Efficacy and safety of salvage-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma: Comparison of 240 mg versus 480 mg doses

Efficacy and safety of salvage-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma: Comparison of 240 mg versus 480 mg doses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of salvage-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma: Comparison of 240 mg versus 480 mg doses Yuko Murashima, Shun Yamamoto, Toshiharu Hirose, Toru Kadono, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4304600/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Jul, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Background Nivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited. Methods We compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line(n=85) or later-line(n=32) nivolumab monotherapy at our institution between January 2016 and December 2021. Results Patient characteristics in the second-line group were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2, 34/61/5% vs 54/42/4%; prior FP, 81.3 vs. 42.3%. Those in the later-line group were as follows: PS 0/1/2, 28/60/12% vs. 14/86/0%; prior FP, 60.0 vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p=0.19) and 0 vs. 14.3% in the later-line group (p=0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35-1.01, p=0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23-1.46, p=0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively. Conclusions The efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC. esophageal cancer esophageal squamous cell carcinoma nivolumab chemotherapy Figures Figure 1 Figure 2 Figure 3 Introduction The annual incidence of newly diagnosed esophageal cancer (EC) was estimated to be 26,382 in Japan in 2019, ranking 11th among all cancers [ 1 ], and to be 20,640 in the US in 2022, accounting for 1.1% of all cancers [2]. EC is classified histologically into squamous cell carcinoma (ESCC) and adenocarcinoma. ESCC has been reported to account for 87.8% of all EC and is more common in Japan than in Western countries [ 3 ]. Smoking and alcohol consumption are known to be major risk factors for ESCC, while Barrett's epithelium, reflux esophagitis, and high body mass index are known to be major risk factors for adenocarcinoma [ 4 – 7 ]. Fluoropyrimidine plus platinum combination therapy was traditionally considered to be first-line therapy for patients with advanced ESCC [ 8 , 9 ]. However, more recently, fluoropyrimidine plus platinum, nivolumab, nivolumab plus ipilimumab, fluoropyrimidine plus platinum, and pembrolizumab have become established as first-line treatments based on the results of the CheckMate 648 and KEYNOTE-590 trials [ 10 , 11 ]. Taxanes, nivolumab monotherapy, and pembrolizumab monotherapy can also be used as second-line therapy [ 12 – 14 ]. In the 2022 Japanese guidelines for EC, nivolumab monotherapy is strongly recommended for ESCC with no prior anti-PD-L1 therapy and pembrolizumab monotherapy is weakly recommended for ESCC with a combined positive score of ≥ 10 and no prior anti-PD-L1 therapy or microsatellite instability-high or tumor mutational burden-high with no prior anti-PD-L1 antibody. Paclitaxel is weakly recommended for patients with no history of taxane use with or without prior anti-PD-L1 antibody therapy. Nivolumab was initially approved at a fixed dosage of 240 mg every 2 weeks (Q2W) in February 2020 based on the results of the ATTRACTION-3 trial [ 12 ]. A fixed dosage of 480 mg every 4 weeks (Q4W) became available in September 2020 based on pharmacokinetics data [ 15 ]. However, there is little clinical information on the difference of efficacy and safety between two dosages in patients with advanced ESCC. Methods Design and patients This study had a single-center, retrospective design and analyzed data from patients with advanced ESCC treated with second-line or later-line nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and December 2021. Performance status (PS) was assessed according to the Eastern Cooperative Oncology Group criteria, and the eighth edition of the Union for International Cancer Control TNM classification was used for cancer staging. This study was approved by the National Cancer Center Hospital’s institutional review board (approval number 2020–287) and conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Although informed consent was not obtained, patients were provided with the opportunity to opt out. Assessments We compared the objective response rate (ORR), progression-free survival (PFS), and adverse event (AE) rate between the fixed dosage of 240 mg Q2W and the fixed dosage of 480 mg Q4W in the second-line or later-line setting. The ORR was defined as the proportion of patients with a complete or partial response to treatment according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. The