Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study

Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study | 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 Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study Shuichiro Hara, Tomoki Makino, Shigeto Nakai, Kota Momose, Kotaro Yamashita, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9186071/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO+IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. Methods: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO+IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. Results: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13–not reached) and 5 months (95% CI: 3–8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein–to–albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI: 1.35–6.63, P = 0.0071). Conclusions: In this large real-world cohort, first-line NIVO+IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection. Figures Figure 1 Figure 2 Figure 3 Introduction Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with poor prognosis despite recent advances in multimodal therapy. 1-3 Immune checkpoint inhibitors have revolutionized the management of several solid tumors, and nivolumab-based regimens have become a standard treatment option for advanced ESCC. 4,5 The phase III CheckMate 648 trial demonstrated that the combination of nivolumab (anti-PD-1 antibody) plus ipilimumab (anti-CTLA-4 antibody) significantly improves overall survival (OS) compared with conventional chemotherapy in the first-line setting, 6,7 leading to worldwide regulatory approval. However, clinical experience with ipilimumab plus nivolumab (NIVO+IPI) for ESCC has been largely limited to this single pivotal trial, and even fewer data are available for Japanese patients. 8 No large-scale real-world data have been published to date, and questions remain regarding the generalizability, safety profile, and efficacy of NIVO+IPI in broader clinical populations, including elderly patients, those with prior chemoradiotherapy, or those with compromised performance status. Importantly, the efficacy and toxicity of immune checkpoint blockade are known to be influenced by host immune-inflammatory status and by tumor immune microenvironment, which may vary according to metastatic organ sites. Given that immune-related adverse events (irAEs) and treatment feasibility may differ between controlled trials and routine practice, 9-11 real-world evidence is essential to establishing the external validity of dual checkpoint blockade in ESCC. Despite these considerations, large-scale real-world analyses evaluating clinical outcomes, organ-specific responses, and immune-related toxicity profiles of NIVO+IPI in ESCC are lacking. To address this knowledge gap, we conducted a multicenter retrospective study of 111 patients treated with first-line NIVO+IPI for unresectable or recurrent ESCC. To the best of our knowledge, this study represents the largest real-world cohort reported to date, providing clinically and immunologically relevant insights into treatment efficacy, organ-specific response patterns, safety, and host-related prognostic factors in patients receiving dual immune checkpoint inhibition. Patients and Methods Study design and patients This multicenter retrospective study included patients with histologically confirmed ESCC who received first-line NIVO+IPI for unresectable or recurrent disease between 2017 and 2024 at participating institutions. Patients were eligible for inclusion if they met all of the following criteria: unresectable or recurrent esophageal cancer treated with or scheduled to be treated with the NIVO+IPI regimen as systemic therapy; histologically confirmed squamous cell carcinoma of the esophagus, verified by pathological examination; presence of at least one measurable or evaluable lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and age ≥20 years at the time of informed consent. Written informed consent was obtained from all patients prior to study enrollment. Patients with active multiple primary malignancies at the initiation of NIVO+IPI therapy were excluded. Active malignancies included synchronous cancers or metachronous cancers diagnosed within 5 years, except for carcinoma in situ or intramucosal lesions judged to be curatively treatable by local therapy, which were not considered active malignancies. The study was approved by the institutional review boards of all participating institutions. Treatment regimen Treatment with NIVO+IPI consisted of 360 mg nivolumab repeated every 3 weeks and 1 mg/kg ipilimumab repeated every 6 weeks according to the dosing schedule adopted in the CheckMate 648 trial. 6-8 Dose modifications were not routinely performed; treatment-related adverse events (TRAEs) including irAEs were managed in accordance with institutional guidelines based on the ESMO recommendations. 12 Treatment was continued until obvious disease progression, unacceptable toxicity, or the patient’s refusal to continue the treatment. Evaluation of response Tumor response was assessed every 6 weeks using RECIST version 1.1 and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). 1 The objective response rate (ORR) was defined as the proportion of patients achieving CR or PR, and the disease control rate (DCR) included CR, PR, and SD. Progression-free survival (PFS) was measured from treatment initiation to disease progression or death, and OS was measured from treatment initiation to death from any cause. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For patients with steroid-refractory TRAEs ≥Grade 3, second-line immunosuppression with mycophenolate mofetil was implemented, consistent with previous Japanese reports. 8 Statistical analysis The relationships between clinicopathological characteristics and tumor response status were analyzed using the chi-squared test for categorical variables. Survival rates were estimated using the Kaplan–Meier method and compared by the log-rank test. The prognostic variables that were significantly associated with OS in the univariate analyses were further assessed in a multivariate Cox proportional hazard model. P < 0.05 was considered to indicate significance. Results Patient characteristics Patient characteristics are provided in Table 1 . A total of 111 patients (86% male) were enrolled in this study, including 40 with unresectable advanced disease and 71 with recurrent disease. Most patients had good performance status (PS 0–1 in 91%). Tumor location was distributed across the cervical/upper thoracic, middle thoracic, and lower thoracic/abdominal esophagus. One metastatic organ was present in 69% of patients, whereas 24% had two metastatic sites and 5% had three or more. The median body mass index (BMI), albumin, neutrophil–lymphocyte ratio (NLR), and C-reactive protein–to–albumin ratio (CAR) indicated generally preserved nutritional and inflammatory profiles at treatment initiation. Table 1. Patient characteristics Characteristic N=111 Age, years Median (range) 73 (52-88) Sex Male/female 96/15 Performance status 0/1/2/3 58/43/7/3 History of smoking n 90 Tumor status Unresectable advanced/recurrence 40/71 Tumor location CeUt/Mt/LtAe 25/51/35 Number of metastatic organs 0/1/2/≥3 3/77/24/5 History of surgery n 68 History of radiation therapy n 10 BMI, kg/m 2 Median (range) 20.1 (13.9-29.0) Albumin, g/dL Median (range) 3.8 (2.3-5.0) NLR Median (range) 3.1 (0.8-22.5) CAR