Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma

Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma Yuki Nemoto, Takanori Endo, Hogara Segawa, Kazutaka Nakamura, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5457716/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Apr, 2025 Read the published version in International Urology and Nephrology → Version 1 posted You are reading this latest preprint version Abstract Purpose To clarify the efficacy and safety profile of nivolumab plus cabozantinib combination therapy in advanced renal cell carcinoma patients older than 80 years. Methods We retrospectively evaluated 42 patients with advanced renal cell carcinoma treated with nivolumab plus cabozantinib as the first-line therapy at our institution. The patients were categorized according to age as those aged ≥ 80 years and those aged < 80 years. Efficacy was analysed by comparing the progression-free survival, overall survival, objective response rate, and disease control rate between the two groups. Safety was assessed by comparing the incidence of adverse events. Results Ten patients (31%) were classified as age ≥ 80 group. No significant differences were observed in the progression-free survival ( p = 0.682), the overall survival ( p = 0.627), objective response rate ( p = 0.195), and disease control rate ( p = 0.070) between the two groups. There was no significant difference in the incidence of all grades of adverse events( p = 1.000), but there was a trend toward a higher incidence of grade 3 or higher adverse events in the group of patients aged < 80 years ( p = 0.066). Conclusions The efficacy and safety of nivolumab plus cabozantinib combination therapy were comparable between the patients aged ≥ 80 years and those aged < 80 years. Thus, chronological age alone is not a contraindication for nivolumab plus cabozantinib combination therapy for advanced renal cell carcinoma. Kidney cancer renal cancer immunotherapy programmed cell death protein 1 tyrosine kinase inhibitor Figures Figure 1 Figure 2 1. Introduction The therapeutic landscape for advanced renal cell carcinoma (aRCC) has changed substantially since the emergence of immune checkpoint inhibitors (ICIs). Currently, ICIs (i.e. pembrolizumab, avelumab, and ipilimumab) targeting immune checkpoints, such as PD-1, PD-ligand 1, and cytotoxic T lymphocyte antigen 4, are the primary treatment for aRCC either in combination with dual ICIs (nivolumab plus ipilimumab) or in combination with tyrosine kinase inhibitors (TKIs) (i.e. pembrolizumab plus axitinib, nivolumab plus cabozantinib, or pembrolizumab plus lenvatinib) [1–4]. In several clinical trials, lesser efficacy of ICI or TKI therapy was observed in elderly patients than in young patients. In the CheckMate 214 trial, nivolumab plus ipilimumab improved the overall survival (OS) compared to sunitinib in patients aged 65 years [1]. In the subgroup analysis of the CheckMate 9ER clinical trial of nivolumab plus cabozantinib, a direct age-specific comparison of the efficacy was not performed. However, for progression-free survival (PFS), the hazard ratio (HR) was 0.44 in patients aged <65 years when comparing the nivolumab plus cabozantinib and sunitinib groups, whereas the HR was 0.68 in patients aged ≥65 years, indicating a trend towards a lower risk [4]. The median age for RCC diagnosis is 64 years, and approximately 50% of kidney tumours in the United States occur in adults aged >65 years [5]. Thus, in clinical practice, elderly patients often require aRCC treatment; a better understanding of the clinical outcomes of ICIs or TKIs in these patients is warranted because such data are limited. Additionally, certain cases present a clinical difference between chronological age and physiological age, and treatment decisions should not necessarily be based uniformly on chronological age alone [6]. Therefore, efforts towards individualized treatment using Geriatric Assessment (GA) are being made in the field of cancer pharmacotherapy. The GA is a scientific evaluation of physical function, comorbidities, nutritional status, mental status, and social background individually for each case, and it has been validated to predict prognosis and adverse events caused by anticancer drugs [5,7]. One of the most popular and internationally used screening tools for GA is the Geriatric-8 (G8), which includes domains of physical function, medications, nutrition, and mood, and it can be applied quickly by medical staff [8]. In a prospective cohort study of cancer patients aged ≥70 years, the G8 was administered before treatment, and patients scoring ≤14 on a 17-point scale had a poorer prognosis than those scoring ≥15 [9]. We previously demonstrated that ICIs such as nivolumab plus ipilimumab as first-line therapy or nivolumab monotherapy as subsequent therapy are as effective and safe in elderly patients with aRCC as in younger patients [10]. Nevertheless, TKI-containing regimens have not been evaluated, and the GA has not been adequately assessed. Therefore, we decided to evaluate the efficacy and safety of nivolumab plus cabozantinib in elderly patients, as the combination regimen is now being used in many patients. 2. Patients and methods 2.1. Study design This retrospective study was approved by the internal Ethics Review Board of the Tokyo Women’s Medical University (ID: 2020-0009) and performed according to the principles of the Declaration of Helsinki. All clinical and laboratory data were obtained from electronic databases and patient medical records. In total, 45 patients received nivolumab plus cabozantinib combination therapy as first-line therapy for aRCC at the Tokyo Women's Medical University Adachi Medical Center from April 2019 to March 2024. Among them, three patients with insufficient follow-up duration were excluded. The remaining 42 patients were included in the study. The efficacy and safety profiles of nivolumab plus cabozantinib treatment were compared across age groups. A cut-off age of 80 years at the start of systemic therapy was used based on the G8 Age Item, a screening tool for elderly cancer patients [ 8 ]. We compared the efficacy and safety profiles of patients aged ≥ 80 years and < 80 years old. In addition, among patients ≥ 80 years of age, patients were divided into two groups: those with G8-screening score ≥ 13 and those with G8-screening score < 13, and each group was also compared for tumor response. 2.2. Protocol for nivolumab plus cabozantinib therapy Nivolumab was administered intravenously at a flat dose of 240 mg every 2 weeks or a flat dose of 480 mg every 4 weeks. Although dose modification of nivolumab was not permitted, the interval could be changed depending on the patient’s condition and the occurrence of adverse events (AEs). Cabozantinib was administered orally at 40 mg/day as the basic dose, alternating between 40 mg and 20 mg daily (similar to 30 mg/day) or 20 mg/day initiation allowed at the attending clinician's discretion, considering the performance status and comorbidities when initiating systemic treatment. To evaluate the tumour response, plain radiography or enhanced computed tomography of the chest, abdomen, and pelvis were conducted at regular intervals of 4–12 weeks, depending on the patient’s condition. Drug administration was continued until radiographic or clinical disease progression was observed or intolerable AEs occurred. 2.3. Evaluation of efficacy To assess the efficacy of nivolumab plus cabozantinib combination therapy, we evaluated the PFS, OS, objective response rate (ORR), and disease control rate (DCR) during the treatment. PFS was calculated from the initiation of systemic treatment until disease progression or death from any cause. OS was calculated from therapy initiation to death from any cause. ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR) as the best overall response, based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1 [ 11 ]. DCR was defined as the percentage of patients achieving CR, PR, or stable disease as the best overall response, based on the RECIST guidelines [ 11 ]. 2.4. Evaluation of safety The safety profile of the ICI-based treatment was assessed by evaluating the incidence and grade of AEs during treatment based on the Common Terminology Criteria for Adverse Events guidelines, version 4 [ 12 ]. 2.5. Statistical analysis All analyses were performed using JMP, version 17 (SAS Institute Inc., Cary, NC, USA). Continuous and categorical variables were analysed using the Mann-Whitney U test and chi-square test, respectively. Survival was calculated using the Kaplan–Meier method and compared using the log-rank test. The risk was expressed as HR with a 95% confidence interval (CI). Differences with a p -value < 0.05 were considered statistically significant. 3. Results 3.1. Patient characteristics based on age Among the 42 patients, 10 (31%) were classified as age ≥ 80 years group, and all of these patients were octogenarian and did not include any patients over 90 years of age. In this group the G8 score, an assessment score for frailty, was used to evaluate the patients. Nine (90%) patients in the age ≥ 80 years group had a G8 score ≤ 14, indicating frailty [ 8 ]. As for the patient characteristics regarding the initial dose of cabozantinib was lower than that of the age < 80 years group ( p < 0.001). No significant differences were observed in sex, Karnofsky Performance Status, prior nephrectomy, histopathological type, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, metastasis status of the lung, liver, bone, brain, lymph nodes, the number of metastatic organ sites, or follow-up period between the two groups ( p > 0.05 for all) (Table 1 ). Table 1 Patients’ characteristics according to age Variable All (n = 42) Age < 80 (n = 32) Age ≥ 80 (n = 10) p value* Age, years 71 (58–79) 65 (56–72) 84 (80–87) < .0001 Sex, male, n (%) 27 (64) 22 (69) 5 (50) 0.280 KPS ≥ 80, n (%) 40 (95) 30 (94) 10 (100) 0.418 G8 score ≤ 14, n (%) – 9 (90) G8 score ≤ 12, n (%) – 5 (50) Prior nephrectomy, n (%) 36 (85) 28 (88) 8 (80) 0.554 Histology, n (%) 0.657 Clear cell renal cell carcinoma 36 (86) 27 (84) 9 (90) IMDC risk, n (%) 0.720 Favorable 12 (29) 9 (28) 3 (30) Intermediate 28 (67) 21 (66) 7 (70) Poor 2 (5) 2 (6) 0 Initinal dose of cabozantinib (%) < .0001 40mg 27 (64) 27 (84) 0 40/20mg alternating dialy 4 (10) 4 (13) 0 20mg 11 (26) 1 (3) 10 (100) Lung metastasis, n (%) 0.234 With (ref. without) 27 (64) 19 (59) 8 (80) Liver metastasis, n (%) 0.240 With (ref. without) 4 (10) 4 (13) 0 Bone metastasis, n (%) 0.610 With (ref. without) 11 (26) 9 (28) 2 (20) Brain metastasis, n (%) f 0.418 With (ref. without) 2 (5) 2 (6) 0 Lymph node metastasis, n (%) 0.449 With (ref. without) 9 (21) 6 (19) 3 (30) Number of organ metastasis, n (%) 0.863 Multiple (ref. single) 22 (52) 17 (53) 5 (50) Follow-up period, months 15.3 (6.4–23.0) 15.6 (6.6–23.6) 12.6 (4.3–21.7) 0.526 * p -values relate to comparisons between ages KPS, Karnofsky Performance Status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium 3.2. Efficacy profile based on age Among the 42 patients, disease progression occurred in 14 (33%), while 8 (19%) patients died during follow-up (median: 15.3 months; interquartile range: 6.4–23.3). The PFS did not differ significantly between the age < 80 years group and the age ≥ 80 years group (median PFS: 20.9 months [95% CI, 14.0–N.R.] vs. 22.5 months [95% CI, 1.6–30.0); p = 0.682) (Fig. 1 a). The OS also did not differ significantly between the age < 80 years group and the age ≥ 80 years group (median OS: 47.3 months [95% CI, 22.5–47.3] vs. N.R. [95% CI, 3.0–N.R.); p = 0.627) (Fig. 1 b). With respect to tumour response, ORR and DCR did not differ significantly between the age < 80 years group and the age ≥ 80 years group (ORR: 88% vs. 70% [ p = 0.195]; DCR: 100% vs. 90% [ p = 0.070]). However, the magnitude of best tumour shrinkage in the target lesions tended to be better in the age < 80 years group than in the age ≥ 80 years group (magnitude of best tumour shrinkage in target lesions: −45.0% vs. −30.9%; p = 0.016) (Table 2 ). Table 2 Tumor response according to age Tumor response All (n = 42) Age < 80 (n = 32) Age ≥ 80 (n = 10) p value* Best overall response, n (%) 0.129 Complete response 2 (5) 2 (6) 0 Partial response 32 (76) 26 (81) 6 (60) Stable disease 7 (17) 4 (13) 3 (30) Progressive disease 1 (2) 0 1 (10) Objective response rate, n (%) 35 (83) 28 (88) 7 (70) 0.195 Disease control rate, n (%) 41 (98) 32 (100) 9 (90) 0.070 Magnitude of best tumor shrinkage in targeted lesions, % -42.2 (-64.7 to -32.2) -45.0 (-68.1 to -34.6) -30.9 (-44.5 to -8.9) 0.016 * p -values relate to comparisons between ages Overall, the univariate analysis of PFS revealed that bone metastasis was a significant factor (HR = 3.42 [95% CI, 1.05–11.1], p = 0.041); however, sex, age, pathological histology, IMDC risk, lung, liver, and lymph node metastases, and multiple metastases were not significant factors for this variable ( p > 0.05 for all) (Table 3 ). Furthermore, univariate analysis of OS also showed that bone metastasis was a significant factor (HR = 25.1 [95% CI, 2.82–224], p = 0.004); however, sex, age, pathological histology, IMDC risk and, lung and multiple metastases were not significant factors for this variable ( p > 0.05 for all) (Table 3 ). Univariate analysis of OS for liver and lymph node metastases was not possible owing to the number of cases. Table 3 Univariate analysis of risk factors for PFS and OS PFS OS Variable HR (95%CI) p value HR (95%CI) p value Sex Male (ref. female) 1.91 (0.58–6.24) 0.286 0.92 (0.20–4.12) 0.910 Age, years ≥ 80 (ref. < 80) 1.28 (0.39–4.22) 0.684 1.51 (0.29–7.80) 0.625 Histology non-ccRCC (ref. ccRCC) 1.62 (0.36–7.36) 0.534 0.86 (0.10–7.18) 0.890 IMDC risk Favorable (ref. Intermediate and Poor) 0.77 (0.17–3.53) 0.741 0.57 (0.07–4.74) 0.601 Lung metastasis With (ref. without) 1.38 (0.42–4.50) 0.593 0.83 (0.19–3.71) 0.805 Liver metastasis With (ref. without) 0.76 (0.10–5.88) 0.794 - - Bone metastasis With (ref. without) 3.42 (1.05–11.1) 0.041 25.1 (2.82–224) 0.004 Lymph node metastasis With (ref. without) 0.65 (0.14–2.96) 0.581 - - Number of organ metastasis Multiple (ref. single) 1.86 (0.60–5.78) 0.284 2.37 (0.46–12.3) 0.302 PFS, progression free survival; OS, overall survival; HR, hazard ratio; RCC, renal cell carcinoma; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium 3.3. Safety profile based on age We compared the incidence and grades of AEs between the age < 80 years group and the age ≥ 80 years group. No difference in the incidence of any grade of AEs was observed between the age < 80 years group and the age ≥ 80 years group (100% vs. 100% [ p = 1.000]) (Table 4 ). In contrast, there was a trend toward a higher incidence of severe grade AEs (i.e., Grade ≥ 3) in the age < 80 years group than in the age ≥ 80 years ( p = 0.066) (Table 4 ). Table 4 AEs according to age Age < 80 (n = 32) Age ≥ 80 (n = 10) p value Any grade 32 (100%) 10 (100%) 1.000 Grade ≥ 3 23 (72%) 4 (40%) 0.066 Interruption of Cabozantinib 27 (84%) 4 (40%) 0.005 Discontinuation of Cabozantinib 5 (16%) 3 (30%) 0.331 Interruption of Nivolumab 5 (16%) 3 (30%) 0.312 Discontinuation of Nivolumab 4 (13%) 2 (20%) 0.554 Discontinuation of Nivo + Cabo 2 (6%) 2 (20%) 0.196 Any grade (n = 32) Grade ≥ 3 (n = 23) Any grade (n = 10) Grade ≥ 3 (n = 4) Cutaneous Rash/pruritus 11 (34%) 1 (3%) 3 (30%) 0 Gastrointestinal Colitis/diarrhea 23 (72%) 5 (16%) 4 (40%) 0 Endocrine Thyroiditis/Hypothyroidism 7 (22%) 0 2 (20%) 0 Adrenal insufficiency 4 (13%) 2 (6%) 2 (20%) 1 (10%) Pulmonary Interstitial pneumonia 1 (3%) 1 (3%) 0 0 Hepatobiliary Elevated hepatic enzyme 24 (75%) 5 (16%) 3 (30%) 1 (10%) Renal Elevated creatinine Proteinurea 1 (3%) 1 (3%) 0 1 (3%) 1 (10%) 0 0 0 Others Elevated pancreatic enzyme 1 (3%) 1 (3%) 0 0 Fatigue 10 (31%) 2 (6%) 6 (60%) 2 (20%) Hand foot syndrome 17 (53%) 4 (13%) 6 (60%) 2 (20%) Heart failure 1 (43%) 1 (3%) 1 (10%) 1 (10%) Hypertension 12 (38%) 5 (16%) 2 (20%) 0 AEs, Adverse events Treatment discontinuation due to cabozantinib AEs was significantly more frequent in the age < 80 years group, but there was no difference in treatment discontinuation between the two groups. For nivolumab, there was no difference in the rate of discontinuation or interruption due to AEs between the two groups (Table 4 ). 