ABSTRACT
Introduction
Immune‐related adverse events (irAEs) frequently occur during combination immune checkpoint inhibition. However, their prognostic impact may vary according to organ involvement and severity. In this study, we exploratorily evaluated whether severe non‐endocrine irAEs represent a temporally distinct and prognostically unfavorable clinical phenotype in patients with metastatic renal cell carcinoma (mRCC) treated with ipilimumab plus nivolumab.
Patients and Methods
We analyzed 63 patients with mRCC treated with ipilimumab plus nivolumab who were followed for at least 5 years. Patients were categorized into non‐irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups. Overall survival (OS) was assessed. Multistate modeling was used to evaluate the transitions between treatment, irAE occurrence, and death. Landmark analyses were performed at 8 and 12 weeks to address immortal time bias.
Results
The severe non‐endocrine irAE group was associated with inferior OS. The multistate analysis revealed a potentially increased risk of direct transition from ipilimumab plus nivolumab to death in the severe non‐endocrine irAE group. A significantly higher proportion of patients in the severe non‐endocrine irAE group experienced irAEs within 30 days. No significant association was observed in the 8‐ and 12‐week landmark analyses.
Conclusion
In this exploratory retrospective study, severe non‐endocrine irAEs showed an association with early onset and potentially unfavorable clinical outcomes in patients with mRCC receiving ipilimumab plus nivolumab. Given the limited sample size, these findings should be interpreted cautiously and require confirmation in larger independent cohorts.
Keywords: immune‐related adverse events, immunotherapy, ipilimumab, metastatic renal cell carcinoma, multistate modeling, nivolumab, prognosis
1. Introduction
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced metastatic renal cell carcinoma (mRCC). The combination of ipilimumab plus nivolumab has become a standard first‐line treatment for patients with mRCC, providing durable responses and long‐term survival [1]. However, ipilimumab plus nivolumab therapy is associated with a high incidence of grade ≥ 3 immune‐related adverse events (irAEs) [2].
IrAEs are associated with better survival [3, 4]. However, their prognostic impact remains controversial, particularly for grade ≥ 3 events [5]. Importantly, irAEs are clinically heterogeneous across organ systems [6]. Endocrine irAEs are generally manageable, whereas severe inflammatory irAEs often require high‐dose corticosteroids and may interrupt treatment [6]. These differences suggest that their prognostic impact may depend not only on severity but also on organ involvement. However, the impact of organ‐specific severe irAEs on long‐term outcomes remains unclear.
To address this gap, we conducted a 5‐year multicenter real‐world study using a multistate model to exploratorily evaluate whether the prognostic impact of grade ≥ 3 irAEs differs by organ involvement and determine how this affects treatment transitions and long‐term survival in patients with mRCC treated with ipilimumab plus nivolumab.
2. Methods
2.1. Study Design and Patients
This multicenter retrospective cohort study included 63 patients with mRCC who received ipilimumab plus nivolumab between September 2018 and August 2020 at seven institutions (Nagoya City University Hospital, Kainan Hospital, Anjo Kosei Hospital, Toyota Kosei Hospital, Konan Kosei Hospital, Nagoya Tokushukai General Hospital, and Gamagori City General Hospital) in Japan. Eligible patients had histologically confirmed mRCC and received at least one cycle of ipilimumab plus nivolumab. The patients were followed up until death or data cut‐off (minimum follow‐up of 5 years). We extracted clinical data from medical records. Treatment response was assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 [7].
2.2. Definition of irAEs and Grouping of Participants
IrAEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Given the distinct clinical course and management strategies of endocrine‐related irAEs, which are typically manageable with hormone replacement therapy and rarely require treatment discontinuation, we predefined an organ‐based classification. Specifically, the patients were categorized into three groups: non‐irAE (n = 18), non‐severe + severe endocrine irAE (n = 27), and severe non‐endocrine irAE (n = 18). The non‐severe + severe endocrine irAE group included patients with grade ≤ 2 irAEs and those with isolated grade ≥ 3 endocrine‐related irAEs. In contrast, patients who developed grade ≥ 3 non‐endocrine irAEs were classified as the severe non‐endocrine irAE group, as they frequently require high‐dose corticosteroids or treatment interruption.