response was evaluated on computed tomography scans obtained every 2–3 months. Overall survival was defined as the interval between the date of initiation of treatment and death (from any cause) or censored at the last date of confirmed survival. PFS was defined as the interval between the start of treatment and the date of the first documentation of disease progression or death (from any cause), whichever occurred first, or was censored at the last date of confirmed survival without disease progression. AEs were graded according to the CTCAE (Common Terminology Criteria of Adverse Events) version 5.0. Statistical analysis The median follow-up duration was estimated using the reversed Kaplan-Meier method. Survival curves were drawn using Kaplan-Meier methods, and these difference between groups was evaluated using the log-rank test. Differences in the distribution of ordinal variables were analyzed using the Chi-squared test or Fisher's exact test. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 16 ]. A p-value of < 0.05 was considered statistically significant. Results Patient characteristics In total, 117 patients with ESCC received nivolumab monotherapy between January 2016 and December 2021. Of the 85 patients who received nivolumab monotherapy as a second-line treatment, 59 received 240 mg Q2W and 26 received 480 mg Q4W. Of the remaining 32 patients who received nivolumab monotherapy as a later-line treatment, 25 received 240 mg Q2W and 7 received 480 mg Q4W (Fig. 1 ). Patients who switched from 240 mg Q2W to 480 mg Q4W during treatment were excluded. The patient characteristics are shown in Tables 1 and 2 . In the second-line group, the median age was 68 (range, 46–85) years in the patients who received 240 mg Q2W and 68.5 (range, 51–84) years in those who received 480 mg Q4W. PS was 0, 1 and 2, respectively, in 34%, 61%, and 5% of patients who received 240 mg Q2W and in 54%, 42%, and 4% of those who received 480 mg Q4W. There was a history of FP therapy in 81.3% of those who received 240 mg Q2W and in 42.3% of those who received 480 mg Q4W. In the later-line group, the median age was 63.5 (range, 47–85) years in the patients who received 240 mg Q2W and 58 (range, 46–80) years in those who received 480 mg Q4W. PS was 0, 1 and 2, respectively, in 28%, 60%, and 12% of patients who received 240 mg Q2W and 14%, 86%, and 0% in those who received 480 mg Q4W. There was a history of FP therapy in 60.0% of patients who received 240 mg Q2W and in 42.8% of those who received 480 mg Q4W. The backgrounds between the 240 mg Q2W and 480 mg Q4W fixed dosages of nivolumab were found to have no significant differences. Table 1 Background characteristics in patients receiving nivolumab as second-line monotherapy for advanced esophageal squamous cell carcinoma Variable 240 mg Q2W (n = 59) 480 mg Q4W (n = 26) p-value Age, years, median (range) 68 (46–85) 68.5 (51–84) 0.712 Male sex, number_(percentage) 52 (88.1) 22 (84.6) 0.730 ECOG PS 0, number_(percentage) 20 (33.9) 14 (53.8) 0.234 ECOG PS 1, number_(percentage) 36 (61.0) 11 (42.3) ECOG PS 2, number_(percentage) 3 (5.1) 1 (3.8) Recurrence, number_(percentage) 33 (55.9) 16 (61.5) 0.812 Organs with metastases, median (range) 2 (1–6) 2 (0–5) 0.769 Prior chemotherapy; FP, number_(percentage) 48 (81.3) 11 (42.3) < 0.05 Prior chemotherapy; DCF, number_(percentage) 11 (18.6) 15 (57.7) Prior radiotherapy, number_(percentage) 45 (76.3) 15 (57.7) 0.120 Prior surgery, number_(percentage) 28 (47.5) 18 (69.2) 0.098 ECOG, Eastern Cooperative Oncology Group; PS, performance status. Table 2 Background characteristics in patients receiving nivolumab as later-line monotherapy for advanced esophageal squamous cell carcinoma Variable 240 mg Q2W (n = 25) 480 mg Q4W (n = 7) p-value Age, years, median (range) 63.5 (47–85) 58 (46–80) 0.661 Male sex, number_(percentage) 21 (84) 6 (85.7) 1 ECOG PS 0, number_(percentage) 7 (28) 1 (14.3) 0.536 ECOG PS 1, number_(percentage) 15 (60) 6 (85.7) ECOG PS 2, number_(percentage) 3 (5.1) 1 (3.8) Recurrence, number_(percentage) 9 (36) 1 (14.3) 0.387 Organs with metastases, median (range) 2 (1–6) 2 (0–5) 0.769 Prior chemotherapy; FP, number_(percentage) 15 (60) 3 (42.8) 0.669 Prior chemotherapy; DCF, number_(percentage) 10 (40) 4 (57.1) Prior radiotherapy, number_(percentage) 24 (96) 5 (71.4) 0.113 Prior surgery, number_(percentage) 9 (36) 1 (14.3) 0.387 ECOG, Eastern Cooperative Oncology Group; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks; PS, performance status Table 3 Adverse events of any grade according to dose strength Adverse event 240 mg Q2W (n = 84) 480 mg Q4W (n = 33) Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Rash 10 (11.9) 4 (4.8) 0 0 1 (3.0) 1 (3.0) 0 0 Pruritus 12 (14.3) 5 (6.0) 0 0 4 (12.1) 0 0 0 Thyroid dysfunction 1 (1.2) 1 (1.2) 0 0 0 2 (6.1) 0 0 Hyponatremia 1 (1.2) 0 0 1 (1.2) 0 0 1 (3.0) 0 Diarrhea 3 (3.6) 4 (4.8) 1 (1.2) 0 1 (3.0) 1 (3.0) 0 0 Anemia 1 (1.2) 1 (1.2) 2 (2.4) 0 3 (9.1) 0 0 0 Elevated hepatic enzymes 0 1 (1.2) 1 (1.2) 0 0 0 1 (3.0) 0 Adrenal insufficiency 1 (1.2) 2 (2.4) 0 0 0 1 (3.0) 1 (3.0) 0 Interstitial pneumonia 0 0 3 (3.6) 0 0 3 (9.1) 2 (6.1) 0 Pneumonia 0 2 (2.4) 4 (4.8) 0 0 1 (3.0) 3 (9.1) 0 Data are presented as the number (%). There were no treatment-related deaths. Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks. Efficacy In the second-line group, 62 patients had measurable lesions according to RECIST version 1.1 at the start of treatment. The ORR was 11.9% in patients who received 240 mg Q2W and 24.0% in those who received 480 mg Q4W (p = 0.193). In the later-line group, there were 21 patients. The ORR was 0% in patients who received 240 mg Q2W and 14.3% in those who received 480 mg Q4W (p = 0.219). The median follow-up duration was 10.3 months in patients who received 240 mg Q2W and 8.1 months in those who received 480 mg Q4W; median PFS was 1.7 months and 4.1 months, respectively (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35–1.01; p = 0.056) (Fig. 2 A). In the later-line group, the median follow-up duration was 4.0 months in patients who received 240 mg Q2W and 5.8 months in those who received 480 mg Q4W; median PFS was 1.4 months and 1.8 months, respectively (HR 0.58, 95% CI 0.23–1.46; p = 0.25) (Fig. 2 B). In the second-line group, the median OS was 22.7 months in patients who received 240 mg Q2W as compared with Not Available (NA) in those who received 480 mg Q4W (HR 1.00, 95% CI 11.8-NA; P = 0.25) (Fig. 3 A). In the later-line group, the median OS was 5.6 months in patients who received 240 mg Q2W as compared with 5.7 months in those who received 480 mg Q4W (HR 1.00, 95% CI 1.97-NA; P = 0.753) (Fig. 3 B). There was no significant difference in ORR, PFS, or OS between the fixed dosages of 240 mg Q2W and 480 mg Q4W in either treatment line. Safety Safety was compared between the dosage regimens independent of treatment line. Treatment-related AEs of any grade were observed in 58.3% of patients in the 240 mg Q2W group and in 69.7% of those in the 480 mg Q4W group (Table 5). The frequencies of grade 1, 2, 3, and 4 AEs were as follows: rash, 11.9%, 4.8%, 0%, and 0%, respectively, in the 240 mg Q2W group and 3.0%, 3.0%, 0%, and 0% in the 480 mg Q4W group; pruritus, 14.3%, 6.0%, 0%, and 0% in the 240 mg Q2W group and 12.1%, 0%, 0%, and 0% in the 480 mg Q4W group; diarrhea, 3.6%, 4.8%, 1.2%, and 0% in the 240 mg Q2W group and 3.0%, 3.0%, 0%, and 0% in the 480 mg Q4W group; and interstitial pneumonia, 0%, 0%, 3.6%, and 0% in the 240 mg Q2W group and 0%, 9.1%, 6.1%, and 0% in the 480 mg Q4W group. There were no treatment-related deaths in either dosage group. Discussion This study found no statistically significant differences in efficacy and safety between the 240 mg Q2W and 480 mg Q4W fixed dosages of nivolumab when used as salvage-line monotherapy for advanced ESCC. Nivolumab monotherapy was first approved at a dosage of 2 mg/kg every 3 weeks for melanoma based on the results of a Phase II trial [ 17 ]. Next, a dosage of 3 mg/kg every 2 weeks was approved for lung cancer based on the results of a Phase III trial [ 18 ]. Subsequently, a fixed dosage of 240 mg Q2W became available based on population pharmacokinetics and exposure-response analyses showing comparability of exposure, safety, and efficacy between dosages of 3 mg/kg every 2 weeks and a fixed dosage of 240 mg Q2W [ 19 ]. Finally, a fixed dosage of 480 mg Q4W was approved based on modeling and simulation showing that the benefit-risk of a fixed dosage of 480 mg Q4W was a similar to that of 3 mg/kg Q2W [2]. In this study, since the approval of 480mg Q4W regimen, 480mg Q4W regimen has been predominantly chosen. A retrospective cohort study of nivolumab as an adjuvant treatment for melanoma compared the duration of therapy and safety of four different dosage (de novo nivolumab 480 mg Q4W, switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3 mg/kg Q2W, de novo nivolumab 3 mg/kg Q2W, and de novo nivolumab 240 mg Q2W) [ 20 ]. The safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar and comparable with the safety profile of nivolumab 3 mg/kg Q2W [ 20 ]. In the present study, ORR was 11.9% in patients who received 240 mg Q2W and 24.0% in those who received 480 mg Q4W (p = 0.193) in the second-line setting and 0% and 14.3%, respectively (p = 0.219) in the later-line setting; the difference according to treatment line was not statistically significant. Median PFS was 1.7 months in patients who received 240 mg Q2W and 4.1 months in those who received 480 mg Q4W as a second-line treatment (HR 0.60, 95% CI 0.35–1.01; p = 0.056]) and 1.4 months and 1.8 months, respectively, in those who received nivolumab as a later-line treatment (HR 0.58, 95% CI 0.23–1.46; p = 