Median (range) 0.1 (0.8-8.6) BMI, body mass index; NLR, neutrophil–lymphocyte ratio; CAR, C-reactive protein-to-albumin ratio Treatment efficacy The best ORR is shown in Supplementary Table 1 . In the cases with target lesions, CR and PR were observed in 6 (8.0%) and 27 (36.0%) cases, respectively, whereas PD occurred in 22 (29.3%) cases, indicating the best ORR and a DCR are 44.0% (33/75) and 70.7% (53/75), respectively. Figure 1 shows the organ-specific response to NIVO+IPI; the DCR by metastasis site was 84.4% (65/77) for lymph nodes, 72.4% (21/29) for the lungs, and 70.0% (7/10) for the liver, whereas the DCR of the primary lesion was 56.5% (13/21). Table 2 compares patient characteristics according to treatment response. Patients with PD after NIVO+IPI therapy had a significantly lower BMI at treatment initiation than patients with non-PD ( P = 0.0154) . Figure 1: Organ-specific responses to treatment with ipilimumab plus nivolumab. CR, complete response; LN, lymph node; PD, progressive disease; PR, partial response; SD, stable disease. Table 2. Comparison of patient characteristics according to treatment response Characteristics Non-PD (n=53) PD (n=22) P -value Age 0.3121 < 75 years 27 (65.9%) 14 (34.2%) ≥ 75 years 26 (76.5%) 8 (23.5%) Sex 0.2712 Male 43 (68.3%) 20 (31.8%) Female 10 (83.3%) 2 (16.7%) PS 0.8244 0-1 49 (71.0%) 20 (29.0%) 2-3 4 (66.7%) 2 (33.3%) Tumor status 0.6777 Unresectable advanced 22 (73.3%) 8 (26.7%) Recurrence 31 (68.9%) 14 (31.1%) BMI 0.0154 < 20 kg/m 2 20 (57.1%) 15 (42.9%) ≥ 20 kg/m 2 33 (82.5%) 7 (17.5%) CAR 0.2300 ≥ 0.4 8 (57.1%) 6 (42.9%) < 0.4 45 (73.8%) 16 (26.2%) NLR 0.7618 ≥ 4.0 15 (68.2%) 7 (31.8%) < 4.0 38 (71.7%) 15 (28.3%) PNI 0.4647 ≥ 45 29 (74.4%) 10 (25.6%) < 45 24 (66.7%) 12 (33.3%) Values are given as n (%). BMI, body mass index; CAR, C-reactive protein-to-albumin ratio; NLR, neutrophil–lymphocyte ratio; PD, progressive disease; PNI, prognostic nutritional index; PS, performance status Treatment-related adverse events (TRAEs) TRAEs ≥Grade 2 and ≥Grade 3 occurred in 58 (52.3%) and 32 (28.8%) patients, respectively ( Supplementary Table 2 ). The most frequent events were adrenal insufficiency (15.3%) and hypothyroidism (15.3%), followed by rash (11.7%), hepatic transaminase elevation (5.4%), and enterocolitis (5.4%). One (0.9%) Grade 4 TRAE (type 1 diabetes) and 2 (1.8%) Grade 5 TRAEs (biliary infection and myocarditis) were observed. Survival analysis The median follow-up period in censored patients was 15 months. The median OS was 22 months (95% confidence interval [CI]: 13–not reached), whereas the median PFS was 5 months (95% CI: 3–8; Figure 2A,B ). Patients who achieved disease control (i.e., non-PD) had significantly longer survival than those with PD (median OS: not reached vs. 9 months, P < 0.0001; Figure 2C ). Patients with TRAEs (≥Grade 2) had significantly longer survival than those without TRAEs (median OS: not reached vs. 15 months, P = 0.0233; Figure 2D ). OS was further assessed according to metastatic organ involvement within each disease status; lymph node metastasis was associated with significantly lower OS in unresectable advanced cases, whereas liver metastasis was associated with significantly lower OS in recurrent cases ( Figure 3 ). A Cox univariate analysis of OS with clinicopathological covariables revealed that the CAR prior to treatment was a significant factor (hazard ratio [HR]=2.50, 95% CI: 1.31-4.78, P = 0.0056), whereas the NLR tended to be clinically relevant (HR=1.80, 95% CI: 0.97-3.33, P = 0.0614; Table 3 ). Multivariate analysis of OS further identified CAR as the only independent prognostic factor (HR=2.99, 95% CI: 1.35-6.63, P = 0.0071; Table 3 ). Figure 2: Overall survival and progression-free survival. (A) Overall survival rate. (B) Progression-free survival rate. (C) Overall survival according to tumor response. (D) Overall survival according to occurrence of immune-related adverse events (TRAEs; ≥Grade 2). CI, confidence interval; PD, progressive disease. Table 3. Univariate and multivariate analysis of overall survival Variable Category Univariate analysis Multivariate analysis HR (95% CI) P -value HR (95% CI) P -value Age < 75 years 1.48 (0.80－2.75) 0.2099 1.73 (0.84－3.57) 0.1346 Sex Female 1.20 (0.53－2.68) 0.6643 1.50 (0.59－3.85) 0.3950 Performance status 2–3 1.56 (0.61－3.98) 0.3518 0.99 (0.33－3.00) 0.9856 History of smoking Yes 1.12 (0.47－2.67) 0.7950 1.20 (0.46－3.17) 0.7095 Tumor status Recurrence 1.19 (0.64－2.20) 0.5853 1.38 (0.66－2.85) 0.3893 BMI Low 1.60 (0.88－2.90) 0.1217 1.36 (0.69－2.67) 0.3776 CAR High 2.50 (1.31－4.78) 0.0056 2.99 (1.35－6.63) 0.0071 NLR High 1.80 (0.97－3.33) 0.0614 1.79 (0.86－3.71) 0.1202 PNI Low 1.49 (0.83-2.70) 0.1857 1.09 (0.55－2.16) 0.8071 BMI, body mass index; CAR, C-reactive protein-to-albumin ratio; CI, confidence interval; HR, hazard ratio; NLR, neutrophil–lymphocyte ratio; PNI, prognostic nutritional index Figure 3: Overall survival rate by metastatic organ and tumor status. (A) Overall survival according to lymph node (LN) metastasis status in unresectable advanced disease. (B) Overall survival according to LN metastasis status in recurrent disease. (C) Overall survival according to lung metastasis status in unresectable advanced disease. (D) Overall survival according to lung metastasis status in recurrent disease. (E) Overall survival according to liver metastasis status in unresectable advanced disease. (F) Overall survival according to liver metastasis status in recurrent disease. CI, confidence interval; HEP, liver metastasis; PUL, lung metastasis Discussion In this multicenter real-world study including 111 patients with unresectable or recurrent ESCC, first-line treatment with nivolumab plus ipilimumab demonstrated meaningful clinical activity with an acceptable safety profile. Importantly, a low pretreatment C-reactive protein–to–albumin ratio (CAR) was significantly associated with favorable treatment response and independently predicted overall survival in multivariate analysis. Given that CAR reflects host immune-inflammatory and nutritional status, these findings suggest that systemic immune fitness may critically influence the efficacy of dual immune checkpoint blockade in real-world clinical practice. Thus, CAR may serve as a simple and clinically actionable biomarker for patient stratification. The ORR of 44.0% in our real-world cohort was notably higher than the 35% reported for the global population of the CheckMate 648 trial 7 and exceeded the response rate of 35.9% observed in the Japanese subgroup of the same study. 6,8 These findings suggest that dual immune checkpoint blockade maintains robust antitumor activity in routine practice and may even yield higher response rates in unselected clinical populations. Several factors may contribute to this difference, including the predominance of lymph node metastases, which demonstrated the highest lesion-level disease control.Lymph node metastases may represent a more immunologically permissive microenvironment, allowing effective T-cell activation and immune-mediated tumor control, whereas hepatic metastases—characterized by immune tolerance—showed lower responsiveness. 