2.3. Multistate Model and Landmark Analysis
A multistate model was used to evaluate the association between irAEs during first‐line treatment and subsequent clinical transitions between the non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups. Three states were defined: ipilimumab plus nivolumab therapy (S1), subsequent‐line therapy (S2), and death (S3), with transitions allowed from S1 → S2, S1 → S3, and S2 → S3. Cox proportional hazards models were applied to each transition, treating the onset of grade ≥ 3 irAEs as a time‐dependent covariate. Cluster‐robust standard errors were estimated using patient identifiers. To assess the robustness of the findings from the multi‐state analysis, Firth's penalized Cox regression was additionally performed using the coxphf package. Sensitivity analyses using 8‐week and 12‐week landmark models were also performed. Statistical analyses were performed using R (version 4.5.2; R Foundation for Statistical Computing, Vienna, Austria).
2.4. Statistical Analyses
Statistical significance was set at p < 0.05. Baseline characteristics were compared using the chi‐squared or Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. Overall survival (OS) was defined as the period from the start of ipilimumab plus nivolumab therapy to death or last follow‐up. Progression‐free survival 2 (PFS2) refers to the period from initiation of ipilimumab plus nivolumab to second‐line therapy. OS, PFS, and PFS2 were estimated using the Kaplan–Meier method and compared using the log‐rank test. Univariate and multivariate Cox regression were performed to assess the risk factors for OS between the non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups. Patients who did not develop irAEs were excluded from the analyses of patient characteristics at the initiation of subsequent therapy, multistate analysis, landmark analysis, and the distribution of irAE onset timing because these analyses were applicable only to patients who developed irAEs. Statistical analyses were performed using GraphPad Prism 9 (GraphPad Software, Boston, MA, USA), R, and EZR software [8].
3. Results
3.1. Patient Characteristics and Therapeutic Features
Baseline characteristics are summarized in Table S1. Age and liver metastasis significantly differed among the groups, whereas other clinical variables were balanced. Detailed irAE profiles are provided in Table S2.
Therapeutic features are summarized in Table S3. Completion of four induction cycles was highest in the non‐severe + severe endocrine irAE group and lowest in the severe non‐endocrine irAE group (p < 0.05). Treatment discontinuation due to irAEs occurred more frequently in the severe non‐endocrine irAE group, whereas discontinuation due to disease progression was most common in the non‐irAE group (p < 0.05). Treatment‐free status after ipilimumab plus nivolumab was more frequently observed in the non‐severe + severe endocrine irAE group (p < 0.05). Systemic corticosteroids and steroid pulse therapy were more frequently used in the severe non‐endocrine irAE group, although cumulative dose and duration of steroid therapy were comparable between the groups.
3.2. Severe Non‐Endocrine irAE Negatively Affects Long‐Term Survival
The objective response rate (ORR) and disease control rate (DCR) were 11.1% (n = 2) and 33.3% (n = 6) in the non‐irAE, 59.3% (n = 16) and 81.5% (n = 22) in the non‐severe + severe endocrine irAE, and 38.9% (n = 7) and 72.2% (n = 13) in the severe non‐endocrine groups, respectively (p < 0.05 for both comparisons, Table S3). Notably, the median progression‐free survival (mPFS) and mPFS2 of the severe non‐endocrine irAE group were significantly shorter than those of the non‐severe + severe endocrine irAE group (mPFS, 3.0 vs. 10.1 months; mPFS2, 18.5 months vs. not reached; p < 0.05, Figure 1A,B). The severe non‐endocrine irAE group tended to have worse prognosis compared with the non‐severe + severe endocrine irAE group (mOS, 28.3 vs. 64.4 months; p = 0.10, Figure 1C). In the univariate analysis, the severe non‐endocrine irAE group was significantly associated with inferior OS (hazard ratio [HR] = 2.30, 95% confidence interval [CI] = 1.04–5.09, p < 0.05, Table 1). This association remained significant in the multivariate analysis (HR = 2.50, 95% CI = 1.05–5.97, p < 0.05).
FIGURE 1.
Survival outcomes by irAE severity. (A–C) Kaplan–Meier survival curves for (A) progression‐free survival (non‐irAE group, n = 18; non‐severe + severe endocrine irAE group, n = 27; and severe non‐endocrine irAE group, n = 18), (B) progression‐free survival 2 (non‐irAE group, n = 18; non‐severe + severe endocrine irAE group, n = 27; and severe non‐endocrine irAE group, n = 18), and (C) overall survival (non‐irAE group, n = 18; non‐severe + severe endocrine irAE group, n = 27; and severe non‐endocrine irAE group, n = 18) in patients. (A–C) Log‐rank test. irAE, immune‐related adverse event; mPFS, median progression‐free survival; mOS, median overall survival.
