Real clinical outcomes of nivolumab plus ipilimumab for renal cell carcinoma in patients over 75 years old

Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years. We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1. Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455–1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737–3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877). The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates.


Introduction
Renal cell carcinoma (RCC) usually affects men aged > 60 years [1], with approximately 30% of all patients already having advanced disease at their first admission [2].
Immune-oncology (IO) therapies have remarkably improved the survival rates of patients with metastatic RCC (mRCC) [3,4].Since 2016, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) antibodies have shown remarkable efficacy when used in combination, with increased response rates observed in patients with mRCC classified as being at intermediate and poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) [5].
In the pivotal CheckMate 214 trial, the survival rate of older patients was relatively worse than that of younger patients treated with nivolumab plus ipilimumab (NIVO + IPI) [6].Further, despite RCC being prevalent in the older population [1], life expectancy in developed countries has increased across all ages, such that a person aged 75 in 2020 is likely to live over 15 years in the United States of America [7].Particularly, the mean life expectancy in Japan rose rapidly after World War II and is among the highest in the world [8].However, IO therapies may result in different clinical outcomes in different geographic regions, mainly because the pharmacokinetics of IO drugs may differ based on ethnicity [9].
Consequently, because the evidence for the efficacy and tolerability of NIVO + IPI in aging Asian patients with mRCC is lacking, this study aimed to retrospectively analyze the clinical outcomes and toxicities of NIVO + IPI therapy in Japanese patients with mRCC aged ≥ 75 years.

Eligibility criteria
The Eastern Cooperative Oncology Group (ECOG) performance status (PS) of all patients with histologically proven mRCC were included in this study.

Primary and secondary endpoints
The primary objective of this study was to compare the objective response rate (ORR) of patients with mRCC aged < 75 and ≥ 75 years.The secondary objectives include the comparisons of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs) between the groups.

Treatment and follow-up examinations
The following examinations were performed before initiating treatment and repeated during therapy based on the decision made by the attending physician: medical history, physical examination, ECOG PS, complete blood counts including differential and platelet counts, biochemical profile (including liver and renal function tests, electrolytes, coagulation, pancreatic amylase, and lipase), and urinalysis.Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0.Tumors were measured using computed tomography scans within 4 weeks before initiating NIVO + IPI therapy.After initiating NIVO + IPI, the assessment interval was scheduled for individual patients by the attending physicians.Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors guidelines version 1.1.

Statistical analysis
ORR was described as the percentage of patients in the treatment group who had partial or complete response to NIVO + IPI.PFS was defined as the time between the initiation of NIVO + IPI and disease progression or death as confirmed by radiological imaging or clinical manifestations of progressive disease.OS was defined as the time between NIVO + IPI initiation and death.Database records were closed upon patient death or final follow-up.Data were expressed as interquartile range (IQR), and differences with a p-value < 0.05 were considered statistically significant.The Chi-square test was used to examine the differences in categorical data.PFS and OS were stratified using the Kaplan-Meier method.The Cox proportional hazard regression model was used to analyze the hazard ratios (HR) and 95% confidence intervals (CI).Statistical analyses were performed using SPSS version 26.0 statistical software (SPSS Japan Inc., Tokyo, Japan).To reduce the effect of selection bias and potential confounders in this observational study, we performed a propensity score analysis.Propensity scores were calculated for each patient using multivariate logistic regression analysis with the following selected as covariates: sex, histology, history of nephrectomy, clinical stage at first diagnosis, and the IMDC risk classification system.

Patient characteristics
This study enrolled 120 patients diagnosed with advanced RCC and treated with NIVO at the participating institutes between August 2015 and January 2023.All patients received at least one cycle of NIVO + IPI and were assessed for treatment efficacy and toxicity.The median patient age was 68 (IQR, 61-73) years.All patients were Japanese and included 86 (71.7%) men and 34 (28.3%)women.At NIVO + IPI therapy initiation, 26 patients were aged ≥ 75 years, while 94 patients were aged < 75 years.On observation, the characteristics of the two groups were comparable (Tables 1 and 2).However, no significant differences were found between the groups regarding factors such as the history of nephrectomy, histology, clinical stage, risk per the IMDC risk classification system, and the number of target sites.

AEs
At the time of data cut-off, 80 (66.7%) patients had experienced an AE (Table 4).Further, 9 (7.5%) patients discontinued NIVO + IPI treatment because of AEs, and 47 (24.6%) presented with AEs of grade 3 or higher.There were no significant differences in the incidence of all AEs of grade ≥ 3 between the two groups (58% vs. 69%, p = 0.239; 38% vs. 39%, p = 1.000).The incidence of NIVO discontinuation due to AEs was equivalent between groups (14.3% vs. 12.7%, p = 0.877) (Table 3).Details of all AEs are summarized in Table 4. Corticosteroids were administered as the primary treatment for immune-related AEs (irAEs), except for hypophysitis, adrenal insufficiency, and type I diabetes mellitus because these irAEs were no longer expected to resolve.Additionally, we administered only steroid supplements or continuous insulin to patients who developed endocrinological insufficiency.