3.4. Effectiveness of the G8-screening score In the age ≥ 80 years group, the distribution of G8-screening scores is shown in Table 2 a. Patients were divided into two groups according to whether they scored 13 or more or less than 13 on the G8-screening score, and five patients were classified in each group. Two partial response (PR) and three stable disease in the group with G8-screening score of 13 or more (i.e., patients in better condition) and less than 13 on the G8-screening score group (i.e., patients in poor condition) had 4 cases of PR and 1 case of progressive disease (Fig. 2 b). This means that a poor G8-screening score does not necessarily make nivolumab plus cabozantinib combination therapy less effective. 4. Discussion This single-center retrospective study found that the efficacy of nivolumab plus cabozantinib were similar in the < 80 years and the ≥ 80 years patients with aRCC. According to our analysis, no deterioration in PFS, OS, ORR, and DCR was observed in the < 80 years and the ≥ 80 years patients. However, the maximum tumour reduction was superior in the < 80 years patients than in the ≥ 80 years patients. As for safety, there was no difference between the two groups in any grades, but there was a tendency for severe AEs to be seen more frequently in the < 80 years patients. Unfortunately, no sub-analysis for only Japanese patients exists in the CheckMate 9ER trial. To the best of our knowledge, this study includes the largest Japanese cohort treated with nivolumab plus cabozantinib. A meta-analysis of ICI and TKI combination therapy for non-small cell lung cancer also demonstrated no statistically significant differences in the PFS and OS between the < 80 years and the ≥ 80 years patients [ 13 ]. In the field of RCC, clinical trial data for avelumab plus axitinib combination therapy have reported treatment efficacy in elderly patients aged ≥ 75 years [ 14 ]. According to this report, avelumab plus axitinib combination therapy demonstrated good efficacy and consistent tolerability across all age groups, including those aged ≥ 75 years [ 14 ]. A report in the RCC field has compared the efficacy of ICI and TKI combination therapy using 70 years as the age cut-off and reported poor PFS in the elderly group [ 15 ], which contradicted our findings. This discrepancy could be due to differences in patient background, age cut-off, and inclusion of treatments other than nivolumab plus cabozantinib, such as pembrolizumab plus lenvatinib and pembrolizumab plus axitinib. In pivotal clinical trials of nivolumab and cabozantinib combination therapy, the initial dose of cabozantinib was set at 40 mg [ 4 ]. However, when choosing the same regimen at our institution, the attending physician administered a dose of 20 mg in the elderly patients. Despite this, the efficacy outcomes were almost the same between the < 80 years and the ≥ 80 years patients. The higher incidence of severe AEs in the < 80 years patients may be due to the fact that the < 80 years patients was exposed to relatively higher doses of cabozantinib than the ≥ 80 years patients. The pharmacokinetics-pharmacodynamics trial results from the CheckMate 9ER trial showed no difference in the blood concentration or effects of cabozantinib [ 16 ], suggesting that it is reasonable to start elderly patients on a lower dose to reduce side effects. In elderly patients, comorbidities, drug tolerance, and life expectancy often result in an inability to proceed beyond the first-line treatment [ 17 ]. Therefore, it is important to ensure that the first-line treatment is safely and effectively continued over the long term. Treatment selection for elderly patients is challenging. The International Society of Geriatric Oncology recommends considering physiological age and using tools such as the G8 and Comprehensive Geriatric Assessment (CGA) [ 18 ]. Among these, the G8 is convenient and is often used in clinical practice. Our study used the G8 to assess elderly patients. Although some patients were classified as frail, we did not observe a decline in treatment efficacy or an increase in AEs; hence, it did not seem particularly useful for patient selection. The CGA is another tool used for geriatric assessment. When evaluating treatment with TKIs using the CGA, results have shown that frail patients have significantly poorer prognoses [ 17 ]. This indicates that it may be possible to select better treatments for elderly patients; however, a more straightforward and practical method is needed for real-world clinical use. This study has several limitations. First, the retrospective nature of our analysis combined with the small sample size inevitably introduced selection biases, which may have affected our findings. Second, we could not evaluate the possibility of pseudoprogression because the tumour response was assessed according to the RECIST guidelines, version 1.1, which do not account for this phenomenon. Third, the relatively short follow-up period made it difficult to interpret the survival findings. This retrospective study shows that the efficacy and safety of nivolumab plus cabozantinib as first-line therapy is comparable in the < 80 years and the ≥ 80 years patients with aRCC. This finding suggests that the ICI and TKI combination therapy can be safely used in elderly patients following the same indications and follow-up protocols for young patients. Abbreviations aRCC, advanced renal cell carcinoma; ICIs, immune checkpoint inhibitors; TKIs, tyrosine kinase inhibitors; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; GA, Geriatric Assessment; G8, Geriatric-8; AEs, adverse events; ORR, objective response rate; DCR, disease control rate; CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; N.R., not reached; CGA, Comprehensive Geriatric Assessment Declarations Conflicts of interest Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical. Competing Interests Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution All authors reviewed the manuscript. Data Availability The data that support the findings of this study are available from the corresponding author, upon reasonable request. References Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378: 1277–1290. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380: 1116–1127. Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. 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Cancer Chemother Pharmacol. 2023;91: 179–189. Pierantoni F, Basso U, Maruzzo M, Lamberti E, Bimbatti D, Tierno G, et al. Comprehensive geriatric assessment is an independent prognostic factor in older patients with metastatic renal cell cancer treated with first-line Sunitinib or Pazopanib: a single center experience. J Geriatr Oncol. 2021;12: 290–297. Kanesvaran R, Le Saux O, Motzer R, Choueiri TK, Scotté F, Bellmunt J, et al. Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology. Lancet Oncol. 2018;19: e317–e326. Additional Declarations Competing interest reported. Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical. Cite Share Download PDF Status: Published Journal Publication published 10 Apr, 2025 Read the published version in International Urology and Nephrology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5457716","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":388139626,"identity":"98800396-0b7a-4924-b50a-de749416c24a","order_by":0,"name":"Yuki Nemoto","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Nemoto","suffix":""},{"id":388139627,"identity":"5f6e09f7-9d78-4f8a-b760-fbd9d002da54","order_by":1,"name":"Takanori Endo","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Takanori","middleName":"","lastName":"Endo","suffix":""},{"id":388139628,"identity":"75e1366d-17aa-4f87-856a-298b492441e8","order_by":2,"name":"Hogara Segawa","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hogara","middleName":"","lastName":"Segawa","suffix":""},{"id":388139629,"identity":"a3b3ee78-1d9a-4b4a-94ee-d19a0acd6602","order_by":3,"name":"Kazutaka Nakamura","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kazutaka","middleName":"","lastName":"Nakamura","suffix":""},{"id":388139631,"identity":"c0b2c8d4-d958-4fba-ba03-793806416a2b","order_by":4,"name":"Koichi Nishimura","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Nishimura","suffix":""},{"id":388139633,"identity":"5203ac59-4bf1-4f5a-a973-df9632cefdd8","order_by":5,"name":"Toshihide Horiuchi","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Toshihide","middleName":"","lastName":"Horiuchi","suffix":""},{"id":388139634,"identity":"a511bb5d-3b12-4b63-8c99-bbb3777c0f1a","order_by":6,"name":"Daisuke Toki","email":"","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Toki","suffix":""},{"id":388139639,"identity":"2e153f8f-4b71-408c-9d2e-15175bff40f0","order_by":7,"name":"Hirohito Kobayashi","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hirohito","middleName":"","lastName":"Kobayashi","suffix":""},{"id":388139640,"identity":"1f80d0cb-b74a-4690-b3b0-88bb7820113b","order_by":8,"name":"Toshio Takagi","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Takagi","suffix":""},{"id":388139642,"identity":"66b63f75-3006-4032-983b-4d2c34717052","order_by":9,"name":"Tsunenori Kondo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYBACCSiG8+XgTMYGvFoM4HxjHlK1MCT2EHKYZHvvwRsfGP7YG9xuPvbg4x6L9P0S2WkSDDV2DMyzsVsjzXMu2XIGg0HihjvH0g1nPJPI7ZHI3SbBcCyZgXHOAaxa5CRyzKR5GAwSDG6AGAeAWqRBWtgOMDDOSMCrxd7gRv43kJZ0HrCWf7i1SEO1MG64kcMG0pIA1sLYhluLZM8ZY8sZBsaJM2+kmUnOOCBh2HP/7WaLxL5kHlx+kTjeY3jjQ4WcPd+N5GcSHw7UybP3nN1448M3OzlDHCEGAQboAkAn8RjOwKMDO5CXIKxmFIyCUTAKRgQAAEf5VSi7cCVbAAAAAElFTkSuQmCC","orcid":"","institution":"Tokyo Women’s Medical University Adachi Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Tsunenori","middleName":"","lastName":"Kondo","suffix":""}],"badges":[],"createdAt":"2024-11-15 05:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5457716/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5457716/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11255-025-04486-2","type":"published","date":"2025-04-10T16:05:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71797293,"identity":"12a52638-a4f4-4d9a-89e0-00e938e07f30","added_by":"auto","created_at":"2024-12-18 16:15:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":117162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression-free survival and overall survival according to age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Progression-free survival and (b) overall survival were compared according to age.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; N.R., not reached\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5457716/v1/15bb0258e9173cfd58bbfc41.png"},{"id":71797295,"identity":"43dfffa6-793a-44b2-9f43-8a717f9046d6","added_by":"auto","created_at":"2024-12-18 16:15:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":119201,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eG8-screening score profiles and best response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Distribution of G8-screening score in the age ≥80 years group\u003c/p\u003e\n\u003cp\u003e(b) Best response by G8-screening score\u003c/p\u003e\n\u003cp\u003eCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5457716/v1/f024352f19f8121401574f92.png"},{"id":80558602,"identity":"ccbfcf2a-0f3a-4d9b-84d1-df8bb63a18f3","added_by":"auto","created_at":"2025-04-14 16:14:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1716520,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5457716/v1/80a0da44-639a-4d44-a3ad-ffa86e59f4c7.pdf"}],"financialInterests":"Competing interest reported. Toshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical.","formattedTitle":"Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe therapeutic landscape for advanced renal cell carcinoma (aRCC) has changed substantially since the emergence of immune checkpoint inhibitors (ICIs). Currently, ICIs (i.e. pembrolizumab, avelumab, and ipilimumab) targeting immune checkpoints, such as PD-1, PD-ligand 1, and cytotoxic T lymphocyte antigen 4, are the primary treatment for aRCC either in combination with dual ICIs (nivolumab plus ipilimumab) or in combination with tyrosine kinase inhibitors (TKIs) (i.e. pembrolizumab plus axitinib, nivolumab plus cabozantinib, or pembrolizumab plus lenvatinib) [1\u0026ndash;4].\u003c/p\u003e\n\u003cp\u003eIn several clinical trials, lesser efficacy of ICI or TKI therapy was observed in elderly patients than in young patients. In the CheckMate 214 trial, nivolumab plus ipilimumab improved the overall survival (OS) compared to sunitinib in patients aged \u0026lt;65 years; however, survival rates were similar between the two treatment arms in patients aged \u0026gt;65 years [1]. In the subgroup analysis of the CheckMate 9ER clinical trial of nivolumab plus cabozantinib, a direct age-specific comparison of the efficacy was not performed. However, for progression-free survival (PFS), the hazard ratio (HR) was 0.44 in patients aged \u0026lt;65 years when comparing the nivolumab plus cabozantinib and sunitinib groups, whereas the HR was 0.68 in patients aged \u0026ge;65 years, indicating a trend towards a lower risk [4]. The median age for RCC diagnosis is 64 years, and approximately 50% of kidney tumours in the United States occur in adults aged \u0026gt;65 years [5]. Thus, in clinical practice, elderly patients often require aRCC treatment; a better understanding of the clinical outcomes of ICIs or TKIs in these patients is warranted because such data are limited.\u003c/p\u003e\n\u003cp\u003eAdditionally, certain cases present a clinical difference between chronological age and physiological age, and treatment decisions should not necessarily be based uniformly on chronological age alone [6]. Therefore, efforts towards individualized treatment using Geriatric Assessment (GA) are being made in the field of cancer pharmacotherapy. The GA is a scientific evaluation of physical function, comorbidities, nutritional status, mental status, and social background individually for each case, and it has been validated to predict prognosis and adverse events caused by anticancer drugs [5,7]. One of the most popular and internationally used screening tools for GA is the Geriatric-8 (G8), which includes domains of physical function, medications, nutrition, and mood, and it can be applied quickly by medical staff [8]. In a prospective cohort study of cancer patients aged \u0026ge;70 years, the G8 was administered before treatment, and patients scoring \u0026le;14 on a 17-point scale had a poorer prognosis than those scoring \u0026ge;15 [9].\u003c/p\u003e\n\u003cp\u003eWe previously demonstrated that ICIs such as nivolumab plus ipilimumab as first-line therapy or nivolumab monotherapy as subsequent therapy are as effective and safe in elderly patients with aRCC as in younger patients [10]. Nevertheless, TKI-containing regimens have not been evaluated, and the GA has not been adequately assessed. Therefore, we decided to evaluate the efficacy and safety of nivolumab plus cabozantinib in elderly patients, as the combination regimen is now being used in many patients.