TABLE 1.
Univariate and multivariate Cox regression analyses between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | p | Hazard ratio | 95% CI | p | |
| Age: ≥ 65 years | 1.63 | 0.55–4.77 | 0.36 | |||
| Sex: Male | 1.07 | 0.44–2.59 | 0.86 | |||
| IMDC risk group: Poor | 1.05 | 0.47–2.32 | 0.89 | 1.20 | 0.51–2.80 | 0.66 |
| Karnofsky Performance Status: ≥ 80 | 0.80 | 0.31–2.03 | 0.64 | |||
| Histological subtype, Clear cell: Yes | 0.74 | 0.28–2.00 | 0.56 | 0.68 | 0.24–1.96 | 0.48 |
| Metastasis site, Bone: Yes | 1.78 | 0.78–4.09 | 0.16 | |||
| Metastasis site, Lung: Yes | 0.89 | 0.40–1.96 | 0.77 | |||
| Metastasis site, Lymph node: Yes | 0.46 | 0.13–1.54 | 0.20 | |||
| Metastasis site, Others: Yes | 1.04 | 0.31–3.49 | 0.94 | |||
| Patients who treated steroid therapy due to irAEs: Yes | 1.35 | 0.59–3.07 | 0.47 | 0.95 | 0.24–1.96 | 0.48 |
| Severe non‐endocrine irAE: Yes | 2.30 | 1.04–5.09 | < 0.05 | 2.50 | 1.05–5.97 | < 0.05 |
Abbreviations: CI, confidence interval; irAEs, immune‐related adverse events.
3.3. Temporal Pattern of irAE Onset
The median time to irAE onset tended to be shorter in the severe non‐endocrine irAE group than in the non‐severe + severe endocrine group (23 [range, 0–140] vs. 49 [range, 0–752] days, p = 0.07, Table 2). Notably, severe non‐endocrine irAEs occurred significantly more frequently within the first 30 days of ipilimumab plus nivolumab (61.1% vs. 20.8%, p < 0.05, Table 2). This difference diminished over time, with no significant differences at 8 or 12 weeks (Table 2).
TABLE 2.
Temporal distribution of irAE onset.
| Characteristics, n (%) | irAE | p | |
|---|---|---|---|
| Non‐severe + severe endocrine | Severe non‐endocrine | ||
| 27 (42.9) | 18 (28.6) | ||
| Median time to onset of irAEs, days (range) | 0.07 | ||
| 49 (0.00–752) | 23 (0.00–140) | ||
| Number of patients who had experienced irAEs within 30 days | < 0.05 | ||
| Yes | 5 (20.8) | 11 (61.1) | |
| Number of patients who had experienced irAEs within 8 weeks | 0.53 | ||
| Yes | 13 (54.3) | 12 (66.7) | |
| Number of patients who had experienced irAEs within 12 weeks | 0.73 | ||
| Yes | 17 (70.8) | 14 (77.8) | |
Abbreviation: irAEs, immune‐related adverse events.
3.4. Multistate Model Analysis and Landmark Analysis Between the Non‐Severe + Severe Endocrine irAE and Severe Non‐Endocrine irAE Groups
A swimmer plot is shown in Figure 2. The transition from first‐line therapy to subsequent therapy (S1 → S2) in the severe non‐endocrine irAE group showed a trend toward increased risk compared with the non‐severe + severe endocrine irAE group (HR = 2.35, 95% CI = 0.95–5.79, p = 0.06, Table 3). Furthermore, the transition from subsequent therapy to death (S2 → S3) was not significantly associated with irAE severity between the two groups (HR = 0.35, 95% CI = 0.09–1.28, p = 0.11, Table 3). In contrast, severe non‐endocrine irAEs were significantly associated with an increased risk of direct transition from first‐line therapy to death (S1 → S3) (HR = 14.3, 95% CI = 2.50–81.8, p < 0.05, Table 3). These results indicate that severe non‐endocrine irAEs may be associated with mortality occurring directly from the first‐line treatment rather than uniformly affecting outcomes after subsequent therapy transitions. As the direct transition from first‐line therapy to death (S1 → S3) was based on a limited number of events, we performed a sensitivity analysis using Firth's penalized Cox regression. The results were consistent with the multistate model analysis, with severe non‐endocrine irAEs remaining significantly associated with an increased risk of direct transition to death (HR = 12.3, 95% CI = 3.12–68.4, p < 0.05, Table 3).