0.25). Although there was no statistically significant difference between the two fixed dosages, 480 mg Q4W showed a trend of slightly better efficacy. This finding may reflect differences in patient background characteristics or differences in the timing of standard treatment. This is the first study to demonstrate the efficacy and safety of nivolumab at these dosages for advanced ESCC, and its findings are similar to those in melanoma and other solid and hematological tumors [ 20 ], [ 21 ]. Our finding of no significant difference in AEs between the two dosages of nivolumab is consistent with a previous report [ 22 ]. Interstitial pneumonia cases tended to be more frequent in patients who received 480 mg Q4W. However, chart review revealed that patients who developed interstitial pneumonia had pre-existing poor lung function because of underlying collagen disease or chronic obstructive pulmonary disease. When there was evidence of pneumonia and an increased oxygen demand, there was a tendency to administer steroids early before the pneumonia became severe. This could reflect implementation of methods to manage immune-related AEs potentially caused by nivolumab. This study has some limitations. First, it had a single-center retrospective cohort design and included a number of patients with poor PS who were started on nivolumab third-line or later-line treatment immediately after the drug received regulatory approval for use in this setting. In several studies of nivolumab in patients with various types of cancer, subgroup analyses in Japanese patients have identified more cases with good PS and an association between PS and overall survival [ 17 , 18 , 23 ]. Patients with better PS are more likely to receive further treatment. Our present findings indicate that the efficacy and safety of the two currently approved fixed dosages of nivolumab were comparable when used as monotherapy in patients with advanced ESCC. Moreover, they are based on real-world data and confirm that the dosages of nivolumab that have been used up to now are safe and effective. In conclusion, the two fixed dosages of nivolumab monotherapy currently approved for patients with advanced ESCC were comparable in terms of efficacy and safety. Declarations Competing Interests KK reports funding to the institution from Merck Sharp & Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. Author Contribution KK, YM, and SY contributed to the conception, design, and planning of the study; all authors contributed to the acquisition of data; YM, and SY contributed to the analysis of data; YM, SY, and YK contributed to the interpretation of results; all authors contributed to the drafting, or critical review and revision of the manuscript; all authors approved the final version to be submitted. Acknowledgement None Data Availability Individual participant data underpinning the results reported in this article will be shared, after de-identification, with investigators whose proposed data usage has been approved. Proposals for data access should be directed to [email protected] . 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Cite Share Download PDF Status: Published Journal Publication published 15 Jul, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted Editorial decision: Revision requested 12 Jun, 2024 Reviews received at journal 10 Jun, 2024 Reviews received at journal 08 May, 2024 Reviewers agreed at journal 05 May, 2024 Reviewers agreed at journal 30 Apr, 2024 Reviewers invited by journal 30 Apr, 2024 Editor assigned by journal 30 Apr, 2024 Submission checks completed at journal 25 Apr, 2024 First submitted to journal 22 Apr, 2024 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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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-4304600","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":295347795,"identity":"c17a9c37-f911-4649-8b78-6359e4e3187b","order_by":0,"name":"Yuko Murashima","email":"","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Murashima","suffix":""},{"id":295347796,"identity":"c596eb7c-16f6-4b55-86f2-e6ef39d8c4ad","order_by":1,"name":"Shun Yamamoto","email":"","orcid":"","institution":"National Cancer Center 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jyunya","middleName":"","lastName":"Oguma","suffix":""},{"id":295347810,"identity":"4c520899-df64-4979-8014-cb51aae39f42","order_by":11,"name":"Hiroyuki Daiko","email":"","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Daiko","suffix":""},{"id":295347811,"identity":"8aabc41d-5641-4490-84aa-ae3f79045b55","order_by":12,"name":"Ken Kato","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACCQYGZhAtBxNgJlJLAoMx6VoSG4h2mGR772GDnz9s0rezH37A+KWCgd2ckBZpnnPJiT0Jabk7e9IMmGXOMDBbErJPTiLH+ABPwuHcDTd4GJgl2xiYDQ4Q0iL/xvjgn4TD6QZEa5GW4DFOBtqSANLC+JEYLZI9OcbGMmlphhvOpBkcZjgjQdgvEsfPGEu+sbGRNzh++OHDHxU2yQRDDAUc5mGQSDYgSQvjDwYGO9K0jIJRMApGwUgAAO6dOK8xfy6EAAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ken","middleName":"","lastName":"Kato","suffix":""}],"badges":[],"createdAt":"2024-04-22 