13 In addition, differences in prior treatments and host inflammatory status, as reflected by CAR, may have further contributed to treatment outcomes. Collectively, these observations underscore the importance of tumor immune microenvironment and host immune status in shaping response to dual checkpoint inhibition. The incidence of TRAEs in our cohort was generally comparable to the incidence reported in the global CheckMate 648 population 7 ; ≥Grade 3 TRAEs occurred in approximately 32% of that population versus 28.8% of the present cohort. Notably, the safety profile remained acceptable despite the inclusion of older patients and those with prior chemoradiotherapy, highlighting that immune-related toxicities associated with dual checkpoint blockade are manageable with appropriate monitoring and intervention in real-world settings. Also, the frequency of TRAEs in our study was similar to or slightly higher than that observed in the Japanese subgroup of CheckMate 648, 6,8 which has been described as having a higher sensitivity to immune-related toxicities. This may also be related to the higher ORR observed in the present study compared with previous CheckMate 648 reports. 6,8 Although NIVO+IPI demonstrated promising survival outcomes in this real-world cohort, the median follow-up of censored patients was relatively short (15 months), limiting firm conclusions regarding long-term prognosis. The median OS was 22 months and the median PFS was 5 months, which are broadly consistent with prior reports and support the early efficacy of dual checkpoint blockade. In CheckMate 648, the long-term benefit of NIVO+IPI was reflected by a characteristic “tail plateau” in the survival curve, suggesting the emergence of durable responders. 6 Whether a similar plateau will develop in real-world practice remains uncertain; longer follow-up in our cohort will be essential to determine whether a sustained survival benefit is maintained over time. Furthermore, survival outcomes differed according to metastatic organ involvement. In unresectable advanced disease, lymph node metastasis was associated with significantly better OS, whereas liver metastasis was associated with markedly worse survival in recurrent disease. These findings further support the concept that organ-specific immune microenvironments critically influence the effectiveness of immune checkpoint blockade. This study has several limitations. Its retrospective design and the heterogeneity of participating institutions may have introduced selection bias, and the relatively short follow-up precludes full assessment of long-term outcomes. Nevertheless, this study represents the largest real-world cohort evaluating NIVO+IPI for ESCC to date. Our findings confirm the real-world feasibility of NIVO+IPI and highlight the importance of host immune-inflammatory status and organ-specific immune contexture in determining treatment outcomes. Future prospective studies with extended follow-up and translational immune analyses are warranted to validate CAR as a prognostic biomarker and to further elucidate the immunological determinants of response to dual checkpoint inhibition. Conclusion In this large multicenter real-world cohort of unresectable or recurrent ESCC, treatment with NIVO+IPI demonstrated meaningful antitumor activity with an acceptable safety profile in routine clinical practice. Disease control was strongly associated with improved prognosis, and a lower CAR, reflecting host immune-inflammatory status, emerged as a potential predictor of favorable treatment response. These findings support the real-world clinical utility of dual immune checkpoint blockade and underscore the importance of host immune context in determining treatment outcomes. Prospective studies incorporating translational immune analyses are warranted to validate CAR as a prognostic and predictive biomarker and to optimize patient selection for immunotherapy. Declarations Author contributions: Shuichiro Hara (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing), Tomoki Makino (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing), Shigeto Nakai (Resources, Writing—review &editing), Kota Momose (Resources, Writing—review &editing), Kotaro Yamashita (Resources, Writing—review &editing), Koji Tanaka (Resources, Writing—review &editing), Taro Satoh (Resources, Methodology, Writing—review &editing), Keijiro Sugimura (Data curation, Resources, Writing—review &editing), Ryohei Kawabata (Data curation, Resources, Writing—review &editing), Atsushi Takeno(Data curation, Resources, Writing—review &editing), Masaaki Motoori (Data curation, Resources, Writing—review &editing), Makoto Yamasaki (Conceptualization, Methodology, Supervision, Writing—review & editing), Hiroshi Miyata (Data curation, Resources, Writing—review &editing), Yutaka Kimura (Data curation, Resources, Writing—review &editing), Takushi Yasuda (Conceptualization, Methodology, Supervision, Writing—review & editing), Hidetoshi Eguchi (Investigation, Supervision, Writing—review & editing) and Yuichiro Doki (Conceptualization, Data curation, Investigation, Supervision, Writing—review & editing) Competing interest: Dr. Makino received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Yamasaki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Doki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. All other authors declare no conflicts of interest. Funding: This study was not supported by any funding. References Makino T, Yamasaki M, Tanaka K, et al. Metabolic Tumor Volume Change Predicts Long-term Survival and Histological Response to Preoperative Chemotherapy in Locally Advanced Esophageal Cancer. Ann Surg. 2019;270(6):1090-1095. Makino T, Yamasaki M, Tanaka K, et al. Multicenter randomised trial of two versus three courses of preoperative cisplatin and fluorouracil plus docetaxel for locally advanced oesophageal squamous cell carcinoma. Br J Cancer. 2022;126(11):1555-1562. Makino T, Yamasaki M, Nakai S, et al. Surgical and long-term outcomes of combined organ resection for esophageal cancer invading adjacent organs: Experience of 90 consecutive cases. J Thorac Cardiovasc Surg. 2025;170(4):957-968. Makino T, Nakai S, Hagi T, et al. Conversion surgery following immunochemotherapy for initially unresectable/recurrent esophageal cancer. Esophagus. 2025. Makino T, Nakai S, Momose K, et al. Efficacy and survival of nivolumab treatment for recurrent/unresectable esophageal squamous-cell carcinoma: real-world clinical data from a large multi-institutional cohort. Esophagus. 2024;21(3):319-327. Kato K, Doki Y, Chau I, et al. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024;13(9):e7235. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462. Kato K, Doki Y, Ogata T, et al. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus. 2023;20(2):291-301. Shiraishi K, Yamamoto S, Yoshinami Y, et al. The safety and short-term efficacy of nivolumab plus ipilimumab for advanced esophageal squamous cell carcinoma. Esophagus. 2025. Natsuki S, Lee S, Kasashima H, et al. Utility of Assessing Early Tumor Shrinkage as an Efficacy Predictor in Patients with Non-Surgically Indicated or Recurrent Esophageal Cancer Treated with Nivolumab plus Ipilimumab. Oncology. 2025;103(3):167-178. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158-168. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. Yu J, Green MD, Li S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27(1):152-164. Additional Declarations Competing interest reported. Dr. Makino received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Yamasaki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Doki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. All other authors declare no conflicts of interest. Supplementary Files CancerImmunologyImmunotherapySupTab.