FIGURE 2.
Swimmer plot of treatment trajectories according to irAE severity. Swimmer plot illustrating individual treatment duration and clinical course in patients treated with first‐line ipilimumab plus nivolumab, stratified by irAE category (non‐irAE group, non‐severe + severe endocrine irAE group, and severe non‐endocrine irAE group). Each horizontal bar represents an individual patient. Bar length indicates the duration of first‐line therapy followed by subsequent treatment lines when applicable. irAE, immune‐related adverse event.
TABLE 3.
Multistate model and Firth's penalized Cox regression between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
| Transition | Events | Multistate model | Firth's penalized Cox regression | ||
|---|---|---|---|---|---|
| Hazard ratio (95% CI) | p | Hazard ratio (95% CI) | p | ||
| S1 → S2 | 25 | 2.35 (0.95–5.79) | 0.06 | 2.37 (1.03–5.24) | < 0.05 |
| S1 → S3 | 10 | 14.3 (2.50–81.8) | < 0.05 | 12.3 (3.12–68.4) | < 0.05 |
| S2 → S3 | 15 | 0.35 (0.09–1.28) | 0.11 | 0.39 (0.10–1.16) | 0.09 |
Abbreviations: CI, confidence interval; rAEs, immune‐related adverse events.
In the landmark analyses at week 8 (HR = 1.05, 95% CI = 0.39–2.82, p = 0.91) and 12 (HR = 1.23, 95% CI = 0.50–3.04, p = 0.64), no significant correlation was observed between severe irAEs occurring up to that point and subsequent outcomes (Table S4).
3.5. Impact of Severe Non‐Endocrine irAE on the Efficacy and Safety of Subsequent Therapy
The interval from ipilimumab plus nivolumab to second‐line therapy, proportion of patients receiving second‐line treatment, duration of second‐line therapy, ORR, and DCR were comparable between the groups (Table S5). In addition, the incidence of treatment‐related adverse events and treatment discontinuation did not differ significantly (Table S5). Outcomes of third‐line and fourth‐line therapies were likewise comparable (Tables S6 and S7).
4. Discussion
This exploratory retrospective study presented two key findings. First, severe non‐endocrine irAEs were associated with inferior long‐term survival, whereas non‐severe + severe endocrine irAEs did not appear to compromise long‐term survival. Second, severe non‐endocrine irAEs were associated with a higher probability of a direct transition from ipilimumab plus nivolumab therapy to death. In contrast, survival outcomes after successful transition to subsequent therapy were broadly comparable across groups. These findings suggest that the association between severe irAEs and clinical outcomes may depend on organ involvement and that severe non‐endocrine irAEs may affect survival during the first‐line phase rather than reducing the efficacy of later treatments.
The treatment landscape of mRCC has rapidly evolved, and ICI plus tyrosine kinase inhibitor (IO + TKI) therapy is now widely used [9, 10, 11, 12, 13, 14] because of its high response rates and early disease control [15, 16, 17]. In contrast, ipilimumab plus nivolumab therapy yields a shorter PFS than IO + TKI therapy; however, OS appears to be comparable between the two approaches in several studies [15, 16]. Furthermore, ipilimumab plus nivolumab therapy has the potential to produce a durable response and long‐term survival [1]. Thus, despite the increasing use of IO + TKI, ipilimumab plus nivolumab therapy remains an important approach for achieving long‐term remission or potential functional cure in selected patients. A major limitation of ipilimumab plus nivolumab therapy is the high incidence of irAEs [1, 2]. The occurrence of irAEs is often associated with improved survival and interpreted as a surrogate for effective immune activation [3, 4]. However, the present findings suggest that this association is not uniform (Figure 1 and Table 1). Therefore, our data suggest that severe irAEs may not uniformly correlate with favorable prognosis and that organ specificity may influence their clinical significance.
Meanwhile, although the pairwise Kaplan–Meier comparison between the non‐severe + severe endocrine irAE group and severe non‐endocrine irAE group did not reach statistical significance after Bonferroni correction following the overall three‐group analysis (Figure 1C), univariate and multivariate Cox regression analyses directly comparing these two groups identified severe non‐endocrine irAEs to be significantly associated with overall survival (Table 1). This apparent discrepancy likely reflects differences in the statistical methods and use of multiple‐comparison adjustment in the Kaplan–Meier analysis.
