Globally, population aging is progressing rapidly, with a proportion of individuals ≥ 65 years old expected to nearly double by 2050 (1). For example, in Japan, 29.3% of the population will be ≥ 65 years old, and 16.8% will be ≥ 75 years old by 2024 (2), making it one of the most aged societies in the world. The Japanese Cancer Registry estimated that approximately 29,000 new cases of renal cancer were diagnosed in 2020, with renal cell carcinoma (RCC) accounting for most. The proportion of patients ≥ 75 years old is 44.4% (3). Therefore, carefully considering treatment options for older adult patients with RCC is essential.

Immune checkpoint inhibitor (ICI)-based combination therapy has revolutionized first-line treatment outcomes by improving the survival and response rates of patients with metastatic RCC (mRCC) (4, 5). The CheckMate 214 trial demonstrated that nivolumab and ipilimumab combination therapy (IO+IO) showed superior efficacy compared with sunitinib (6, 7). Furthermore, the survival benefits of first-line ICI plus tyrosine kinase inhibitor (IO+TKI) therapies have been widely reported, and several regimens have been established as treatment options (8–11). However, the safety and efficacy of ICI-based combination therapies in older adult patients remain controversial. The proportion of older adult patients enrolled in clinical trials is relatively low, which limits the comprehensive evaluation of treatment safety and efficacy. This is primarily due to older adult patients often meeting the exclusion criteria, including multiple primary cancers, impaired renal function, or reduced cardiac function. For example, patients aged ≥ 70 years accounted for only 17.4% of the total population in the CheckMate 214 trial (6), and in the KEYNOTE-426 trial, patients aged ≥ 65 years comprised approximately 40% of the total population (9). There have been reports that the average age of patients with RCC in real-world settings is 6.49 years older than those included in clinical trials (12), indicating a discrepancy between real-world and clinical trial data regarding patient age. Furthermore, immune aging is characterized by impaired T cell function and altered inflammatory environments, potentially causing reduced ICI effectiveness (13, 14). However, it is unclear whether these treatment strategies offer comparable efficacy and safety in older adult and non-older adult patients.

Therefore, evaluating the treatment outcomes in older adult patients and comparing them with those of non-older adult patients is crucial. In this study, we aimed to retrospectively analyze the clinical outcomes and toxicities of IO+IO and IO+TKI as first-line combination therapies in Japanese patients with mRCC aged ≥ 75 years.

In this study, we revealed no significant differences in the PFS, OS, or AEs frequency between the older adult and non-older adult groups. Our findings indicated that ICI-based combination therapies, when managed appropriately, can be effective in older adult patients with mRCC. We propose that treatment decisions should not be based solely on chronological age; rather, the characteristics of each regimen should be considered.

Focusing on IO+IO, we found similar response rates (ORR and DCR) across both age groups. Crucially, the incidence and severity of irAEs, alongside the rates of treatment discontinuation owing to irAEs, were comparable between the older adults and non-older adult groups.

These real-world observations regarding IO+IO in older adults are consistent with a growing body of evidence. The CheckMate 214 trial’s age-stratified analysis of OS did not show the superiority of IO+IO over sunitinib in older adult patients definitively (6); however, its conditional OS was favorable even in this group, suggesting its contribution to long-term outcomes (7). Furthermore, real-world data from the IMDC stated that survival benefits from ICI-based combination therapies are maintained even in patients aged ≥ 70 years, emphasizing that only chronological age should not dictate treatment selection (19). In addition, several studies have demonstrated non-inferior IO+IO treatment outcomes in older adult patients compared with younger patients, reinforcing our findings (20–23).

In the IO+TKI cohort, the older adult group showed a lower ORR trend than the non-older adult group. Nevertheless, the DOR was nearly identical, and no significant differences were observed in OS or PFS. The overall incidence of AEs was similar between groups; however, treatment discontinuation due to AEs was significantly higher. Moreover, the time to discontinuation was shorter in older adults, despite no differences in the initial TKI dose or RDI. These findings suggest that, in the IO+TKI regimen, older adults may discontinue treatment earlier due to AEs even when receiving the same initial TKI dose as non-older adults, despite experiencing a similar overall frequency of AEs. Therefore, a greater reduction in the TKI dose than in non-older adults may help maintain treatment in older adults. Several subgroup analyses have been conducted in clinical trials on IO+TKI therapy. Tomita et al. suggested that patients > 75 years old who underwent avelumab plus axitinib treatment would have a similar survival benefit as those aged 65–74 years (24). Varkaris et al. reported that treatment comprising pembrolizumab and axitinib prolonged PFS and OS compared with sunitinib even in patients aged ≥ 65 years (25). While there are a few real-world reports, Iinuma et al. reported that the median PFS for patients aged ≥ 70 years was significantly shorter than for patients aged < 70 years in their study utilizing various IO+TKI regimens (26). However, these findings were based on a relatively small cohort of 51 patients. More studies are needed to clarify the optimal management and outcomes of IO+TKI therapy in older adults.