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 May, 2026 Reviews received at journal 05 May, 2026 Reviews received at journal 05 May, 2026 Reviewers agreed at journal 26 Apr, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers invited by journal 28 Mar, 2026 Editor assigned by journal 23 Mar, 2026 Submission checks completed at journal 23 Mar, 2026 First submitted to journal 21 Mar, 2026 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. 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Center","correspondingAuthor":false,"prefix":"","firstName":"Ryohei","middleName":"","lastName":"Kawabata","suffix":""},{"id":614382428,"identity":"979397d3-be38-4fee-a944-b10e4c7fe85f","order_by":9,"name":"Atsushi Takeno","email":"","orcid":"","institution":"NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Takeno","suffix":""},{"id":614382429,"identity":"f8d2806f-94e9-4f93-b02a-b502cff7c510","order_by":10,"name":"Masaaki Motoori","email":"","orcid":"","institution":"Osaka General Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Masaaki","middleName":"","lastName":"Motoori","suffix":""},{"id":614382430,"identity":"748c687e-12bd-46fe-bca3-339c0931e97a","order_by":11,"name":"Makoto Yamasaki","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Yamasaki","suffix":""},{"id":614382431,"identity":"a1572dc5-01bc-4310-bbd5-399636f80612","order_by":12,"name":"Hiroshi Miyata","email":"","orcid":"","institution":"Osaka International Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Miyata","suffix":""},{"id":614382432,"identity":"ee7acc9f-c2ff-4fd4-891b-9e4fa00d5c14","order_by":13,"name":"Yutaka Kimura","email":"","orcid":"","institution":"Kindai University Nara Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"Kimura","suffix":""},{"id":614382433,"identity":"fe2228f0-4123-4bd0-b277-99f15496a180","order_by":14,"name":"Takushi Yasuda","email":"","orcid":"","institution":"Kindai University","correspondingAuthor":false,"prefix":"","firstName":"Takushi","middleName":"","lastName":"Yasuda","suffix":""},{"id":614382434,"identity":"4938e96c-90d2-4fbc-b02b-12087101e565","order_by":15,"name":"Hidetoshi Eguchi","email":"","orcid":"","institution":"The University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Hidetoshi","middleName":"","lastName":"Eguchi","suffix":""},{"id":614382435,"identity":"b737fef5-b02b-4aa7-8c0c-b0b998015cfe","order_by":16,"name":"Yuichiro Doki","email":"","orcid":"","institution":"The University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Yuichiro","middleName":"","lastName":"Doki","suffix":""}],"badges":[],"createdAt":"2026-03-21 13:25:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9186071/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9186071/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106288588,"identity":"fad5dc65-c9a3-47c3-9740-ac8a61ad9c8b","added_by":"auto","created_at":"2026-04-07 07:26:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79682,"visible":true,"origin":"","legend":"\u003cp\u003eOrgan-specific responses to treatment with ipilimumab plus nivolumab. CR, complete response; LN, lymph node; PD, progressive disease; PR, partial response; SD, stable disease.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-9186071/v1/7c6556275d55b0b4a6fa9376.png"},{"id":106288587,"identity":"7608f6ea-101f-4d56-a229-3d0b18019a34","added_by":"auto","created_at":"2026-04-07 07:26:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":449499,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival and progression-free survival. (A) Overall survival rate. (B) Progression-free survival rate. (C) Overall survival according to tumor response. (D) Overall survival according to occurrence of immune-related adverse events (TRAEs; ≥Grade 2). CI, confidence interval; PD, progressive disease.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-9186071/v1/cbb4a8bf6bba14a4869ac619.png"},{"id":106288845,"identity":"b9fa992c-bf2d-4008-90b1-9f0751b94f63","added_by":"auto","created_at":"2026-04-07 07:27:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":818200,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival rate by metastatic organ and tumor status. (A) Overall survival according to lymph node (LN) metastasis status in unresectable advanced disease. (B) Overall survival according to LN metastasis status in recurrent disease. (C) Overall survival according to lung metastasis status in unresectable advanced disease. (D) Overall survival according to lung metastasis status in recurrent disease. (E) Overall survival according to liver metastasis status in unresectable advanced disease. (F) Overall survival according to liver metastasis status in recurrent disease. CI, confidence interval; HEP, liver metastasis; PUL, lung metastasis\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9186071/v1/5b5dac17c4adab0f49606199.jpg"},{"id":106289203,"identity":"9837749c-4385-4a3e-ab35-f644dd30910e","added_by":"auto","created_at":"2026-04-07 07:29:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2256694,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9186071/v1/4c6452ea-d545-41f8-b9c3-4c907f0b3bc5.pdf"},{"id":106288584,"identity":"f488d293-a310-401d-9c46-d3e4d33ee98b","added_by":"auto","created_at":"2026-04-07 07:26:21","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19938,"visible":true,"origin":"","legend":"","description":"","filename":"CancerImmunologyImmunotherapySupTab.docx","url":"https://assets-eu.researchsquare.com/files/rs-9186071/v1/ea5fb3889bb9d32339310f3c.docx"}],"financialInterests":"Competing interest reported. Dr. Makino received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Yamasaki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Doki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. All other authors declare no conflicts of interest.","formattedTitle":"Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with poor prognosis despite recent advances in multimodal therapy.\u003csup\u003e1-3\u003c/sup\u003e Immune checkpoint inhibitors have revolutionized the management of several solid tumors, and nivolumab-based regimens have become a standard treatment option for advanced ESCC.\u003csup\u003e4,5\u003c/sup\u003e The phase III CheckMate 648 trial demonstrated that the combination of nivolumab (anti-PD-1 antibody) plus ipilimumab (anti-CTLA-4 antibody) significantly improves overall survival (OS) compared with conventional chemotherapy in the first-line setting,\u003csup\u003e6,7\u003c/sup\u003e leading to worldwide regulatory approval. However, clinical experience with ipilimumab plus nivolumab (NIVO+IPI) for ESCC has been largely limited to this single pivotal trial, and even fewer data are available for Japanese patients.\u003csup\u003e8\u003c/sup\u003e No large-scale real-world data have been published to date, and questions remain regarding the generalizability, safety profile, and efficacy of NIVO+IPI in broader clinical populations, including elderly patients, those with prior chemoradiotherapy, or those with compromised performance status.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eImportantly, the efficacy and toxicity of immune checkpoint blockade are known to be influenced by host immune-inflammatory status and by tumor immune microenvironment, which may vary according to metastatic organ sites. Given that immune-related adverse events (irAEs) and treatment feasibility may differ between controlled trials and routine practice,\u003csup\u003e9-11\u003c/sup\u003e real-world evidence is essential to establishing the external validity of dual checkpoint blockade in ESCC.