Many studies have demonstrated an association between the occurrence of endocrine‐related irAEs and better PFS and OS, indicating that endocrine‐related irAEs may serve as a favorable prognostic biomarker in patients receiving ICIs [18, 19, 20, 21, 22, 23]. Although these previous reports did not consider severity, they support our data classifying severe endocrine‐related irAEs as having a favorable prognosis. Several factors may explain why endocrine‐related irAEs are associated with more favorable prognoses compared with other severe irAEs. First, except in cases such as adrenal crisis, high‐dose corticosteroids are rarely used for endocrine‐related irAEs [24, 25, 26]. Second, once stabilized with appropriate hormone replacement therapy, patients who have experienced endocrine‐related irAEs can resume ICI therapy, including ipilimumab plus nivolumab. In our cohort, the non‐severe + severe endocrine irAE group had higher rates of completing the ipilimumab plus nivolumab therapy and achieving treatment‐free status, suggesting that appropriate management may help maintain treatment continuity and maximize the benefit of immune checkpoint inhibition.
In contrast, severe non‐endocrine irAEs—such as colitis, pneumonitis, or hepatitis—frequently involve systemic inflammatory activation, necessitate high‐dose corticosteroids or steroid pulse therapy, and often lead to treatment interruption or discontinuation [6, 27]. Consistently, in the current study, the severe non‐endocrine irAE group had more patients requiring treatment discontinuation due to irAEs and steroid pulse therapy. Although the relationship between high‐dose corticosteroids or steroid pulse therapy and efficacy of ICI remains unclear, especially in mRCC, some studies have reported a negative correlation [28]. A large‐scale multicenter retrospective study demonstrated that early use of high‐dose glucocorticoids (> 60 mg prednisone equivalent per day) for irAE management is independently associated with worse PFS and OS [29]. Although the precise molecular and immunologic mechanisms underlying the negative effect of high‐dose corticosteroids on ICI efficacy and survival require further elucidation, our findings suggest that the higher proportion of steroid pulse therapy and the increased rate of early mortality during first‐line treatment observed in the severe non‐endocrine irAE group may partly explain the inverse association with long‐term survival in this cohort. However, in our multivariable analysis, steroid initiation was not independently associated with OS, and cumulative dose and treatment duration were comparable between the groups, suggesting that corticosteroid exposure alone does not fully account for the observed prognostic differences.
An alternative explanation is that patients who develop severe non‐endocrine irAE may have an inflammatory state that is associated with poor clinical outcomes. Systemic inflammatory markers are associated with irAEs occurrence in patients receiving ICI therapy [30]. Therefore, the association between severe non‐endocrine irAE and poor survival outcomes may be partly attributable to an underlying inflammatory state that predisposes patients to both severe irAEs and unfavorable clinical outcomes. Further studies using longitudinal immune profiling and biomarker analyses are needed to clarify the mechanisms underlying the association between severe non‐endocrine irAE and survival outcomes.
Interestingly, once patients successfully transitioned to second‐line or later‐line therapy, the efficacy and safety of subsequent treatments were comparable between the non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups. Of note, the adverse prognostic impact was concentrated in the first‐line treatment phase. Severe non‐endocrine irAE may not necessarily be associated with reduced efficacy of second‐line or later‐line therapy. Patients who reached subsequent therapy were still able to derive meaningful benefit, suggesting that survival potential may be preserved if transition to the next therapeutic state is achieved.
Severe non‐endocrine irAE tended to occur earlier than non‐severe + severe endocrine irAEs, with a marked difference within the first 30 days of treatment. More than 60% of patients who experienced severe non‐endocrine irAE developed it within 30 days, whereas only 20.8% of non‐severe + severe endocrine irAEs occurred during this period. This early clustering during the induction phase may partly explain the increased risk of direct transition from first‐line therapy to death observed in the multistate analysis. These findings suggest that the adverse prognostic impact of severe non‐endocrine irAE is temporally concentrated in the early treatment phase. The apparent discrepancy between the multistate and landmark analyses likely reflects the different clinical questions addressed by these methods. Meanwhile, the multistate model evaluated the direct transition from first‐line therapy to death; the landmark analyses evaluated overall survival among patients who survived to the landmark time points.
