Impact of high relative dose intensity on effectiveness and treatment continuity of IO-TKI therapy in Japanese advanced renal cell carcinoma

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A total of 145 patients receiving first-line treatment were analyzed: 55 received IO-TKI therapy and 90 received immuno-oncology combination (IO-IO) therapy. Patients in the IO-TKI group were divided based on an RDI threshold of 80% into high- and low-RDI groups. Median progression-free survival (mPFS) was significantly longer in the IO-TKI group compared to the IO-IO group (P < 0.05), while no significant difference in median overall survival (mOS) was observed (P = 0.53). Interestingly, the mOS tended to be shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI (P = 0.05) and IO-IO groups (P = 0.13). Moreover, treatment discontinuation due to adverse effects occurred earlier in the IO-TKI high-RDI group (P < 0.05). These findings suggest that maintaining an RDI ≥ 80% in IO-TKI therapy may accelerate treatment discontinuation due to AEs and negatively affect the prognosis.. Careful dose adjustment of TKIs may be necessary to optimize outcomes in Japanese patients with RCC receiving IO-TKI combination therapy. Biological sciences/Cancer Health sciences/Oncology relative dose intensity immune checkpoint inhibitor tyrosine kinase inhibitor renal cell carcinoma efficacy adverse event Figures Figure 1 Figure 2 Figure 3 Introduction Renal cell carcinoma (RCC) is among the most malignant cancers [ 1 ]; however, the situation is gradually improving, with the five-year survival rate increasing to approximately 18 owing to the development of immuno-oncology (IO) therapy [ 2 – 7 ]. Five regimens of IO plus tyrosine kinase inhibitor (IO-TKI) therapy and IO combination (IO-IO) therapy are strongly or weakly recommended by the National Comprehensive Cancer Network as standard first-line therapies for RCC, including pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, pembrolizumab plus lenvatinib, and ipilimumab plus nivolumab [ 2 – 7 ]. However, evidence to determine whether IO-TKI or IO-IO therapy is the best treatment option is lacking. To address this gap, evidence to select optimal treatments in terms of efficacy and safety should be gathered. Although evidence for IO-IO therapy is accumulating [ 8 – 12 ], that for IO-TKI therapy is lacking, necessitating further studies to complement the evidence for the efficacy of IO-TKI therapy. Relative dose intensity (RDI), calculated as the ratio of the actual dose to the maximum dose during the planned treatment period, is used to assess the amount of drug administered. RDI is a well-known a simple index associated with chemotherapy efficacy [ 13 , 14 ]. The association of RDI with the efficacy of TKIs is known [ 15 , 16 ]. For example, a higher RDI of TKI used as second-line therapy in patients with RCC is associated with higher efficacy [ 15 ]. In contrast, patients with a high RDI have a higher blood concentration of TKI, leading to a higher incidence of adverse events (AEs), especially the case in Japanese patients [ 17 – 21 ]. Therefore, it is important to investigate the appropriate RDI range in terms of efficacy and safety among Japanese patients receiving TKIs. However, no report has focused on the association between the RDI of TKI and safety in patients with RCC treated with IO-TKI therapy. In this study, we examined whether the RDI of TKI affects the efficacy and safety of IO-TKI therapy in Japanese patients with RCC. Results Patient characteristics in the IO-TKI and IO-IO groups The patient characteristics in the IO-TKI (n = 55) and IO-IO (n = 90) groups are summarized in Supplementary Table S1 . Treatments administered included pembrolizumab plus axitinib (18.2%, n = 10), avelumab plus axitinib (9.1%, n = 5), nivolumab plus cabozantinib (20.0%, n = 11), and pembrolizumab plus lenvatinib (52.7%, n = 29). Age, sex ratio, body weight, histological subtype, sarcomatoid change, and metastasis site (bone, liver, lung, adrenal glands, lymph nodes) did not differ between the IO-TKI and IO-IO groups. The ratios of International mRCC Database Consortium risk classification and metastasis site (brain) differed significantly between the IO-TKI and IO-IO groups. Comparison of efficacy between the IO-TKI and IO-IO groups First, we examined the differences in efficacy between the IO-TKI and IO-IO groups. The best responses in the IO-TKI and IO-IO groups was complete response (CR) in 1.8% (n = 1) and 4.4% (n = 4), partial response (PR) in 58.2% (n = 32) and 37.8% (n = 34), stable disease (SD) in 21.8% (n = 12) and 25.6% (n = 23), and progressive disease (PD) in 3.6% (n = 2) and 27.8% (n = 25) of the patients, respectively (Table 1 ). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the IO-TKI group than those in the IO-IO group (ORR: 60.0% vs. 42.2%; DCR: 81.8% vs. 67.8%; P < 0.05; Table 1 ). Although median progression-free survival (mPFS) in the IO-TKI group was significantly longer than that in the IO-IO group (IO-TKI group, not reached vs. IO-IO group, 12.8 months, P < 0.05; Fig. 1 A), the median overall survival (mOS) did not differ between the IO-TKI and IO-IO groups (IO-TKI group, not reached vs. IO-IO group, 47.4 months, P = 0.53; Fig. 1 B). Table 1 Efficacy data of patients with IO-TKI or IO-IO groups Characteristics, n (%) IO-TKI group IO-IO group P value 55 (100) 90 (100) Best response to treatment, n (%) < 0.05 Complete response 1 (1.8) 4 (4.4) Partial response 32 (58.2) 34 (37.8) Stable disease 12 (21.8) 23 (25.6) Progression disease 2 (3.6) 25 (27.8) Not evaluable 8 (14.5) 4 (4.4) Overall response rate, n (%) 33 (60.0) 38 (42.2) < 0.05 Disease control rate, n (%) 45 (81.8) 61 (67.8) < 0.05 IO: immuno-oncology, TKI: tyrosine kinase inhibitors Association between RDI and clinical outcomes Next, we examined whether the RDI of TKI, which is the period from initiation to the end of IO-TKI therapy, was associated with prognosis and efficacy. The number of patients who maintained an RDI of 80–100% (n = 26) was the highest, followed by those who maintained an RDI of 40–60% (n = 16), 20–40% (n = 9), 60–80% (n = 3), and 0–20% (n = 1; Fig. 2 A). We defined RDI 80% as the cut-off and divided the IO-TKI group into two subgroups based on RDI 80% (IO-TKI low-RDI and IO-TKI high-RDI groups). Patient characteristics did not differ between the IO-TKI low-and high-RDI groups (Supplementary Table S2 ). mPFS of the IO-TKI low-RDI group was significantly longer than that of the IO-IO group (not reached vs. 12.8 months, P < 0.05; Fig. 2 B). The mPFS of the IO-TKI high-RDI group did not differ compared with the IO-TKI low-RDI (not reached vs. not reached, P = 0.88; Fig. 2 B) and IO-IO groups (not reached vs. 12.8 months, P = 0.81; Fig. 2 B). In contrast, the mOS of the IO-TKI low-RDI group did not differ from that of the IO-IO group (not reached vs. 47.4 months, P = 1.00; Fig. 2 C). The mOS of the IO-TKI high-RDI group tended to be shorter than that of the IO-TKI low-RDI (20.0 months vs. not reached, P = 0.05; Fig. 2 C) and the IO-IO groups (20.0 vs. 47.4 months, P = 0.13; Fig. 2 C), suggesting that RDI ≥ 80% may negatively affect prognosis. Association between early discontinuation of treatment and high RDI We examined the association between the incidence of AEs and RDI. The incidence of AEs of any grade in the IO-TKI low-RDI group was higher than that in the IO-TKI high-RDI and IO-IO groups (IO-TKI low-RDI, 96.6%; IO-TKI high-RDI, 73.1%; IO-IO group, 71.1%; Table 2 ). In contrast, the incidence of grade 3 AEs in the IO-IO group was higher than that in the IO-TKI low-RDI and IO-TKI high-RDI groups (IO-TKI low-RDI: 27.6%, IO-TKI high-RDI: 19.2%, IO-IO group: 41.1%, Table 2 ). While the proportion of patients who experienced discontinuation due to PD was highest in the IO-IO group among the three groups (IO-TKI low-RDI, 13.8%; IO-TKI high-RDI, 11.5%; IO-IO group, 51.1%; Table 3 ), the proportion of patients who experienced discontinuation due to AEs was lowest in the IO-IO group among the three groups (IO-TKI low-RDI, 44.8%; IO-TKI high-RDI, 46.2%; IO-IO group, 21.1%; Table 3 ). The proportion of patients who discontinued treatment owing to AEs was similar between the IO-TKI low-RDI and IO-TKI high-RDI groups (Table 3 ). Table 2 The number of patients who experienced any type of AEs IO-TKI low-RDI group IO-TKI high-RDI group IO-IO group P value Number of patients, n (%) 29 (100) 26 (100) 90 (100) Any grade AEs 28 (96.6) 19 (73.1) 64 (71.1) < 0.05 ≥grade 3 AEs 8 (27.6) 5 (19.2) 37 (41.1) 0.08 AEs: adverse events, irAEs: immune-related adverse events, IO: immuno-oncology, TKI: tyrosine kinase inhibitors Table 3 Reasons for discontinuing treatment of patients with IO-TKI or IO-IO groups IO-TKI low-RDI group IO-TKI high-RDI group IO-IO group P value Number of patients, n (%) 29 (100) 26 (100) 90 (100) Discontinued due to progression disease 4 (13.8) 3 (11.5) 46 (51.1) < 0.05 Discontinued due to AEs 13 (44.8) 12 (46.2) 19 (21.1) < 0.05 AEs: adverse events, IO: immuno-oncology, TKI: tyrosine kinase inhibitors Finally, we examined the association between time to treatment discontinuation and RDI. The median time to treatment discontinuation owing to PD in the IO-IO group was the shortest among the three groups (IO-TKI low RDI: not reached vs. IO-TKI high RDI: not reached vs. IO-IO group; 25.0 months, Fig. 3 ). Notably, the median time to treatment discontinuation due to AEs in the IO-TKI high-RDI group was the shortest among the three groups (IO-TKI low-RDI; 13.8 months vs IO-TKI high-RDI; 8.8 months vs IO-IO group: not reached; Fig. 3 ). Discussion This study is the first to report an association between the RDI and the efficacy and continuity of IO-TKI therapy in patients with RCC with two key findings: first, while the efficacy of IO-TKI therapy was higher than that of IO-IO therapy, the prognosis of patients with RCC treated with IO-TKI and IO-IO therapy was comparable. Second, the prognosis of the IO-TKI high-RDI group may be worse because of early treatment discontinuation owing to AEs. Although whether IO-TKI or IO-IO therapy is the best first-line treatment option in terms of efficacy and prognosis is unclear, five studies have analyzed the comparative efficacy and prognosis of IO-TKI and IO-IO therapies in patients with RCC [ 23 – 27 ]. Santoni et al. reported better OS and PFS in the intermediate-risk IO-TKI group than in the intermediate-risk IO-IO group [ 27 ]. In contrast, two study groups reported that PFS in the IO-TKI group was better than that in the IO-IO group but OS did not differ between the IO-TKI and IO-IO therapies [ 23 , 26 ]. Furthermore, the other two Japanese groups showed no differences in terms of OS and PFS between IO-TKI and IO-IO therapies [ 24 , 25 ]. Consistent with the four study groups, our study showed similar OS between the IO-TKI and IO-IO groups (Fig. 1 B). Although the controversial results of our and previous studies are reflected in different patient characteristics, the reports show no difference in long-term survival between IO-TKI and IO-IO therapies. Large-scale clinical studies are needed to address this discrepancy, but an important aspect of RCC treatment for long-term survival is the selection of the first-line treatment after considering multidisciplinary treatment strategies, including second- and third-line therapies and deferred cytoreductive nephrectomy. RDI is a crucial factor associated with efficacy and safety in patients with RCC receiving TKI therapy [ 15 , 16 , 28 ]. For instance, Naoki Fukuda et al. reported significantly longer OS and PFS in patients who received RDI ≥ 60% of lenvatinib than those with thyroid cancer who received RDI < 60% of lenvatinib (OS; not reached vs. 27.6 months, PFS; not reached vs. 11.0 months [ 16 ]). Shirotake reported that RDI < 70% increased the risk of disease progression and poor prognosis in patients with RCC receiving TKI monotherapy [ 15 ]. Although the optimal cutoff value of the TKI-RDI in patients with RCC has not been determined, many researchers have stated that maintaining a high TKI-RDI is important for better efficacy and prognosis. However, our results differ from those of previous studies (Fig. 2 B and C). RDI ≥ 80% is associated with poor prognosis owing to early discontinuation due to AEs (Fig. 2 C and Fig. 3 ). A low RDI is not sufficient. An RDI < 50% may also be associated with poor prognosis (Supplementary Figure S1 ), suggesting that an appropriate range of RDI in terms of efficacy and safety. Planned drug holidays are associated with better clinical outcomes and tolerability [ 29 , 30 ]. Moreover, Noda et al. revealed an appropriate range of blood lenvatinib concentrations to maintain disease control and reduce severe AEs in patients with hepatocellular carcinoma [ 19 ]. Therefore, maintaining the RDI in an appropriate range is important, such as between 50% and 80%, depending on the patient's condition, to safely and effectively continue treatment without early discontinuation in Japanese patients with RCC receiving IO-TKI therapy. The incidence of AEs induced by TKIs is related to the blood concentration of TKIs [ 17 – 21 ]. High blood concentrations of TKIs increase the incidence of AEs, such as anorexia, hypertension, and hepatotoxicity, in patients with hepatocellular carcinoma and thyroid cancer [ 17 – 21 ]. Furthermore, subgroup analysis of clinical trials demonstrated increased blood concentrations of TKIs in Japanese patients with thyroid cancer compared with non-Japanese patients [ 20 ]. Increased blood concentrations of TKI are associated with treatment discontinuation due to AEs [ 21 ]. Interestingly, we found that the time to treatment discontinuation owing to AEs was significantly shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI group (Fig. 3 ). Although the association between the blood concentration of TKIs and the incidence of AEs in patients with RCC remains unclear, several studies have explained this association. Ours and previous studies suggest that physicians should consider the dose of TKI when administering it to Japanese patients with RCC. This study had some limitations that warrant further consideration. The number of participants was small, and because this was a retrospective