\u0026nbsp;Despite these considerations, large-scale real-world analyses evaluating clinical outcomes, organ-specific responses, and immune-related toxicity profiles of NIVO+IPI in ESCC are lacking.\u003c/p\u003e\n\u003cp\u003eTo address this knowledge gap, we conducted a multicenter retrospective study of 111 patients treated with first-line NIVO+IPI for unresectable or recurrent ESCC. To the best of our knowledge, this study represents the largest real-world cohort reported to date, providing clinically and immunologically relevant insights into treatment efficacy, organ-specific response patterns, safety, and host-related prognostic factors in patients receiving dual immune checkpoint inhibition.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design and patients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter retrospective study included patients with histologically confirmed ESCC who received first-line NIVO+IPI for unresectable or recurrent disease between 2017 and 2024 at participating institutions. Patients were eligible for inclusion if they met all of the following criteria: unresectable or recurrent esophageal cancer treated with or scheduled to be treated with the NIVO+IPI regimen as systemic therapy; histologically confirmed squamous cell carcinoma of the esophagus, verified by pathological examination; presence of at least one measurable or evaluable lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and age ≥20 years at the time of informed consent. Written informed consent was obtained from all patients prior to study enrollment. Patients with active multiple primary malignancies at the initiation of NIVO+IPI therapy were excluded. Active malignancies included synchronous cancers or metachronous cancers diagnosed within 5 years, except for carcinoma in situ or intramucosal lesions judged to be curatively treatable by local therapy, which were not considered active malignancies. The study was approved by the institutional review boards of all participating institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment regimen\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment with NIVO+IPI consisted of 360 mg nivolumab repeated every 3 weeks and 1 mg/kg ipilimumab repeated every 6 weeks according to the dosing schedule adopted in the CheckMate 648 trial.\u003csup\u003e6-8\u003c/sup\u003e Dose modifications were not routinely performed;\u0026nbsp;treatment-related adverse events (TRAEs) including irAEs were managed in accordance with institutional guidelines based on the ESMO recommendations.\u003csup\u003e12\u003c/sup\u003e Treatment was continued until obvious disease progression, unacceptable toxicity, or the patient’s refusal to continue the treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEvaluation of response\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTumor response was assessed every 6 weeks using RECIST version 1.1 and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).\u003csup\u003e1\u003c/sup\u003e The objective response rate (ORR) was defined as the proportion of patients achieving CR or PR, and the disease control rate (DCR) included CR, PR, and SD. Progression-free survival (PFS) was measured from treatment initiation to disease progression or death, and OS was measured from treatment initiation to death from any cause. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For patients with steroid-refractory TRAEs ≥Grade 3, second-line immunosuppression with mycophenolate mofetil was implemented, consistent with previous Japanese reports.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relationships between clinicopathological characteristics and tumor response status were analyzed using the chi-squared test for categorical variables. Survival rates were estimated using the Kaplan–Meier method and compared by the log-rank test. The prognostic variables that were significantly associated with OS in the univariate analyses were further assessed in a multivariate Cox proportional hazard model. \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05 was considered to indicate significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics are provided in \u003cstrong\u003eTable 1\u003c/strong\u003e. A total of 111 patients (86% male) were enrolled in this study, including 40 with unresectable advanced disease and 71 with recurrent disease. Most patients had good performance status (PS 0\u0026ndash;1 in 91%). Tumor location was distributed across the cervical/upper thoracic, middle thoracic, and lower thoracic/abdominal esophagus. One metastatic organ was present in 69% of patients, whereas 24% had two metastatic sites and 5% had three or more. The median body mass index (BMI), albumin, neutrophil\u0026ndash;lymphocyte ratio (NLR), and C-reactive protein\u0026ndash;to\u0026ndash;albumin ratio (CAR) indicated generally preserved nutritional and inflammatory profiles at treatment initiation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eN=111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73 (52-88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMale/female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e96/15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePerformance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0/1/2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e58/43/7/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHistory of smoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTumor status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnresectable advanced/recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40/71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTumor location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCeUt/Mt/LtAe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25/51/35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNumber of metastatic organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0/1/2/\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3/77/24/5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHistory of surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHistory of radiation therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian (range)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.1 (13.9-29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlbumin, g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.8 (2.3-5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.1 (0.8-22.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1 (0.8-8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBMI, body mass index; NLR, neutrophil\u0026ndash;lymphocyte ratio; CAR, C-reactive protein-to-albumin ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment efficacy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe best ORR is shown in \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e. In the cases with target lesions, CR and PR were observed in 6 (8.0%) and 27 (36.0%) cases, respectively, whereas PD occurred in 22 (29.3%) cases, indicating the best ORR and a DCR are 44.0% (33/75) and 70.7% (53/75), respectively.