Our findings highlight the need for predictive biomarkers of irAEs. In this study, severe non‐endocrine irAEs were associated with poorer long‐term survival, primarily due to increased early mortality during first‐line therapy. These results suggest that early identification and appropriate management of high‐risk patients may help maintain treatment continuity and optimize the benefit of immune checkpoint inhibition, as well as support safe transition to second‐line or later‐line therapies. Therefore, establishing reliable biomarkers to predict irAEs is of clinical importance. Numerous studies have reported on multiple candidate biomarkers, including peripheral blood cell parameters, cytokines, autoantibodies, and immune cell subsets [30]. Among these, we have focused on peripheral eosinophils as a biomarker [5]. However, to date, no such practical biomarker has been established. Prospective large‐scale studies integrating immune phenotyping and dynamic biomarker assessment are warranted to validate predictive models for irAEs. The establishment of reliable biomarkers is essential to enable risk‐adapted management strategies and fully realize the long‐term survival benefits of immune checkpoint inhibition.
This study has some limitations, including its retrospective design, modest sample size, baseline imbalances, and the lack of adjustment for multiple comparisons. In particular, the severe non‐endocrine irAE group consisted of only 18 patients, which limited the precision of the estimated effect size and resulted in relatively wide confidence intervals. The wide confidence limits observed in the multistate analysis suggest that these findings should be interpreted as hypothesis‐generating. The relatively small sample size may limit generalizability.
5. Conclusions
In this cohort of patients with mRCC treated with ipilimumab plus nivolumab, the association between severe irAEs and clinical outcomes appeared to differ according to the affected organ system rather than being uniform. Severe non‐endocrine irAEs showed an association with inferior long‐term survival, potentially reflecting an increased risk of early mortality during the first‐line treatment phase. These exploratory findings suggest the potential clinical relevance of early identification and management of severe irAEs; however, validation in larger independent cohorts is required.
Author Contributions
Hiroaki Ikoma: data curation, writing – review and editing. Yusuke Noda: data curation, writing – review and editing. Yoshihiko Tasaki: conceptualization, data curation, formal analysis, writing – original draft, writing – review and editing, funding acquisition. Shuzo Hamamoto: conceptualization, data curation, formal analysis, writing – original draft, writing – review and editing. Yohei Tsubouchi: data curation, writing – review and editing. Hiroko Suzuki: data curation, writing – review and editing. Masayuki Usami: data curation, writing – review and editing. Kengo Kawase: data curation, writing – review and editing. Misato Tomita: data curation, writing – review and editing. Kazumasa Sato: data curation, formal analysis, writing – original draft, writing – review and editing. Takuya Sakata: data curation, writing – review and editing. Rei Unno: data curation, writing – review and editing. Yosuke Sugiyama: data curation, formal analysis, writing – review and editing. Yoshihisa Mimura: data curation, writing – review and editing. Ryuga Kato: data curation, writing – review and editing. Yoko Furukawa‐Hibi: data curation, writing – review and editing, supervision. Toshiki Etani: data curation, writing – review and editing. Takahiro Yasui: data curation, writing – review and editing, supervision. Taku Naiki: data curation, writing – review and editing. Takashi Nagai: data curation, writing – review and editing.
Funding
This work was supported by JSPS KAKENHI (Grant Number 25K18657 to Yoshihiko Tasaki).
Ethics Statement
This study was approved by the institutional review boards of all participating centers (approval number: 70‐25‐0001) and was conducted in accordance with the principles of the Declaration of Helsinki.
Consent
Given the retrospective design of this study, the requirement for written informed consent was waived, and the opt‐out approach allowed patients to decline participation through institutional websites.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Clinical features before ipilimumab plus nivolumab among non irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups.
Table S2: Profile of irAEs.
Table S3: Therapeutic features of ipilimumab plus nivolumab among non irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups.
Table S4: Landmark analyses at 8 and 12 weeks between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S5: Therapeutic features of second‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S6: Therapeutic features of third‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S7: Therapeutic features of fourth‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Acknowledgments
This work was supported by JSPS KAKENHI (Grant Number 25K18657 to Yoshihiko Tasaki).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Clinical features before ipilimumab plus nivolumab among non irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups.
Table S2: Profile of irAEs.
Table S3: Therapeutic features of ipilimumab plus nivolumab among non irAE, non‐severe + severe endocrine irAE, and severe non‐endocrine irAE groups.
Table S4: Landmark analyses at 8 and 12 weeks between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S5: Therapeutic features of second‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S6: Therapeutic features of third‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Table S7: Therapeutic features of fourth‐line therapy between non‐severe + severe endocrine irAE and severe non‐endocrine irAE groups.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.