study, we could not control for patient bias. Furthermore, we validated four different regimens in the IO-TKI group. We did not examine the blood concentration of TKIs or analyze the relationship between RDI and blood concentration. Therefore, we plan to confirm these findings in a large-scale prospective study. In conclusion, an IO-TKI RDI ≥ 80% may negatively affect long-term survival in Japanese patients with RCC treated with IO-TKI therapy. Physicians should carefully adjust the dose of TKIs such that the severity of AEs is manageable, and Japanese patients can continue to receive IO-TKI therapy for an extended period without discontinuing owing to AEs. Methods Patients and treatment We retrospectively analyzed the efficacy and safety of IO-TKI therapy (IO-TKI group (n = 55); pembrolizumab (200 or 400 mg/kg every 3 or 6 weeks) plus axitinib (10 mg twice daily), avelumab (10 mg/kg every 2 weeks) plus axitinib (10 mg twice daily), nivolumab (240 or 480 mg/kg every 2 or 4 weeks) plus cabozantinib (40 mg once daily), and pembrolizumab (200 or 400 mg/kg every 3 or 6 weeks) plus lenvatinib (20 mg once daily) or IO-IO therapy (IO-IO group (n = 90); 1 mg/kg ipilimumab and 240 mg/body nivolumab on day 1, every 3 weeks) as first-line therapy in Japanese patients with RCC between October 2015 and December 2024 at four hospitals in Japan (Nagoya City University Hospital, Kainan Hospital, Anjo Kosei Hospital, and Konan Kosei Hospital). Physicians decided on the first-line treatment from among these five regimens based on the patient’s condition. The TKI dosage during treatment was adjusted by the physician based on the severity of AEs. Pathologists diagnosed RCC based on histological analyses. However, 13 cases were not diagnosed based on the histological subtype because of an insufficient amount of tissue or inability to collect tissue. Therefore, experienced radiologists and urologists diagnosed RCC by computed tomography and magnetic resonance imaging analyses. All data were obtained from the patients’ medical records. This study was approved by the Ethics Committee of Nagoya City University Hospital (approval number 60-22-0076) and conducted following the tenets outlined in the Declaration of Helsinki. As the current study was a retrospective study, patient consent was deemed unnecessary by the approval committee. Patients were also allowed to opt out of the study via the authors’ institutional websites. Evaluation of efficacy Responses were classified by experienced physicians based on radiology reports or imaging reviews using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1: CR, PR, SD, and PD). The ORR and DCR were defined as CR + PR, CR, and PR + SD. All patients were followed up until death or loss of contact. OS was defined as the period from the initiation of IO-TKI or IO-IO therapy to death or loss of contact. PFS was defined as the period from initiation of IO-TKI or IO-IO therapy to disease progression. Evaluation of safety AEs were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RDI The RDI was calculated as the ratio of the actual dose to the maximum dose during the period from initiation till the end of IO-TKI therapy. Statistical analyses A P -value < 0.05 was considered statistically significant. Fisher’s exact test was used to assess differences in patient characteristics. mOS and mPFS were calculated using the Kaplan–Meier method and log-rank tests, followed by the Bonferroni test. The cumulative incidence rates of treatment discontinuation due to PD and AEs were analyzed using Gray's test. Statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 22 ]. Declarations Funding statement: This study was supported by the JSPS KAKENHI Grant Number 25K18657 (Y. Tasaki). Conflict of interest statement: The authors declare no conflict of interest. Author Contribution Yoshihiko Tasaki and Shuzo Hamamoto designed and directed the study. Yoshihiko Tasaki analyzed the majority of the data. Yoshihiko Tasaki, Shuzo Hamamoto, Hiroaki Ikoma, Misato Tomita, Takuya Sakata, Hiroko Suzuki, Yusuke Noda, Masayuki Usami, Yohei Tsubouchi, Toshiharu Morikawa, Yoshihisa Mimura, Yosuke Sugiyama, Takashi Nagai, Rei Unno, Toshiki Etani, Taku Naiki, Yoko Furukawa-Hibi, and Takahiro Yasui acquired the data. Yosuke Sugiyama conducted the statistical analyses. Yoshihiko Tasaki and Shuzo Hamamoto prepared the manuscript. All authors discussed the results and commented on the manuscript. Acknowledgements Yoshihiko Tasaki and Shuzo Hamamoto designed and directed the study. Yoshihiko Tasaki analyzed the majority of the data. Yoshihiko Tasaki, Shuzo Hamamoto, Hiroaki Ikoma, Misato Tomita, Takuya Sakata, Hiroko Suzuki, Yusuke Noda, Masayuki Usami, Yohei Tsubouchi, Toshiharu Morikawa, Yoshihisa Mimura, Yosuke Sugiyama, Takashi Nagai, Rei Unno, Toshiki Etani, Taku Naiki, Yoko Furukawa-Hibi, and Takahiro Yasui acquired the data. Yosuke Sugiyama conducted the statistical analyses. Yoshihiko Tasaki and Shuzo Hamamoto prepared the manuscript. All authors discussed the results and commented on the manuscript. Data Availability The datasets analyzed during the current study available from the first and corresponding author (Yoshihiko Tasaki and Shuzo Hamamoto) on reasonable request. References Siegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. & Jemal, A. Cancer statistics, 2025. CA Cancer J. Clin. 75 , 10–45 (2025). Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl. J. Med. 384 , 829–841 (2021). Hamamoto, S. et al. Efficacy and safety of immuno-oncology plus tyrosine kinase inhibitors as late-line combination therapy for patients with advanced renal cell carcinoma. J. Clin. Med. 13 , 3365 (2024). Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl. J. Med. 384 , 1289–1300 (2021). Motzer, R. J. et al. 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Supplementary Files 4supplementaryfigure.pptx 5supplementarytable.docx Cite Share Download PDF Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 03 Oct, 2025 Reviews received at journal 30 Sep, 2025 Reviewers agreed at journal 24 Sep, 2025 Reviews received at journal 12 Aug, 2025 Reviewers agreed at journal 07 Aug, 2025 Reviewers agreed at journal 05 Aug, 2025 Reviewers invited by journal 05 Aug, 2025 Editor assigned by journal 05 Aug, 2025 Editor invited by journal 16 Jul, 2025 Submission checks completed at journal 14 Jul, 2025 First submitted to journal 14 Jul, 2025 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. 