09:08:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4304600/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4304600/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12029-024-01092-w","type":"published","date":"2024-07-15T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55764023,"identity":"bd6aac5c-2fba-4a12-9f27-2c54832721ea","added_by":"auto","created_at":"2024-05-02 19:50:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92059,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram showing the patient selection process. ESCC, esophageal squamous cell carcinoma.\u003c/p\u003e","description":"","filename":"MOFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4304600/v1/22a7aa0354d69d797312ac12.png"},{"id":55763699,"identity":"5756fb6e-bfd4-4e4c-8105-02f18891320d","added_by":"auto","created_at":"2024-05-02 19:42:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45010,"visible":true,"origin":"","legend":"\u003cp\u003eA. Progression-free survival in patients receiving nivolumab as second-line monotherapy for advanced esophageal squamous cell carcinoma. The median follow-up duration was 10.3 months in the 240 mg Q2W group and 8.1 months in the 480 mg Q4W group; median progression-free survival was 1.7 months (95% CI 1.38-2.30) and 4.1 months (95% CI 1.81-7.79), respectively (hazard ratio 0.60, 95% CI 0.35-1.01, p=0.056). CI, confidence interval; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks.\u003c/p\u003e\n\u003cp\u003eB. Progression-free survival in patients receiving nivolumab as later-line monotherapy for advanced esophageal squamous cell carcinoma. The median follow-up duration was 4.0 months in the 240 mg Q2W group and 5.8 months in the 480 mg Q4W group; median progression-free-survival was 1.4 months (95% CI 1.22-1.84) and 1.8 months (95% CI 0.23-5.55), respectively (hazard ratio 0.58, 95% CI 0.23-1.46, p=0.251). CI, confidence interval; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4304600/v1/9d11134e7c24c6a060123c90.png"},{"id":55763701,"identity":"e4fb1728-16d0-41bf-8c6b-f29a317f2f7d","added_by":"auto","created_at":"2024-05-02 19:42:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50851,"visible":true,"origin":"","legend":"\u003cp\u003eA. Overall survival in patients receiving nivolumab as second-line monotherapy for advanced esophageal squamous cell carcinoma. The median overall survival was 22.8 months (95% CI 11.8-NA) and NA, respectively (hazard ratio 0.99, 95% CI 0.99-1.00, p=0.26). NA, not available; CI, confidence interval; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks.\u003c/p\u003e\n\u003cp\u003eB. Overall survival in patients receiving nivolumab as later-line monotherapy for advanced esophageal squamous cell carcinoma. The median overall survival was 5.6 months (95% CI 1.98-NA) and 5.7 months (95% CI 1.18-NA), respectively (hazard ratio 0.99, 95% CI 0.99-1.00, p=0.75). NA, not available; CI, confidence interval; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4304600/v1/c9297f34aa11c2a7f8647a95.png"},{"id":61595147,"identity":"208bd2e5-c8e3-46a5-afc7-87ff40b30964","added_by":"auto","created_at":"2024-08-01 17:20:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":690688,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4304600/v1/c74977a4-2bc9-4348-b0ae-dd8d540e15e6.pdf"}],"financialInterests":"Competing interest reported. KK reports funding to the institution from Merck Sharp \u0026 Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai.","formattedTitle":"Efficacy and safety of salvage-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma: Comparison of 240 mg versus 480 mg doses","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe annual incidence of newly diagnosed esophageal cancer (EC) was estimated to be 26,382 in Japan in 2019, ranking 11th among all cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], and to be 20,640 in the US in 2022, accounting for 1.1% of all cancers [2]. EC is classified histologically into squamous cell carcinoma (ESCC) and adenocarcinoma. ESCC has been reported to account for 87.8% of all EC and is more common in Japan than in Western countries [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Smoking and alcohol consumption are known to be major risk factors for ESCC, while Barrett's epithelium, reflux esophagitis, and high body mass index are known to be major risk factors for adenocarcinoma [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Fluoropyrimidine plus platinum combination therapy was traditionally considered to be first-line therapy for patients with advanced ESCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, more