\u003cstrong\u003e\u0026nbsp;Figure 1\u003c/strong\u003e shows the organ-specific response to NIVO+IPI; the DCR by metastasis site was 84.4% (65/77) for lymph nodes, 72.4% (21/29) for the lungs, and 70.0% (7/10) for the liver, whereas the DCR of the primary lesion was 56.5% (13/21). \u003cstrong\u003eTable 2\u003c/strong\u003e compares patient characteristics according to treatment response. Patients with PD after NIVO+IPI therapy had a significantly lower BMI at treatment initiation than patients with non-PD (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.0154) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1:\u0026nbsp;\u003c/strong\u003eOrgan-specific responses to treatment with ipilimumab plus nivolumab. CR, complete response; LN, lymph node; PD, progressive disease; PR, partial response; SD, stable disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Comparison of patient characteristics according to treatment response\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"float: left;width: 100%;border: none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNon-PD\u003cbr\u003e\u0026nbsp;(n=53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePD\u003cbr\u003e\u0026nbsp;(n=22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3121\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 75 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (65.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (34.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge; 75 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26 (76.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (23.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2712\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43 (68.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (31.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (83.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8244\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e49 (71.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (29.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTumor status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6777\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnresectable advanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22 (73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31 (68.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (31.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.0154\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 20 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge; 20 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33 (82.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45 (73.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 (26.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7618\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge; 4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (68.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (31.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38 (71.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (28.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4647\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ge; 45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 (74.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (25.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are given as n (%). BMI, body mass index; CAR, C-reactive protein-to-albumin ratio; NLR, neutrophil\u0026ndash;lymphocyte ratio; PD, progressive disease; PNI, prognostic nutritional index; PS, performance status\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment-related adverse events\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;(TRAEs)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTRAEs \u0026ge;Grade 2 and \u0026ge;Grade 3 occurred in 58 (52.3%) and 32 (28.8%) patients, respectively (\u003cstrong\u003eSupplementary Table 2\u003c/strong\u003e). The most frequent events were adrenal insufficiency (15.3%) and hypothyroidism (15.3%), followed by rash (11.7%), hepatic transaminase elevation (5.4%), and enterocolitis (5.4%). One (0.9%) Grade 4 TRAE (type 1 diabetes) and 2 (1.8%) Grade 5 TRAEs (biliary infection and myocarditis) were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSurvival analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up period in censored patients was 15 months. The median OS was 22 months (95% confidence interval [CI]: 13\u0026ndash;not reached), whereas the median PFS was 5 months (95% CI: 3\u0026ndash;8; \u003cstrong\u003eFigure 2A,B\u003c/strong\u003e). Patients who achieved disease control (i.e., non-PD) had significantly longer survival than those with PD (median OS: not reached vs. 9 months, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001; \u003cstrong\u003eFigure 2C\u003c/strong\u003e). Patients with TRAEs (\u0026ge;Grade 2) had significantly longer survival than those without TRAEs (median OS: not reached vs. 15 months, \u003cem\u003eP\u003c/em\u003e = 0.0233; \u003cstrong\u003eFigure 2D\u003c/strong\u003e). OS was further assessed according to metastatic organ involvement within each disease status; lymph node metastasis was associated with significantly lower OS in unresectable advanced cases, whereas liver metastasis was associated with significantly lower OS in recurrent cases (\u003cstrong\u003eFigure 3\u003c/strong\u003e). A Cox univariate analysis of OS with clinicopathological covariables revealed that the CAR prior to treatment was a significant factor (hazard ratio [HR]=2.50, 95% CI: 1.31-4.78, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.0056), whereas the NLR tended to be clinically relevant (HR=1.80, 95% CI: 0.97-3.33, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.0614; \u003cstrong\u003eTable 3\u003c/strong\u003e). Multivariate analysis of OS further identified CAR as the only independent prognostic factor (HR=2.99, 95% CI: 1.35-6.63, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.0071; \u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2:\u0026nbsp;\u003c/strong\u003eOverall survival and progression-free survival. (A) Overall survival rate. (B) Progression-free survival rate. (C) Overall survival according to tumor response. (D) Overall survival according to occurrence of immune-related adverse events (TRAEs; \u0026ge;Grade 2). CI, confidence interval; PD, progressive disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Univariate and multivariate analysis of overall survival\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"border: none; width: 100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eCategory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 75 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.48 (0.80－2.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.73 (0.84－3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1346\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.20 (0.53－2.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6643\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.50 (0.59－3.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3950\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePerformance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.56 (0.61－3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.99 (0.33－3.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.9856\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHistory of smoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.12 (0.47－2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.20 (0.46－3.