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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-7096420","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":497392675,"identity":"9b6aaadc-964d-4af0-b667-64caaa91bab3","order_by":0,"name":"Yoshihiko Tasaki","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiko","middleName":"","lastName":"Tasaki","suffix":""},{"id":497392676,"identity":"791f52ea-0502-4f34-8c97-acbbd528a02a","order_by":1,"name":"Shuzo 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Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Ikoma","suffix":""},{"id":497392679,"identity":"be840963-5d19-47d3-9237-6ab28912ef5c","order_by":3,"name":"Misato Tomita","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Misato","middleName":"","lastName":"Tomita","suffix":""},{"id":497392681,"identity":"a05b120a-3cab-4762-8190-cc6a587b3ef1","order_by":4,"name":"Takuya Sakata","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Sakata","suffix":""},{"id":497392683,"identity":"b0c542dc-1164-41ef-855f-f61b0e3f8df1","order_by":5,"name":"Hiroko Suzuki","email":"","orcid":"","institution":"Kainan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroko","middleName":"","lastName":"Suzuki","suffix":""},{"id":497392684,"identity":"7b6099ed-3a41-4cab-8c17-502b13732e50","order_by":6,"name":"Yusuke Noda","email":"","orcid":"","institution":"Anjo Kosei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Noda","suffix":""},{"id":497392686,"identity":"40670e83-a61d-463e-97e2-5c6433a8d827","order_by":7,"name":"Masayuki Usami","email":"","orcid":"","institution":"Toyota Kosei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Usami","suffix":""},{"id":497392688,"identity":"cc43ba4a-163f-476e-b0de-9d4634761629","order_by":8,"name":"Yohei Tsubouchi","email":"","orcid":"","institution":"Konan Kosei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Tsubouchi","suffix":""},{"id":497392689,"identity":"9559e68c-b3d2-4cc5-a304-8597a440c693","order_by":9,"name":"Toshiharu Morikawa","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Toshiharu","middleName":"","lastName":"Morikawa","suffix":""},{"id":497392691,"identity":"8fa92deb-b55b-4f67-ae57-adb9ec4161b0","order_by":10,"name":"Yoshihisa Mimura","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yoshihisa","middleName":"","lastName":"Mimura","suffix":""},{"id":497392692,"identity":"301083ac-9d6f-49b6-b1ad-f9a0252ec476","order_by":11,"name":"Yosuke Sugiyama","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Sugiyama","suffix":""},{"id":497392693,"identity":"9f87a045-fcb9-4c07-9055-a5f42cccb758","order_by":12,"name":"Takashi Nagai","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Nagai","suffix":""},{"id":497392694,"identity":"805e9488-f1f2-499a-a99e-15b456d349a0","order_by":13,"name":"Rei Unno","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rei","middleName":"","lastName":"Unno","suffix":""},{"id":497392696,"identity":"b6339b68-b3a8-452b-91c0-1a86bdcd4ba7","order_by":14,"name":"Toshiki Etani","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Toshiki","middleName":"","lastName":"Etani","suffix":""},{"id":497392697,"identity":"91e27c0a-ae58-4db6-a595-2381d5993478","order_by":15,"name":"Taku Naiki","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Taku","middleName":"","lastName":"Naiki","suffix":""},{"id":497392698,"identity":"446f41f3-6092-4138-9ece-767d5d9967e2","order_by":16,"name":"Yoko Furukawa-Hibi","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yoko","middleName":"","lastName":"Furukawa-Hibi","suffix":""},{"id":497392699,"identity":"9ad4b53d-99f2-4c70-8973-d3c23348a77c","order_by":17,"name":"Takahiro Yasui","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Yasui","suffix":""}],"badges":[],"createdAt":"2025-07-10 23:38:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7096420/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7096420/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-43607-4","type":"published","date":"2026-03-12T15:59:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88772996,"identity":"73bc2cee-8a72-463e-8bcb-bbe0bc441a18","added_by":"auto","created_at":"2025-08-11 09:55:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19118,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall and progression-free survival in immuno-oncology plus tyrosine kinase inhibitors and immuno-oncology combination therapy groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA–B, Kaplan–Meier survival curves for (A) progression-free survival (IO-TKI group, n=55; IO-IO group, n=90) and (B) overall survival (IO-TKI group, n=55; IO-IO group, n=90) of patients with renal cell carcinoma. (A–B) Log-rank test using the Bonferroni test. IO, immuno-oncology; TKI, tyrosine kinase inhibitor.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/d1b5d1ffe313e27a8ac8bedf.png"},{"id":88772995,"identity":"6ff195dd-2131-4417-b428-18bff897baae","added_by":"auto","created_at":"2025-08-11 09:55:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33880,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes by relative dose intensity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: The bar graph shows the number of patients at each relative dose intensity. B–C Kaplan–Meier survival curves for (B) progression-free survival (IO-TKI low-RDI group: n=29; IO-TKI high-RDI group: n=26; IO-IO group: n=90) and (C) overall survival (IO-TKI low-RDI group: n=29; IO-TKI high-RDI group: n=26; IO-IO group: n=90) in patients with renal cell carcinoma. (B–C) Log-rank test using the Bonferroni test. IO, immuno-oncology; TKI, tyrosine kinase inhibitor; RDI, relative dose intensity.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/9752c973312a8acc857cc5cd.png"},{"id":88773001,"identity":"ade3d662-e05f-4694-bd78-ffac07319cf6","added_by":"auto","created_at":"2025-08-11 09:55:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27346,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative incidence rate of treatment discontinuation by relative dose intensity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves for the cumulative incidence of treatment discontinuation owing to disease progression and adverse events (IO-TKI low-RDI group, n=29; IO-TKI high-RDI group, n=26; IO-IO group, n=90). Gray's Test. IO, immuno-oncology; TKI, tyrosine kinase inhibitor; RDI, relative dose intensity.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/5ef5c19d9b9597cbffbc70ce.png"},{"id":104739464,"identity":"1a2f5783-bae5-4cbe-b5d7-7ac18743ad99","added_by":"auto","created_at":"2026-03-16 16:07:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":942521,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/83bb6561-eec6-4772-9d51-5bf7042baa4e.pdf"},{"id":88774876,"identity":"3f91e986-67ca-4251-be5c-329965ed6dec","added_by":"auto","created_at":"2025-08-11 10:03:43","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44487,"visible":true,"origin":"","legend":"","description":"","filename":"4supplementaryfigure.