recently, fluoropyrimidine plus platinum, nivolumab, nivolumab plus ipilimumab, fluoropyrimidine plus platinum, and pembrolizumab have become established as first-line treatments based on the results of the CheckMate 648 and KEYNOTE-590 trials [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Taxanes, nivolumab monotherapy, and pembrolizumab monotherapy can also be used as second-line therapy [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the 2022 Japanese guidelines for EC, nivolumab monotherapy is strongly recommended for ESCC with no prior anti-PD-L1 therapy and pembrolizumab monotherapy is weakly recommended for ESCC with a combined positive score of \u0026ge;\u0026thinsp;10 and no prior anti-PD-L1 therapy or microsatellite instability-high or tumor mutational burden-high with no prior anti-PD-L1 antibody. Paclitaxel is weakly recommended for patients with no history of taxane use with or without prior anti-PD-L1 antibody therapy.\u003c/p\u003e \u003cp\u003eNivolumab was initially approved at a fixed dosage of 240 mg every 2 weeks (Q2W) in February 2020 based on the results of the ATTRACTION-3 trial [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A fixed dosage of 480 mg every 4 weeks (Q4W) became available in September 2020 based on pharmacokinetics data [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, there is little clinical information on the difference of efficacy and safety between two dosages in patients with advanced ESCC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDesign and patients\u003c/h2\u003e \u003cp\u003eThis study had a single-center, retrospective design and analyzed data from patients with advanced ESCC treated with second-line or later-line nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and December 2021. Performance status (PS) was assessed according to the Eastern Cooperative Oncology Group criteria, and the eighth edition of the Union for International Cancer Control TNM classification was used for cancer staging. This study was approved by the National Cancer Center Hospital\u0026rsquo;s institutional review board (approval number 2020\u0026ndash;287) and conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Although informed consent was not obtained, patients were provided with the opportunity to opt out.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eWe compared the objective response rate (ORR), progression-free survival (PFS), and adverse event (AE) rate between the fixed dosage of 240 mg Q2W and the fixed dosage of 480 mg Q4W in the second-line or later-line setting. The ORR was defined as the proportion of patients with a complete or partial response to treatment according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. The response was evaluated on computed tomography scans obtained every 2\u0026ndash;3 months. Overall survival was defined as the interval between the date of initiation of treatment and death (from any cause) or censored at the last date of confirmed survival. PFS was defined as the interval between the start of treatment and the date of the first documentation of disease progression or death (from any cause), whichever occurred first, or was censored at the last date of confirmed survival without disease progression. AEs were graded according to the CTCAE (Common Terminology Criteria of Adverse Events) version 5.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe median follow-up duration was estimated using the reversed Kaplan-Meier method. Survival curves were drawn using Kaplan-Meier methods, and these difference between groups was evaluated using the log-rank test. Differences in the distribution of ordinal variables were analyzed using the Chi-squared test or Fisher's exact test. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eIn total, 117 patients with ESCC received nivolumab monotherapy between January 2016 and December 2021. Of the 85 patients who received nivolumab monotherapy as a second-line treatment, 59 received 240 mg Q2W and 26 received 480 mg Q4W. Of the remaining 32 patients who received nivolumab monotherapy as a later-line treatment, 25 received 240 mg Q2W and 7 received 480 mg Q4W (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients who switched from 240 mg Q2W to 480 mg Q4W during treatment were excluded. The patient characteristics are shown in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the second-line group, the median age was 68 (range, 46\u0026ndash;85) years in the patients who received 240 mg Q2W and 68.5 (range, 51\u0026ndash;84) years in those who received 480 mg Q4W. PS was 0, 1 and 2, respectively, in 34%, 61%, and 5% of patients who received 240 mg Q2W and in 54%, 42%, and 4% of those who received 480 mg Q4W. There was a history of FP therapy in 81.3% of those who received 240 mg Q2W and in 42.3% of those who received 480 mg Q4W. In the later-line group, the median age was 63.5 (range, 47\u0026ndash;85) years in the patients who received 240 mg Q2W and 58 (range, 46\u0026ndash;80) years in those who received 480 mg Q4W. PS was 0, 1 and 2, respectively, in 28%, 60%, and 12% of patients who received 240 mg Q2W and 14%, 86%, and 0% in those who received 480 mg Q4W. There was a history of FP therapy in 60.0% of patients who received 240 mg Q2W and in 42.8% of those who received 480 mg Q4W. The backgrounds between the 240 mg Q2W and 480 mg Q4W fixed dosages of nivolumab were found to have no significant differences.