\u0026nbsp;\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design\u003c/h2\u003e \u003cp\u003e This retrospective study was approved by the internal Ethics Review Board of the Tokyo Women\u0026rsquo;s Medical University (ID: 2020-0009) and performed according to the principles of the Declaration of Helsinki. All clinical and laboratory data were obtained from electronic databases and patient medical records.\u003c/p\u003e \u003cp\u003eIn total, 45 patients received nivolumab plus cabozantinib combination therapy as first-line therapy for aRCC at the Tokyo Women's Medical University Adachi Medical Center from April 2019 to March 2024. Among them, three patients with insufficient follow-up duration were excluded. The remaining 42 patients were included in the study. The efficacy and safety profiles of nivolumab plus cabozantinib treatment were compared across age groups.\u003c/p\u003e \u003cp\u003eA cut-off age of 80 years at the start of systemic therapy was used based on the G8 Age Item, a screening tool for elderly cancer patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We compared the efficacy and safety profiles of patients aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years and \u0026lt;\u0026thinsp;80 years old.\u003c/p\u003e \u003cp\u003eIn addition, among patients\u0026thinsp;\u0026ge;\u0026thinsp;80 years of age, patients were divided into two groups: those with G8-screening score\u0026thinsp;\u0026ge;\u0026thinsp;13 and those with G8-screening score\u0026thinsp;\u0026lt;\u0026thinsp;13, and each group was also compared for tumor response.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Protocol for nivolumab plus cabozantinib therapy\u003c/h2\u003e \u003cp\u003eNivolumab was administered intravenously at a flat dose of 240 mg every 2 weeks or a flat dose of 480 mg every 4 weeks. Although dose modification of nivolumab was not permitted, the interval could be changed depending on the patient\u0026rsquo;s condition and the occurrence of adverse events (AEs). Cabozantinib was administered orally at 40 mg/day as the basic dose, alternating between 40 mg and 20 mg daily (similar to 30 mg/day) or 20 mg/day initiation allowed at the attending clinician's discretion, considering the performance status and comorbidities when initiating systemic treatment.\u003c/p\u003e \u003cp\u003eTo evaluate the tumour response, plain radiography or enhanced computed tomography of the chest, abdomen, and pelvis were conducted at regular intervals of 4\u0026ndash;12 weeks, depending on the patient\u0026rsquo;s condition. Drug administration was continued until radiographic or clinical disease progression was observed or intolerable AEs occurred.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Evaluation of efficacy\u003c/h2\u003e \u003cp\u003eTo assess the efficacy of nivolumab plus cabozantinib combination therapy, we evaluated the PFS, OS, objective response rate (ORR), and disease control rate (DCR) during the treatment. PFS was calculated from the initiation of systemic treatment until disease progression or death from any cause. OS was calculated from therapy initiation to death from any cause. ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR) as the best overall response, based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. DCR was defined as the percentage of patients achieving CR, PR, or stable disease as the best overall response, based on the RECIST guidelines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Evaluation of safety\u003c/h2\u003e \u003cp\u003eThe safety profile of the ICI-based treatment was assessed by evaluating the incidence and grade of AEs during treatment based on the Common Terminology Criteria for Adverse Events guidelines, version 4 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical analysis\u003c/h2\u003e \u003cp\u003eAll analyses were performed using JMP, version 17 (SAS Institute Inc., Cary, NC, USA). Continuous and categorical variables were analysed using the Mann-Whitney U test and chi-square test, respectively. Survival was calculated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. The risk was expressed as HR with a 95% confidence interval (CI). Differences with a \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Patient characteristics based on age\u003c/h2\u003e \u003cp\u003eAmong the 42 patients, 10 (31%) were classified as age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group, and all of these patients were octogenarian and did not include any patients over 90 years of age. In this group the G8 score, an assessment score for frailty, was used to evaluate the patients. Nine (90%) patients in the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group had a G8 score\u0026thinsp;\u0026le;\u0026thinsp;14, indicating frailty [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. As for the patient characteristics regarding the initial dose of cabozantinib was lower than that of the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in sex, Karnofsky Performance Status, prior nephrectomy, histopathological type, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, metastasis status of the lung, liver, bone, brain, lymph nodes, the number of metastatic organ sites, or follow-up period between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; characteristics according to age\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (58\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (56\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84 (80\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, male, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.280\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKPS\u0026thinsp;\u0026ge;\u0026thinsp;80, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.418\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eG8 score\u0026thinsp;\u0026le;\u0026thinsp;14, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eG8 score\u0026thinsp;\u0026le;\u0026thinsp;12, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior nephrectomy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.554\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.657\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell renal cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIMDC risk, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.720\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFavorable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitinal dose of cabozantinib (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40/20mg alternating dialy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.610\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003ef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.418\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph node metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of organ metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.863\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple (ref. single)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up period, months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.3 (6.4\u0026ndash;23.