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/d2ebe169fab82721f683485c.pptx"},{"id":88773003,"identity":"6b928131-0c53-445a-ad92-26e2124b21e3","added_by":"auto","created_at":"2025-08-11 09:55:43","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":38649,"visible":true,"origin":"","legend":"","description":"","filename":"5supplementarytable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7096420/v1/29f4a943737425dfdbbc3be0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of high relative dose intensity on effectiveness and treatment continuity of IO-TKI therapy in Japanese advanced renal cell carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRenal cell carcinoma (RCC) is among the most malignant cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]; however, the situation is gradually improving, with the five-year survival rate increasing to approximately 18 owing to the development of immuno-oncology (IO) therapy [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Five regimens of IO plus tyrosine kinase inhibitor (IO-TKI) therapy and IO combination (IO-IO) therapy are strongly or weakly recommended by the National Comprehensive Cancer Network as standard first-line therapies for RCC, including pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, pembrolizumab plus lenvatinib, and ipilimumab plus nivolumab [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, evidence to determine whether IO-TKI or IO-IO therapy is the best treatment option is lacking. To address this gap, evidence to select optimal treatments in terms of efficacy and safety should be gathered. Although evidence for IO-IO therapy is accumulating [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], that for IO-TKI therapy is lacking, necessitating further studies to complement the evidence for the efficacy of IO-TKI therapy.\u003c/p\u003e\u003cp\u003eRelative dose intensity (RDI), calculated as the ratio of the actual dose to the maximum dose during the planned treatment period, is used to assess the amount of drug administered. RDI is a well-known a simple index associated with chemotherapy efficacy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The association of RDI with the efficacy of TKIs is known [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. For example, a higher RDI of TKI used as second-line therapy in patients with RCC is associated with higher efficacy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In contrast, patients with a high RDI have a higher blood concentration of TKI, leading to a higher incidence of adverse events (AEs), especially the case in Japanese patients [\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, it is important to investigate the appropriate RDI range in terms of efficacy and safety among Japanese patients receiving TKIs. However, no report has focused on the association between the RDI of TKI and safety in patients with RCC treated with IO-TKI therapy.\u003c/p\u003e\u003cp\u003eIn this study, we examined whether the RDI of TKI affects the efficacy and safety of IO-TKI therapy in Japanese patients with RCC.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient characteristics in the IO-TKI and IO-IO groups\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe patient characteristics in the IO-TKI (n\u0026thinsp;=\u0026thinsp;55) and IO-IO (n\u0026thinsp;=\u0026thinsp;90) groups are summarized in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Treatments administered included pembrolizumab plus axitinib (18.2%, n\u0026thinsp;=\u0026thinsp;10), avelumab plus axitinib (9.1%, n\u0026thinsp;=\u0026thinsp;5), nivolumab plus cabozantinib (20.0%, n\u0026thinsp;=\u0026thinsp;11), and pembrolizumab plus lenvatinib (52.7%, n\u0026thinsp;=\u0026thinsp;29). Age, sex ratio, body weight, histological subtype, sarcomatoid change, and metastasis site (bone, liver, lung, adrenal glands, lymph nodes) did not differ between the IO-TKI and IO-IO groups. The ratios of International mRCC Database Consortium risk classification and metastasis site (brain) differed significantly between the IO-TKI and IO-IO groups.\u003c/p\u003e\u003cp\u003e\u003cb\u003eComparison of efficacy between the IO-TKI and IO-IO groups\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFirst, we examined the differences in efficacy between the IO-TKI and IO-IO groups. The best responses in the IO-TKI and IO-IO groups was complete response (CR) in 1.8% (n\u0026thinsp;=\u0026thinsp;1) and 4.4% (n\u0026thinsp;=\u0026thinsp;4), partial response (PR) in 58.2% (n\u0026thinsp;=\u0026thinsp;32) and 37.8% (n\u0026thinsp;=\u0026thinsp;34), stable disease (SD) in 21.8% (n\u0026thinsp;=\u0026thinsp;12) and 25.6% (n\u0026thinsp;=\u0026thinsp;23), and progressive disease (PD) in 3.6% (n\u0026thinsp;=\u0026thinsp;2) and 27.8% (n\u0026thinsp;=\u0026thinsp;25) of the patients, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the IO-TKI group than those in the IO-IO group (ORR: 60.0% vs. 42.2%; DCR: 81.8% vs. 67.8%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Although median progression-free survival (mPFS) in the IO-TKI group was significantly longer than that in the IO-IO group (IO-TKI group, not reached vs. IO-IO group, 12.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), the median overall survival (mOS) did not differ between the IO-TKI and IO-IO groups (IO-TKI group, not reached vs. IO-IO group, 47.4 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\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\u003eEfficacy data of patients with IO-TKI or IO-IO groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIO-TKI group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIO-IO group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55 (100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90 (100)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBest response to treatment, n (%)\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=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32 (58.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34 (37.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12 (21.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23 (25.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e25 (27.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot evaluable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverall response rate, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33 (60.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e38 (42.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease control rate, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45 (81.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61 (67.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eIO: immuno-oncology, TKI: tyrosine kinase inhibitors\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssociation between RDI and clinical outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNext, we examined whether the RDI of TKI, which is the period from initiation to the end of IO-TKI therapy, was associated with prognosis and efficacy. The number of patients who maintained an RDI of 80\u0026ndash;100% (n\u0026thinsp;=\u0026thinsp;26) was the highest, followed by those who maintained an RDI of 40\u0026ndash;60% (n\u0026thinsp;=\u0026thinsp;16), 20\u0026ndash;40% (n\u0026thinsp;=\u0026thinsp;9), 60\u0026ndash;80% (n\u0026thinsp;=\u0026thinsp;3), and 0\u0026ndash;20% (n\u0026thinsp;=\u0026thinsp;1; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). We defined RDI 80% as the cut-off and divided the IO-TKI group into two subgroups based on RDI 80% (IO-TKI low-RDI and IO-TKI high-RDI groups). Patient characteristics did not differ between the IO-TKI low-and high-RDI groups (Supplementary Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003emPFS of the IO-TKI low-RDI group was significantly longer than that of the IO-IO group (not reached vs. 12.