Discussion
We found that the therapeutic efficacy of NIVO + IPI was similar between patients with mRCC aged ≥ 75 and those < 75 years with respect to their ORR, PFS, and OS  rates.In addition, the frequency and severity of AEs did not differ between the two groups, and the incidence of treatment discontinuation due to AEs was also equivalent between the groups.NIVO + IPI is the standard first-line treatment for mRCC in intermediate-and poor-risk patients; however, according to the findings of CheckMate 214, it may be more effective in young than in old patients.Besides, in an age subgroup analysis of patients included in a pivotal study, the OS rate of the NIVO + IPI arm was inferior in patients aged ≥ 75 years compared to those < 65 years who showed superior OS (HR: 0.53, 95% CI 0.40-0.71)[6].However, the authors in the above study discussed that the survival benefit from NIVO + IPI was unclear in patients aged ≥ 75 years, as only 8.2% of the patients who received NIVO + IPI were aged ≥ 75 years, and the intergroup difference was not statistically significant (HR: 0.97, 95% CI 0.48-1.95)[6].Therefore, they could not fully assess the efficacy of NIVO + IPI in older patients.

A B
A prior study reported that the meager survival outcome of older patients might be associated with immune senescence, deterioration of the immune system, and disorders related to adaptive and cell-mediated immunity secondary to thymic involution [10].Immune-senescence is characterized by the loss of naive CD8 + T cells coupled with an increase in memory subsets [11], skewed T cell receptor repertoire [12], and immune cells, creating a tolerogenic environment composed of regulatory T cell populations [13].Memory T cells generated from naïve T cells of older individuals demonstrate lower proliferation rates and effector cytokine production [14], resulting in an inferior immune response compared to those generated from naïve T cells of younger individuals [15].Another possible explanation is that epigenetic alterations in aging immune and cancer cells also play a role in anti-cancer response [16], as demonstrated in the ongoing studies on epigenetic biomarkers and combined epigenetic therapy with immunotherapy [17].Hence, because of the above-mentioned immune alterations, there is an ongoing debate regarding the effects of aging on the immune checkpoint system [18].
Despite some concerns regarding the immune system in older adults, favorable responses and adequate tolerability of IO drugs have been reported in older patients with melanoma and non-small cell lung cancer [19][20][21].Although some studies have reported that the mutational load of cancer cells can increase in an age-dependent manner [22], others have shown that advanced age is also associated with increased production of pro-inflammatory cytokines and autoantibodies, which might lead to subclinical autoimmune diseases in the older population [23].Therefore, we consider that these interesting aspects of tumor and immune biology might explain why anti-PD-1 antibodies or PD-L1 inhibitors remain effective in older patients [24].However, in this study, 88% of our patients showed a favorable response (including partial response or disease stability).In addition, our results also showed better outcomes, even in patients aged ≥ 75 years, than those in the earlier mentioned pivotal study [6].Regardless of these findings, an outcome comparison among different studies was not feasible.Hence, further large-scale studies are necessary to elucidate the clinical benefits of NIVO + IPI therapy in older patients.This study has some limitations.First, because of the retrospective design, there were no general guidelines regarding the treatment indication, decision for NIVO + IPI discontinuation, and administration of steroids for AEs.Second, selection bias might exist because patient characteristics differed between the groups at the start of NIVO + IPI therapy.Third, the optimal cut-off age was not confirmed.Although 75 years was used as the cut-off age in accordance with a pivotal study [6], the optimal age might be different from that used in registration studies.Finally, the main limitation of this study is the lack of statistical power, which might lead to type II error owing to our small sample size.Therefore, studies with larger cohorts are required to validate these results.
In conclusion, we have shown that the effectiveness of NIVO + IPI in the treatment of patients with mRCC aged ≥ 75 years was comparable to that in patients aged < 75 years.In addition, no significant differences were found in ORR, PFS, OS, and AE incidence rates between the groups.Thus, our study suggests that NIVO + IPI therapy may be effective and well-tolerated by patients with mRCC aged ≥ 75 years.

Fig. 1 Fig. 2
Fig. 1 Progression-free survival (A) and overall survival (B) were compared between nivolumab plus ipilimumab-treated patients with mRCC aged ≥ 75 and < 75 years using the Cox proportional hazard regression model, and the Kaplan-Meier curve was plotted

Fig. 3
Fig.3Progression-free survival (A) and overall survival (B) were compared between nivolumab plus ipilimumab-treated patients with mRCC aged ≥ 75 and < 75 years after adjusting for sex, histology, his-

Table 2
Treatment outcome of nivolumab plus ipilimumab therapy for mRCC mRCC metastatic renal cell carcinoma, CR complete remission, PR partial response, SD stable disease, PD progressive disease

Table 3
Summary of adverse eventsPD progressive disease, AE adverse event, irAE immune-related adverse event

Table 4
Immuno-related adverse events in the both groups irAE immune related adverse event, DM diabetes mellitus, ALS amyotrophic lateral sclerosis