a non-negligible number of exceptions were observed in old individuals with RCC. It was well known that, historically, the IMDC/MSKCC criteria have categorized RCC into three prognostic groups, with each group showing a markedly different response to ICIs. The rationale for this difference might be found in the distinct biological characteristics of these risk subgroups, as indicated by biomarker analysis.13 14 Patients with favorable risk and intermediate risk appear to have a more angiogenic profile than the immunogenic profile seen in poor risk individuals. Moreover, the inclusion of five risk factors in the IMDC model or six factors in the MSKCC model signaled an inflammatory state, whereas their absence suggests a non-inflamed tumor microenvironment, which is known to be less responsive to ICIs.15 Therefore, despite the irresistible immunosenescence in elderly individuals, favorable outcomes were still noted in those with poor risks.
In conclusion, by defining age 60 as the optimal threshold between young and old, our study revealed that immunotherapy was associated with favorable outcomes in young patients. For patients over 60 years old, clinicians need to carefully balance efficacy, safety, and patients’ preferences to offer personalized medicine. These findings may influence treatment decision-making, aid in clinical trial design and interpretation, and promote personalized immunotherapy.
Supplementary material
The sponsor does not participate in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Footnotes
Funding: This work was funded by the National Natural Science Foundation of China (No 82373367) and Joint Funds for the Innovation of Science and Technology, Fujian Province, China (grant number: 2025YJRHPD05).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: Not applicable.
Data availability free text: All the data and materials generated and analyzed in the current study are included within the manuscript.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.