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The mPFS of the IO-TKI high-RDI group did not differ compared with the IO-TKI low-RDI (not reached vs. not reached, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.88; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) and IO-IO groups (not reached vs. 12.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.81; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). In contrast, the mOS of the IO-TKI low-RDI group did not differ from that of the IO-IO group (not reached vs. 47.4 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). The mOS of the IO-TKI high-RDI group tended to be shorter than that of the IO-TKI low-RDI (20.0 months vs. not reached, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) and the IO-IO groups (20.0 vs. 47.4 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.13; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), suggesting that RDI\u0026thinsp;\u0026ge;\u0026thinsp;80% may negatively affect prognosis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssociation between early discontinuation of treatment and high RDI\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe examined the association between the incidence of AEs and RDI. The incidence of AEs of any grade in the IO-TKI low-RDI group was higher than that in the IO-TKI high-RDI and IO-IO groups (IO-TKI low-RDI, 96.6%; IO-TKI high-RDI, 73.1%; IO-IO group, 71.1%; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In contrast, the incidence of grade 3 AEs in the IO-IO group was higher than that in the IO-TKI low-RDI and IO-TKI high-RDI groups (IO-TKI low-RDI: 27.6%, IO-TKI high-RDI: 19.2%, IO-IO group: 41.1%, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). While the proportion of patients who experienced discontinuation due to PD was highest in the IO-IO group among the three groups (IO-TKI low-RDI, 13.8%; IO-TKI high-RDI, 11.5%; IO-IO group, 51.1%; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the proportion of patients who experienced discontinuation due to AEs was lowest in the IO-IO group among the three groups (IO-TKI low-RDI, 44.8%; IO-TKI high-RDI, 46.2%; IO-IO group, 21.1%; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The proportion of patients who discontinued treatment owing to AEs was similar between the IO-TKI low-RDI and IO-TKI high-RDI groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\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\u003eThe number of patients who experienced any type of AEs\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=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" 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\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIO-TKI low-RDI group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIO-TKI high-RDI group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIO-IO group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of patients, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90 (100)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny grade AEs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e28 (96.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19 (73.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e64 (71.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;grade 3 AEs\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (27.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (19.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37 (41.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eAEs: adverse events, irAEs: immune-related adverse events, IO: immuno-oncology, TKI: tyrosine kinase inhibitors\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\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\u003eReasons for discontinuing treatment of patients with IO-TKI or IO-IO groups\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=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" 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\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIO-TKI low-RDI group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIO-TKI high-RDI group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIO-IO group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of patients, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90 (100)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiscontinued due to progression disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (13.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3 (11.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e46 (51.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiscontinued due to AEs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13 (44.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12 (46.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19 (21.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eAEs: adverse events, IO: immuno-oncology, TKI: tyrosine kinase inhibitors\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFinally, we examined the association between time to treatment discontinuation and RDI. The median time to treatment discontinuation owing to PD in the IO-IO group was the shortest among the three groups (IO-TKI low RDI: not reached vs. IO-TKI high RDI: not reached vs. IO-IO group; 25.0 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, the median time to treatment discontinuation due to AEs in the IO-TKI high-RDI group was the shortest among the three groups (IO-TKI low-RDI; 13.8 months vs IO-TKI high-RDI; 8.8 months vs IO-IO group: not reached; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the first to report an association between the RDI and the efficacy and continuity of IO-TKI therapy in patients with RCC with two key findings: first, while the efficacy of IO-TKI therapy was higher than that of IO-IO therapy, the prognosis of patients with RCC treated with IO-TKI and IO-IO therapy was comparable. Second, the prognosis of the IO-TKI high-RDI group may be worse because of early treatment discontinuation owing to AEs.\u003c/p\u003e\u003cp\u003eAlthough whether IO-TKI or IO-IO therapy is the best first-line treatment option in terms of efficacy and prognosis is unclear, five studies have analyzed the comparative efficacy and prognosis of IO-TKI and IO-IO therapies in patients with RCC [\u003cspan additionalcitationids=\"CR24 CR25 CR26\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e–\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Santoni \u003cem\u003eet al.