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTumor status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.19 (0.64－2.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.5853\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.38 (0.66－2.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.60 (0.88－2.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1217\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.36 (0.69－2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3776\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.50 (1.31－4.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.0056\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.99 (1.35－6.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.0071\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.80 (0.97－3.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0614\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.79 (0.86－3.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1202\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.49 (0.83-2.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.09 (0.55－2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBMI, body mass index; CAR, C-reactive protein-to-albumin ratio; CI, confidence interval; HR, hazard ratio; NLR, neutrophil\u0026ndash;lymphocyte ratio; PNI, prognostic nutritional index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3:\u0026nbsp;\u003c/strong\u003eOverall survival rate by metastatic organ and tumor status. (A) Overall survival according to lymph node (LN) metastasis status in unresectable advanced disease. (B) Overall survival according to LN metastasis status in recurrent disease. (C) Overall survival according to lung metastasis status in unresectable advanced disease. (D) Overall survival according to lung metastasis status in recurrent disease. (E) Overall survival according to liver metastasis status in unresectable advanced disease. (F) Overall survival according to liver metastasis status in recurrent disease. CI, confidence interval; HEP, liver metastasis; PUL, lung metastasis\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this multicenter real-world study including 111 patients with unresectable or recurrent ESCC, first-line treatment with nivolumab plus ipilimumab demonstrated meaningful clinical activity with an acceptable safety profile. Importantly, a low pretreatment C-reactive protein–to–albumin ratio (CAR) was significantly associated with favorable treatment response and independently predicted overall survival in multivariate analysis. Given that CAR reflects host immune-inflammatory and nutritional status, these findings suggest that systemic immune fitness may critically influence the efficacy of dual immune checkpoint blockade in real-world clinical practice. Thus, CAR may serve as a simple and clinically actionable biomarker for patient stratification.\u003c/p\u003e\n\u003cp\u003eThe ORR of 44.0% in our real-world cohort was notably higher than the 35% reported for the global population of the CheckMate 648 trial\u003csup\u003e7\u003c/sup\u003e and exceeded the response rate of 35.9% observed in the Japanese subgroup of the same study.\u003csup\u003e6,8\u003c/sup\u003e These findings suggest that dual immune checkpoint blockade maintains robust antitumor activity in routine practice and may even yield higher response rates in unselected clinical populations. Several factors may contribute to this difference, including the predominance of lymph node metastases, which demonstrated the highest lesion-level disease control.Lymph node metastases may represent a more immunologically permissive microenvironment, allowing effective T-cell activation and immune-mediated tumor control, whereas hepatic metastases—characterized by immune tolerance—showed lower responsiveness.\u003csup\u003e13\u003c/sup\u003e In addition, differences in prior treatments and host inflammatory status, as reflected by CAR, may have further contributed to treatment outcomes. Collectively, these observations underscore the importance of tumor immune microenvironment and host immune status in shaping response to dual checkpoint inhibition.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The incidence of TRAEs in our cohort was generally comparable to the incidence reported in the global CheckMate 648 population\u003csup\u003e7\u003c/sup\u003e; ≥Grade 3 TRAEs occurred in approximately 32% of that population versus 28.8% of the present cohort. Notably, the safety profile remained acceptable despite the inclusion of older patients and those with prior chemoradiotherapy, highlighting that immune-related toxicities associated with dual checkpoint blockade are manageable with appropriate monitoring and intervention in real-world settings. Also, the frequency of TRAEs in our study was similar to or slightly higher than that observed in the Japanese subgroup of CheckMate 648,\u003csup\u003e6,8\u003c/sup\u003e which has been described as having a higher sensitivity to immune-related toxicities.\u0026nbsp;This may also be related to the higher ORR observed in the present study compared with previous CheckMate 648 reports.\u003csup\u003e6,8\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAlthough NIVO+IPI demonstrated promising survival outcomes in this real-world cohort, the median follow-up of censored patients was relatively short (15 months), limiting firm conclusions regarding long-term prognosis. The median OS was 22 months and the median PFS was 5 months, which are broadly consistent with prior reports and support the early efficacy of dual checkpoint blockade. In CheckMate 648, the long-term benefit of NIVO+IPI was reflected by a characteristic “tail plateau” in the survival curve, suggesting the emergence of durable responders.\u003csup\u003e6\u003c/sup\u003e Whether a similar plateau will develop in real-world practice remains uncertain; longer follow-up in our cohort will be essential to determine whether a sustained survival benefit is maintained over time. Furthermore, survival outcomes differed according to metastatic organ involvement. In unresectable advanced disease, lymph node metastasis was associated with significantly better OS, whereas liver metastasis was associated with markedly worse survival in recurrent disease. These findings further support the concept that organ-specific immune microenvironments critically influence the effectiveness of immune checkpoint blockade.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. Its retrospective design and the heterogeneity of participating institutions may have introduced selection bias, and the relatively short follow-up precludes full assessment of long-term outcomes. Nevertheless, this study represents the largest real-world cohort evaluating NIVO+IPI for ESCC to date. Our findings confirm the real-world feasibility of NIVO+IPI and highlight the importance of host immune-inflammatory status and organ-specific immune contexture in determining treatment outcomes. Future prospective studies with extended follow-up and translational immune analyses are warranted to validate CAR as a prognostic biomarker and to further elucidate the immunological determinants of response to dual checkpoint inhibition.