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.6 (6.6\u0026ndash;23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.6 (4.3\u0026ndash;21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.526\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*\u003cem\u003ep\u003c/em\u003e-values relate to comparisons between ages\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eKPS, Karnofsky Performance Status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Efficacy profile based on age\u003c/h2\u003e \u003cp\u003eAmong the 42 patients, disease progression occurred in 14 (33%), while 8 (19%) patients died during follow-up (median: 15.3 months; interquartile range: 6.4\u0026ndash;23.3). The PFS did not differ significantly between the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group and the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group (median PFS: 20.9 months [95% CI, 14.0\u0026ndash;N.R.] vs. 22.5 months [95% CI, 1.6\u0026ndash;30.0); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.682) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The OS also did not differ significantly between the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group and the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group (median OS: 47.3 months [95% CI, 22.5\u0026ndash;47.3] vs. N.R. [95% CI, 3.0\u0026ndash;N.R.); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.627) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWith respect to tumour response, ORR and DCR did not differ significantly between the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group and the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group (ORR: 88% vs. 70% [\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.195]; DCR: 100% vs. 90% [\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.070]). However, the magnitude of best tumour shrinkage in the target lesions tended to be better in the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group than in the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group (magnitude of best tumour shrinkage in target lesions: \u0026minus;45.0% vs. \u0026minus;30.9%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumor response according to age\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBest overall response, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObjective response rate, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease control rate, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMagnitude of best tumor shrinkage in targeted lesions, %\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-42.2 (-64.7 to -32.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-45.0 (-68.1 to -34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-30.9 (-44.5 to -8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*\u003cem\u003ep\u003c/em\u003e-values relate to comparisons between ages\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOverall, the univariate analysis of PFS revealed that bone metastasis was a significant factor (HR\u0026thinsp;=\u0026thinsp;3.42 [95% CI, 1.05\u0026ndash;11.1], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041); however, sex, age, pathological histology, IMDC risk, lung, liver, and lymph node metastases, and multiple metastases were not significant factors for this variable (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, univariate analysis of OS also showed that bone metastasis was a significant factor (HR\u0026thinsp;=\u0026thinsp;25.1 [95% CI, 2.82\u0026ndash;224], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004); however, sex, age, pathological histology, IMDC risk and, lung and multiple metastases were not significant factors for this variable (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Univariate analysis of OS for liver and lymph node metastases was not possible owing to the number of cases.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of risk factors for PFS and OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003eMale (ref. female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.91 (0.58\u0026ndash;6.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92 (0.20\u0026ndash;4.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;80 (ref. \u0026lt; 80) \u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28 (0.39\u0026ndash;4.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.51 (0.29\u0026ndash;7.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003cp\u003enon-ccRCC (ref. ccRCC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.62 (0.36\u0026ndash;7.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.534\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86 (0.10\u0026ndash;7.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMDC risk\u003c/p\u003e \u003cp\u003eFavorable (ref. Intermediate and Poor)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.77 (0.17\u0026ndash;3.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57 (0.07\u0026ndash;4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.601\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastasis\u003c/p\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38 (0.42\u0026ndash;4.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.83 (0.19\u0026ndash;3.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.805\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastasis\u003c/p\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.76 (0.10\u0026ndash;5.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone metastasis\u003c/p\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.42 (1.05\u0026ndash;11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.1 (2.82\u0026ndash;224)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node metastasis\u003c/p\u003e \u003cp\u003eWith (ref. without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.65 (0.14\u0026ndash;2.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.581\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of organ metastasis\u003c/p\u003e \u003cp\u003eMultiple (ref. single)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.86 (0.60\u0026ndash;5.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.37 (0.46\u0026ndash;12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.302\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ePFS, progression free survival; OS, overall survival; HR, hazard ratio; RCC, renal cell carcinoma; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Safety profile based on age\u003c/h2\u003e \u003cp\u003eWe compared the incidence and grades of AEs between the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group and the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group. No difference in the incidence of any grade of AEs was observed between the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group and the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group (100% vs. 100% [\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000]) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In contrast, there was a trend toward a higher incidence of severe grade AEs (i.e., Grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group than in the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.066) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAEs according to age\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;80 (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAny grade\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e32 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e10 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e23 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e4 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInterruption of Cabozantinib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e27 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e4 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiscontinuation of Cabozantinib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.331\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInterruption of Nivolumab\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.312\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiscontinuation of Nivolumab\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.554\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiscontinuation of Nivo\u0026thinsp;+\u0026thinsp;Cabo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCutaneous\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash/pruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGastrointestinal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColitis/diarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndocrine\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroiditis/Hypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenal insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePulmonary\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHepatobiliary\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated hepatic enzyme\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRenal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated creatinine\u003c/p\u003e \u003cp\u003eProteinurea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOthers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated pancreatic enzyme\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAEs, Adverse events\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTreatment discontinuation due to cabozantinib AEs was significantly more frequent in the age\u0026thinsp;\u0026lt;\u0026thinsp;80 years group, but there was no difference in treatment discontinuation between the two groups. For nivolumab, there was no difference in the rate of discontinuation or interruption due to AEs between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Effectiveness of the G8-screening score\u003c/h2\u003e \u003cp\u003eIn the age\u0026thinsp;\u0026ge;\u0026thinsp;80 years group, the distribution of G8-screening scores is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea. Patients were divided into two groups according to whether they scored 13 or more or less than 13 on the G8-screening score, and five patients were classified in each group. Two partial response (PR) and three stable disease in the group with G8-screening score of 13 or more (i.e., patients in better condition) and less than 13 on the G8-screening score group (i.e., patients in poor condition) had 4 cases of PR and 1 case of progressive disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). This means that a poor G8-screening score does not necessarily make nivolumab plus cabozantinib combination therapy less effective.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis single-center retrospective study found that the efficacy of nivolumab plus cabozantinib were similar in the \u0026lt;\u0026thinsp;80 years and the \u0026ge;\u0026thinsp;80 years patients with aRCC. According to our analysis, no deterioration in PFS, OS, ORR, and DCR was observed in the \u0026lt;\u0026thinsp;80 years and the \u0026ge;\u0026thinsp;80 years patients. However, the maximum tumour reduction was superior in the \u0026lt;\u0026thinsp;80 years patients than in the \u0026ge;\u0026thinsp;80 years patients. As for safety, there was no difference between the two groups in any grades, but there was a tendency for severe AEs to be seen more frequently in the \u0026lt;\u0026thinsp;80 years patients. Unfortunately, no sub-analysis for only Japanese patients exists in the CheckMate 9ER trial. To the best of our knowledge, this study includes the largest Japanese cohort treated with nivolumab plus cabozantinib.\u003c/p\u003e \u003cp\u003eA meta-analysis of ICI and TKI combination therapy for non-small cell lung cancer also demonstrated no statistically significant differences in the PFS and OS between the \u0026lt;\u0026thinsp;80 years and the \u0026ge;\u0026thinsp;80 years patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In the field of RCC, clinical trial data for avelumab plus axitinib combination therapy have reported treatment efficacy in elderly patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. According to this report, avelumab plus axitinib combination therapy demonstrated good efficacy and consistent tolerability across all age groups, including those aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A report in the RCC field has compared the efficacy of ICI and TKI combination therapy using 70 years as the age cut-off and reported poor PFS in the elderly group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which contradicted our findings. This discrepancy could be due to differences in patient background, age cut-off, and inclusion of treatments other than nivolumab plus cabozantinib, such as pembrolizumab plus lenvatinib and pembrolizumab plus axitinib.\u003c/p\u003e \u003cp\u003eIn pivotal clinical trials of nivolumab and cabozantinib combination therapy, the initial dose of cabozantinib was set at 40 mg [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, when choosing the same regimen at our institution, the attending physician administered a dose of 20 mg in the elderly patients. Despite this, the efficacy outcomes were almost the same between the \u0026lt;\u0026thinsp;80 years and the \u0026ge;\u0026thinsp;80 years patients. The higher incidence of severe AEs in the \u0026lt;\u0026thinsp;80 years patients may be due to the fact that the \u0026lt;\u0026thinsp;80 years patients was exposed to relatively higher doses of cabozantinib than the \u0026ge;\u0026thinsp;80 years patients. The pharmacokinetics-pharmacodynamics trial results from the CheckMate 9ER trial showed no difference in the blood concentration or effects of cabozantinib [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], suggesting that it is reasonable to start elderly patients on a lower dose to reduce side effects. In elderly patients, comorbidities, drug tolerance, and life expectancy often result in an inability to proceed beyond the first-line treatment [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, it is important to ensure that the first-line treatment is safely and effectively continued over the long term.\u003c/p\u003e \u003cp\u003eTreatment selection for elderly patients is challenging. The International Society of Geriatric Oncology recommends considering physiological age and using tools such as the G8 and Comprehensive Geriatric Assessment (CGA) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Among these, the G8 is convenient and is often used in clinical practice. Our study used the G8 to assess elderly patients. Although some patients were classified as frail, we did not observe a decline in treatment efficacy or an increase in AEs; hence, it did not seem particularly useful for patient selection. The CGA is another tool used for geriatric assessment. When evaluating treatment with TKIs using the CGA, results have shown that frail patients have significantly poorer prognoses [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This indicates that it may be possible to select better treatments for elderly patients; however, a more straightforward and practical method is needed for real-world clinical use.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the retrospective nature of our analysis combined with the small sample size inevitably introduced selection biases, which may have affected our findings. Second, we could not evaluate the possibility of pseudoprogression because the tumour response was assessed according to the RECIST guidelines, version 1.1, which do not account for this phenomenon. Third, the relatively short follow-up period made it difficult to interpret the survival findings.\u003c/p\u003e \u003cp\u003eThis retrospective study shows that the efficacy and safety of nivolumab plus cabozantinib as first-line therapy is comparable in the \u0026lt;\u0026thinsp;80 years and the \u0026ge;\u0026thinsp;80 years patients with aRCC. This finding suggests that the ICI and TKI combination therapy can be safely used in elderly patients following the same indications and follow-up protocols for young patients.