\u003c/em\u003e reported better OS and PFS in the intermediate-risk IO-TKI group than in the intermediate-risk IO-IO group [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In contrast, two study groups reported that PFS in the IO-TKI group was better than that in the IO-IO group but OS did not differ between the IO-TKI and IO-IO therapies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, the other two Japanese groups showed no differences in terms of OS and PFS between IO-TKI and IO-IO therapies [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Consistent with the four study groups, our study showed similar OS between the IO-TKI and IO-IO groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Although the controversial results of our and previous studies are reflected in different patient characteristics, the reports show no difference in long-term survival between IO-TKI and IO-IO therapies. Large-scale clinical studies are needed to address this discrepancy, but an important aspect of RCC treatment for long-term survival is the selection of the first-line treatment after considering multidisciplinary treatment strategies, including second- and third-line therapies and deferred cytoreductive nephrectomy.\u003c/p\u003e\u003cp\u003eRDI is a crucial factor associated with efficacy and safety in patients with RCC receiving TKI therapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. For instance, Naoki Fukuda \u003cem\u003eet al.\u003c/em\u003e reported significantly longer OS and PFS in patients who received RDI ≥ 60% of lenvatinib than those with thyroid cancer who received RDI \u0026lt; 60% of lenvatinib (OS; not reached vs. 27.6 months, PFS; not reached vs. 11.0 months [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]). Shirotake reported that RDI \u0026lt; 70% increased the risk of disease progression and poor prognosis in patients with RCC receiving TKI monotherapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although the optimal cutoff value of the TKI-RDI in patients with RCC has not been determined, many researchers have stated that maintaining a high TKI-RDI is important for better efficacy and prognosis. However, our results differ from those of previous studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and C). RDI ≥ 80% is associated with poor prognosis owing to early discontinuation due to AEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A low RDI is not sufficient. An RDI \u0026lt; 50% may also be associated with poor prognosis (Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), suggesting that an appropriate range of RDI in terms of efficacy and safety. Planned drug holidays are associated with better clinical outcomes and tolerability [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Moreover, Noda \u003cem\u003eet al.\u003c/em\u003e revealed an appropriate range of blood lenvatinib concentrations to maintain disease control and reduce severe AEs in patients with hepatocellular carcinoma [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, maintaining the RDI in an appropriate range is important, such as between 50% and 80%, depending on the patient's condition, to safely and effectively continue treatment without early discontinuation in Japanese patients with RCC receiving IO-TKI therapy.\u003c/p\u003e\u003cp\u003eThe incidence of AEs induced by TKIs is related to the blood concentration of TKIs [\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. High blood concentrations of TKIs increase the incidence of AEs, such as anorexia, hypertension, and hepatotoxicity, in patients with hepatocellular carcinoma and thyroid cancer [\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, subgroup analysis of clinical trials demonstrated increased blood concentrations of TKIs in Japanese patients with thyroid cancer compared with non-Japanese patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Increased blood concentrations of TKI are associated with treatment discontinuation due to AEs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Interestingly, we found that the time to treatment discontinuation owing to AEs was significantly shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Although the association between the blood concentration of TKIs and the incidence of AEs in patients with RCC remains unclear, several studies have explained this association. Ours and previous studies suggest that physicians should consider the dose of TKI when administering it to Japanese patients with RCC.\u003c/p\u003e\u003cp\u003eThis study had some limitations that warrant further consideration. The number of participants was small, and because this was a retrospective study, we could not control for patient bias. Furthermore, we validated four different regimens in the IO-TKI group. We did not examine the blood concentration of TKIs or analyze the relationship between RDI and blood concentration. Therefore, we plan to confirm these findings in a large-scale prospective study.\u003c/p\u003e\u003cp\u003eIn conclusion, an IO-TKI RDI ≥ 80% may negatively affect long-term survival in Japanese patients with RCC treated with IO-TKI therapy. Physicians should carefully adjust the dose of TKIs such that the severity of AEs is manageable, and Japanese patients can continue to receive IO-TKI therapy for an extended period without discontinuing owing to AEs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003ePatients and treatment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe retrospectively analyzed the efficacy and safety of IO-TKI therapy (IO-TKI group (n = 55); pembrolizumab (200 or 400 mg/kg every 3 or 6 weeks) plus axitinib (10 mg twice daily), avelumab (10 mg/kg every 2 weeks) plus axitinib (10 mg twice daily), nivolumab (240 or 480 mg/kg every 2 or 4 weeks) plus cabozantinib (40 mg once daily), and pembrolizumab (200 or 400 mg/kg every 3 or 6 weeks) plus lenvatinib (20 mg once daily) or IO-IO therapy (IO-IO group (n = 90); 1 mg/kg ipilimumab and 240 mg/body nivolumab on day 1, every 3 weeks) as first-line therapy in Japanese patients with RCC between October 2015 and December 2024 at four hospitals in Japan (Nagoya City University Hospital, Kainan Hospital, Anjo Kosei Hospital, and Konan Kosei Hospital). Physicians decided on the first-line treatment from among these five regimens based on the patient’s condition. The TKI dosage during treatment was adjusted by the physician based on the severity of AEs. Pathologists diagnosed RCC based on histological analyses. However, 13 cases were not diagnosed based on the histological subtype because of an insufficient amount of tissue or inability to collect tissue. Therefore, experienced radiologists and urologists diagnosed RCC by computed tomography and magnetic resonance imaging analyses. All data were obtained from the patients’ medical records. This study was approved by the Ethics Committee of Nagoya City University Hospital (approval number 60-22-0076) and conducted following the tenets outlined in the Declaration of Helsinki. As the current study was a retrospective study, patient consent was deemed unnecessary by the approval committee. Patients were also allowed to opt out of the study via the authors’ institutional websites.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEvaluation of efficacy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eResponses were classified by experienced physicians based on radiology reports or imaging reviews using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1: CR, PR, SD, and PD). The ORR and DCR were defined as CR + PR, CR, and PR + SD. All patients were followed up until death or loss of contact. OS was defined as the period from the initiation of IO-TKI or IO-IO therapy to death or loss of contact. PFS was defined as the period from initiation of IO-TKI or IO-IO therapy to disease progression.