Kaymakcalan et al. and Donskov et al. identified older age as a predictive factor for treatment discontinuation due to AEs among patients treated with TKI monotherapies (27, 28). However, Carina et al. reported that the increased incidence of treatment interruptions and dose reductions among older adult patients did not affect the overall efficacy despite the significantly lower TKI doses observed. Sustained drug exposure in each patient, rather than the absolute dose in milligrams, contributes to the clinical benefit of targeted therapies (29). These studies focused on TKI monotherapy; however, their findings share commonalities with our results in IO+TKI combination therapy, highlighting the importance of dose management, including TKI dose reduction. A recent report proposed the “start-low, go-slow” (SLGS) strategy, which involves initiating cancer treatment at lower-than-standard doses in older patients with solid tumors to reduce toxicity without affecting survival (30). Our findings suggest that in IO+TKI treatment of mRCC, SLGS strategy may help mitigate toxicity and prolong the duration of first-line therapy.

In previous reports, the occurrence of irAEs or treatment discontinuation due to irAEs did not negatively impact OS. The early occurrence of irAEs has been suggested to reflect immune activation, and in some cases, may even prolong OS (31–33). In our study, the results for the IO+IO regimen support this finding. Although the data for older patients were limited and the difference was not statistically significant, the presence of irAEs suggested a potential benefit to OS. In contrast, the lack of a significant association in the IO+TKI regimen may be due to the high number of TKI-related AEs. These results highlight the clinical significance of AEs and the need for further investigation.

Previous studies have shown that while IO+TKI therapy offers superior PFS compared with IO+IO, OS remains similar (34–36). The favorable PFS of IO+TKI is thought to result from the interaction between tumor immunity and angiogenesis, as anti-angiogenic therapy may enhance ICI efficacy (37). However, while IO+IO demonstrates inferior PFS compared with IO+TKI, it is considered non-inferior in OS due to several factors: the potential for durable long-term responses and better treatment-free survival (38), the sustained efficacy of vascular endothelial growth factor-TKIs even after ICI-based combination therapy (39, 40), and the fact that PFS is not a perfect surrogate for OS (41). Our study showed similar results in the non-older adult cohort; however, we suggest that this trend may be attenuated in older adults. In addition, the attenuated trend may be attributable to the higher frequency of treatment discontinuation due to AEs with IO+TKI therapy in the older adult group. These findings may have important implications for treatment decision-making in older adults. However, the small sample size limits the statistical power of this analysis, and the results should be interpreted with caution.

This study has some limitations. First, the participants were few, and this was a retrospective study. While the number of patients is especially limited for each IO+TKI regimen, real-world data on IO+TKI therapy in older adult patients remain scarce, underscoring the significance of our findings. Second, there were no explicit criteria for regimen selection, and the choice was left to the treating physician’s discretion. Particularly, the selection of IO+TKI regimens lacked uniformity. Such biases inherent in retrospective, real-world studies were recognized in other analyses concerning IO+IO by our group (42, 43). Third, data regarding geriatric assessment were insufficient, so the KPS and CCI were used as surrogate indicators. Fourth, the participants in our study with mRCC were all Japanese, and the clinical outcomes of ICI combination therapy could have been influenced by geographic region and ethnicity. Therefore, patient bias could not be controlled. Larger-scale studies are warranted.

In conclusion, our findings suggest that the treatment outcomes of immune combination therapy in patients with mRCC aged ≥ 75 years are not inferior to those in patients younger than 75. IO+IO and IO+TKI are distinct treatment modalities; therefore, understanding their individual characteristics is crucial for appropriate treatment selection and management. ICI-based combination therapy may be an effective treatment option, even in older adult patients.