\u003c/p\u003e"},{"header":"Abbreviations","content":" \u003cdiv id=\"Par16\" class=\"Para\"\u003eaRCC, advanced renal cell carcinoma; ICIs, immune checkpoint inhibitors; TKIs, tyrosine kinase inhibitors; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; GA, Geriatric Assessment; G8, Geriatric-8; AEs, adverse events; ORR, objective response rate; DCR, disease control rate; CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; N.R., not reached; CGA, Comprehensive Geriatric Assessment\u003c/div\u003e \u003c/li\u003e\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest\u003c/h2\u003e \u003cp\u003eToshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical.\u003c/p\u003e \u003ch2\u003eCompeting Interests\u003c/strong\u003e\u003cp\u003eToshio Takagi received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb and Ono Pharmaceutical.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMotzer RJ, Tannir NM, McDermott DF, Ar\u0026eacute;n Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378: 1277\u0026ndash;1290.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380: 1116\u0026ndash;1127.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384: 1289\u0026ndash;1300.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021;384: 829\u0026ndash;841.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColl PP, Korc-Grodzicki B, Ristau BT, Shahrokni A, Koshy A, Filippova OT, et al. Cancer Prevention and Screening for Older Adults: Part 1. Lung, Colorectal, Bladder, and Kidney Cancer. J Am Geriatr Soc. 2020;68: 2399\u0026ndash;2406.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDotan E, Walter LC, Browner IS, Clifton K, Cohen HJ, Extermann M, et al. NCCN Guidelines\u0026reg; Insights: Older Adult Oncology, Version 1.2021. J Natl Compr Canc Netw. 2021;19: 1006\u0026ndash;1019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen MLG, Extermann M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32: 2595\u0026ndash;2603.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellera CA, Rainfray M, Mathoulin-P\u0026eacute;lissier S, Mertens C, Delva F, Fonck M, et al. Screening older cancer patients: first evaluation of the G-8 geriatric screening tool. Ann Oncol. 2012;23: 2166\u0026ndash;2172.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKenis C, Decoster L, Van Puyvelde K, De Gr\u0026egrave;ve J, Conings G, Milisen K, et al. Performance of two geriatric screening tools in older patients with cancer. J Clin Oncol. 2014;32: 19\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNemoto Y, Ishihara H, Nakamura K, Tachibana H, Fukuda H, Yoshida K, et al. Efficacy and safety of immune checkpoint inhibitors in elderly patients with metastatic renal cell carcinoma. Int Urol Nephrol. 2022;54: 47\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228\u0026ndash;247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInstitutes of Health N. Common Terminology Criteria for Adverse Events v. 4.0 (CTCAE). Bethesda: NIH.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan X, Tian X, Wu Z, Han W. Impact of Age on the Efficacy of Immune Checkpoint Inhibitor-Based Combination Therapy for Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Front Oncol. 2020;10: 1671.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTomita Y, Motzer RJ, Choueiri TK, Rini BI, Miyake H, Uemura H, et al. Efficacy and safety of avelumab plus axitinib in elderly patients with advanced renal cell carcinoma: extended follow-up results from JAVELIN Renal 101. ESMO Open. 2022;7: 100450.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIinuma K, Yamada T, Kameyama K, Taniguchi T, Kawada K, Ishida T, et al. The Efficacy and Safety of Immune Checkpoint Inhibitor and Tyrosine Kinase Inhibitor Combination Therapy for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Real-World Cohort Study. Cancers. 2023;15. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers15030947\u003c/span\u003e\u003cspan address=\"10.3390/cancers15030947\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran BD, Li J, Ly N, Faggioni R, Roskos L. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. Cancer Chemother Pharmacol. 2023;91: 179\u0026ndash;189.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePierantoni F, Basso U, Maruzzo M, Lamberti E, Bimbatti D, Tierno G, et al. Comprehensive geriatric assessment is an independent prognostic factor in older patients with metastatic renal cell cancer treated with first-line Sunitinib or Pazopanib: a single center experience. J Geriatr Oncol. 2021;12: 290\u0026ndash;297.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanesvaran R, Le Saux O, Motzer R, Choueiri TK, Scott\u0026eacute; F, Bellmunt J, et al. Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology. Lancet Oncol. 2018;19: e317\u0026ndash;e326.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Kidney cancer, renal cancer, immunotherapy, programmed cell death protein 1, tyrosine kinase inhibitor","lastPublishedDoi":"10.21203/rs.3.rs-5457716/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5457716/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo clarify the efficacy and safety profile of nivolumab plus cabozantinib combination therapy in advanced renal cell carcinoma patients older than 80 years.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively evaluated 42 patients with advanced renal cell carcinoma treated with nivolumab plus cabozantinib as the first-line therapy at our institution. The patients were categorized according to age as those aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years and those aged\u0026thinsp;\u0026lt;\u0026thinsp;80 years. Efficacy was analysed by comparing the progression-free survival, overall survival, objective response rate, and disease control rate between the two groups. Safety was assessed by comparing the incidence of adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTen patients (31%) were classified as age\u0026thinsp;\u0026ge;\u0026thinsp;80 group. No significant differences were observed in the progression-free survival (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.682), the overall survival (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.627), objective response rate (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.195), and disease control rate (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.070) between the two groups. There was no significant difference in the incidence of all grades of adverse events(\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000), but there was a trend toward a higher incidence of grade 3 or higher adverse events in the group of patients aged\u0026thinsp;\u0026lt;\u0026thinsp;80 years (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.066).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe efficacy and safety of nivolumab plus cabozantinib combination therapy were comparable between the patients aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years and those aged\u0026thinsp;\u0026lt;\u0026thinsp;80 years. Thus, chronological age alone is not a contraindication for nivolumab plus cabozantinib combination therapy for advanced renal cell carcinoma.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 16:15:53","doi":"10.21203/rs.3.rs-5457716/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3fa69c5b-da9b-4671-bfc8-ba9028ed1bd7","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-14T16:08:38+00:00","versionOfRecord":{"articleIdentity":"rs-5457716","link":"https://doi.org/10.1007/s11255-025-04486-2","journal":{"identity":"international-urology-and-nephrology","isVorOnly":false,"title":"International Urology and Nephrology"},"publishedOn":"2025-04-10 16:05:11","publishedOnDateReadable":"April 10th, 2025"},"versionCreatedAt":"2024-12-18 16:15:53","video":"","vorDoi":"10.1007/s11255-025-04486-2","vorDoiUrl":"https://doi.org/10.1007/s11255-025-04486-2","workflowStages":[]},"version":"v1","identity":"rs-5457716","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5457716","identity":"rs-5457716","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}