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this large multicenter real-world cohort of unresectable or recurrent ESCC, treatment with NIVO+IPI demonstrated meaningful antitumor activity with an acceptable safety profile in routine clinical practice. Disease control was strongly associated with improved prognosis, and a lower CAR, reflecting host immune-inflammatory status, emerged as a potential predictor of favorable treatment response. These findings support the real-world clinical utility of dual immune checkpoint blockade and underscore the importance of host immune context in determining treatment outcomes. Prospective studies incorporating translational immune analyses are warranted to validate CAR as a prognostic and predictive biomarker and to optimize patient selection for immunotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eShuichiro Hara (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review \u0026amp; editing), Tomoki Makino (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review \u0026amp; editing), Shigeto Nakai (Resources, Writing—review \u0026amp;editing), Kota Momose (Resources, Writing—review \u0026amp;editing), Kotaro Yamashita (Resources, Writing—review \u0026amp;editing), Koji Tanaka (Resources, Writing—review \u0026amp;editing), Taro Satoh (Resources, Methodology, Writing—review \u0026amp;editing), Keijiro Sugimura (Data curation, Resources, Writing—review \u0026amp;editing), Ryohei Kawabata (Data curation, Resources, Writing—review \u0026amp;editing), Atsushi Takeno(Data curation, Resources, Writing—review \u0026amp;editing), Masaaki Motoori (Data curation, Resources, Writing—review \u0026amp;editing), Makoto Yamasaki (Conceptualization, Methodology, Supervision, Writing—review \u0026amp; editing), Hiroshi Miyata (Data curation, Resources, Writing—review \u0026amp;editing), Yutaka Kimura (Data curation, Resources, Writing—review \u0026amp;editing), Takushi Yasuda (Conceptualization, Methodology, Supervision, Writing—review \u0026amp; editing), Hidetoshi Eguchi (Investigation, Supervision, Writing—review \u0026amp; editing) and Yuichiro Doki (Conceptualization, Data curation, Investigation, Supervision, Writing—review \u0026amp; editing)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest:\u0026nbsp;\u003c/strong\u003eDr. Makino received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Yamasaki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Doki received lecture fees from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. All other authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This study was not supported by any funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMakino T, Yamasaki M, Tanaka K, et al. Metabolic Tumor Volume Change Predicts Long-term Survival and Histological Response to Preoperative Chemotherapy in Locally Advanced Esophageal Cancer. \u003cem\u003eAnn Surg. \u003c/em\u003e2019;270(6):1090-1095.\u003c/li\u003e\n\u003cli\u003eMakino T, Yamasaki M, Tanaka K, et al. Multicenter randomised trial of two versus three courses of preoperative cisplatin and fluorouracil plus docetaxel for locally advanced oesophageal squamous cell carcinoma. \u003cem\u003eBr J Cancer. \u003c/em\u003e2022;126(11):1555-1562.\u003c/li\u003e\n\u003cli\u003eMakino T, Yamasaki M, Nakai S, et al. Surgical and long-term outcomes of combined organ resection for esophageal cancer invading adjacent organs: Experience of 90 consecutive cases. \u003cem\u003eJ Thorac Cardiovasc Surg. \u003c/em\u003e2025;170(4):957-968.\u003c/li\u003e\n\u003cli\u003eMakino T, Nakai S, Hagi T, et al. Conversion surgery following immunochemotherapy for initially unresectable/recurrent esophageal cancer. \u003cem\u003eEsophagus. \u003c/em\u003e2025.\u003c/li\u003e\n\u003cli\u003eMakino T, Nakai S, Momose K, et al. Efficacy and survival of nivolumab treatment for recurrent/unresectable esophageal squamous-cell carcinoma: real-world clinical data from a large multi-institutional cohort. \u003cem\u003eEsophagus. \u003c/em\u003e2024;21(3):319-327.\u003c/li\u003e\n\u003cli\u003eKato K, Doki Y, Chau I, et al. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. \u003cem\u003eCancer Med. \u003c/em\u003e2024;13(9):e7235.\u003c/li\u003e\n\u003cli\u003eDoki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. \u003cem\u003eN Engl J Med. \u003c/em\u003e2022;386(5):449-462.\u003c/li\u003e\n\u003cli\u003eKato K, Doki Y, Ogata T, et al. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). \u003cem\u003eEsophagus. \u003c/em\u003e2023;20(2):291-301.\u003c/li\u003e\n\u003cli\u003eShiraishi K, Yamamoto S, Yoshinami Y, et al. The safety and short-term efficacy of nivolumab plus ipilimumab for advanced esophageal squamous cell carcinoma. \u003cem\u003eEsophagus. \u003c/em\u003e2025.\u003c/li\u003e\n\u003cli\u003eNatsuki S, Lee S, Kasashima H, et al. Utility of Assessing Early Tumor Shrinkage as an Efficacy Predictor in Patients with Non-Surgically Indicated or Recurrent Esophageal Cancer Treated with Nivolumab plus Ipilimumab. \u003cem\u003eOncology. \u003c/em\u003e2025;103(3):167-178.\u003c/li\u003e\n\u003cli\u003ePostow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. \u003cem\u003eN Engl J Med. \u003c/em\u003e2018;378(2):158-168.\u003c/li\u003e\n\u003cli\u003eHaanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. \u003cem\u003eAnn Oncol. \u003c/em\u003e2022;33(12):1217-1238.\u003c/li\u003e\n\u003cli\u003eYu J, Green MD, Li S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. \u003cem\u003eNat Med. \u003c/em\u003e2021;27(1):152-164.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9186071/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9186071/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCombination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO+IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO+IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13–not reached) and 5 months (95% CI: 3–8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein–to–albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI: 1.35–6.63, \u003cem\u003eP \u003c/em\u003e= 0.0071).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In this large real-world cohort, first-line NIVO+IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.\u003c/p\u003e","manuscriptTitle":"Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 07:23:47","doi":"10.21203/rs.3.rs-9186071/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-05T17:50:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T12:23:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T11:59:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"281147974323601787942651552914607169847","date":"2026-04-26T17:12:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175233891702889944307997729955715109447","date":"2026-03-28T13:21:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-28T12:57:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-24T02:33:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-24T02:33:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2026-03-21T13:10:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"debd2822-3c7c-4bc6-9fff-3e898341c05e","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-05T17:50:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T12:23:42+00:00","index":85,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T11:59:59+00:00","index":84,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-17T16:23:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 07:23:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9186071","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9186071","identity":"rs-9186071","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}