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEvaluation of safety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAEs were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRDI\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe RDI was calculated as the ratio of the actual dose to the maximum dose during the period from initiation till the end of IO-TKI therapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA \u003cem\u003eP\u003c/em\u003e-value \u0026lt; 0.05 was considered statistically significant. Fisher’s exact test was used to assess differences in patient characteristics. mOS and mPFS were calculated using the Kaplan–Meier method and log-rank tests, followed by the Bonferroni test. The cumulative incidence rates of treatment discontinuation due to PD and AEs were analyzed using Gray's test. Statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding statement:\u003c/h2\u003e\u003cp\u003eThis study was supported by the JSPS KAKENHI Grant Number 25K18657 (Y. Tasaki).\u003c/p\u003e\u003cp\u003eConflict of interest statement: The authors declare no conflict of interest.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYoshihiko Tasaki and Shuzo Hamamoto designed and directed the study. Yoshihiko Tasaki analyzed the majority of the data. Yoshihiko Tasaki, Shuzo Hamamoto, Hiroaki Ikoma, Misato Tomita, Takuya Sakata, Hiroko Suzuki, Yusuke Noda, Masayuki Usami, Yohei Tsubouchi, Toshiharu Morikawa, Yoshihisa Mimura, Yosuke Sugiyama, Takashi Nagai, Rei Unno, Toshiki Etani, Taku Naiki, Yoko Furukawa-Hibi, and Takahiro Yasui acquired the data. Yosuke Sugiyama conducted the statistical analyses. Yoshihiko Tasaki and Shuzo Hamamoto prepared the manuscript. All authors discussed the results and commented on the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eYoshihiko Tasaki and Shuzo Hamamoto designed and directed the study. Yoshihiko Tasaki analyzed the majority of the data. Yoshihiko Tasaki, Shuzo Hamamoto, Hiroaki Ikoma, Misato Tomita, Takuya Sakata, Hiroko Suzuki, Yusuke Noda, Masayuki Usami, Yohei Tsubouchi, Toshiharu Morikawa, Yoshihisa Mimura, Yosuke Sugiyama, Takashi Nagai, Rei Unno, Toshiki Etani, Taku Naiki, Yoko Furukawa-Hibi, and Takahiro Yasui acquired the data. Yosuke Sugiyama conducted the statistical analyses. Yoshihiko Tasaki and Shuzo Hamamoto prepared the manuscript. All authors discussed the results and commented on the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets analyzed during the current study available from the first and corresponding author (Yoshihiko Tasaki and Shuzo Hamamoto) on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. \u0026amp; Jemal, A. Cancer statistics, 2025. \u003cem\u003eCA Cancer J. Clin.\u003c/em\u003e \u003cb\u003e75\u003c/b\u003e, 10\u0026ndash;45 (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChoueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for Advanced Renal-Cell Carcinoma. \u003cem\u003eN Engl. J. 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A prospective cohort study exploring the effect of lenvatinib planned drug holidays in treatment of differentiated thyroid cancer. \u003cem\u003eThyroid\u003c/em\u003e 34, 566\u0026thinsp;\u0026ndash;\u0026thinsp;74 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"relative dose intensity, immune checkpoint inhibitor, tyrosine kinase inhibitor, renal cell carcinoma, efficacy, adverse event","lastPublishedDoi":"10.21203/rs.3.rs-7096420/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7096420/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e This study investigated the impact of relative dose intensity (RDI) on the effectiveness and safety of immuno-oncology plus tyrosine kinase inhibitor (IO-TKI) therapy in Japanese patients with renal cell carcinoma (RCC). A total of 145 patients receiving first-line treatment were analyzed: 55 received IO-TKI therapy and 90 received immuno-oncology combination (IO-IO) therapy. Patients in the IO-TKI group were divided based on an RDI threshold of 80% into high- and low-RDI groups. Median progression-free survival (mPFS) was significantly longer in the IO-TKI group compared to the IO-IO group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while no significant difference in median overall survival (mOS) was observed (P\u0026thinsp;=\u0026thinsp;0.53). Interestingly, the mOS tended to be shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI (P\u0026thinsp;=\u0026thinsp;0.05) and IO-IO groups (P\u0026thinsp;=\u0026thinsp;0.13). Moreover, treatment discontinuation due to adverse effects occurred earlier in the IO-TKI high-RDI group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These findings suggest that maintaining an RDI\u0026thinsp;\u0026ge;\u0026thinsp;80% in IO-TKI therapy may accelerate treatment discontinuation due to AEs and negatively affect the prognosis.. Careful dose adjustment of TKIs may be necessary to optimize outcomes in Japanese patients with RCC receiving IO-TKI combination therapy.\u003c/p\u003e","manuscriptTitle":"Impact of high relative dose intensity on effectiveness and treatment continuity of IO-TKI therapy in Japanese advanced renal cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-11 09:55:38","doi":"10.21203/rs.3.rs-7096420/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-03T09:03:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-30T06:22:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181479178495304734429162556076998872157","date":"2025-09-24T07:23:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-12T06:56:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77095917554498792171438924687377259450","date":"2025-08-07T23:55:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130876103459704184569084227668910607762","date":"2025-08-05T11:54:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-05T11:31:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-05T11:24:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-16T06:40:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-14T09:32:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-07-14T07:08:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a0b6e386-1e16-4f0e-94a8-deac0ca45c7d","owner":[],"postedDate":"August 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":52837325,"name":"Biological sciences/Cancer"},{"id":52837326,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-16T16:03:15+00:00","versionOfRecord":{"articleIdentity":"rs-7096420","link":"https://doi.org/10.1038/s41598-026-43607-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-12 15:59:28","publishedOnDateReadable":"March 12th, 2026"},"versionCreatedAt":"2025-08-11 09:55:38","video":"","vorDoi":"10.1038/s41598-026-43607-4","vorDoiUrl":"https://doi.org/10.1038/s41598-026-43607-4","workflowStages":[]},"version":"v1","identity":"rs-7096420","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7096420","identity":"rs-7096420","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}