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBackground characteristics in patients receiving nivolumab as second-line monotherapy for advanced esophageal squamous cell carcinoma\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e240 mg Q2W (n\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e480 mg Q4W (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (46\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.5 (51\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (88.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (84.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.730\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 0, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 1, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (61.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (42.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 2, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (55.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (61.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrgans with metastases, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.769\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior chemotherapy; FP, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (81.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (42.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior chemotherapy; DCF, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (18.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (57.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior radiotherapy, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (76.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (57.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior surgery, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (47.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (69.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eECOG, Eastern Cooperative Oncology Group; PS, performance status.\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=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBackground characteristics in patients receiving nivolumab as later-line monotherapy for advanced esophageal squamous cell carcinoma\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e240 mg Q2W (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e480 mg Q4W (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.5 (47\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (46\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.661\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 0, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.536\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 1, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (85.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS 2, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.387\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrgans with metastases, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.769\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior chemotherapy; FP, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.669\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior chemotherapy; DCF, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (57.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior radiotherapy, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior surgery, number_(percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.387\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eECOG, Eastern Cooperative Oncology Group; Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks; PS, performance status\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\u003eAdverse events of any grade according to dose strength\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e240 mg Q2W (n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c10\" namest=\"c7\"\u003e \u003cp\u003e480 mg Q4W (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated hepatic enzymes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenal insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eData are presented as the number (%). There were no treatment-related deaths. Q2W, fixed dosage every two weeks; Q4W, fixed dosage every four weeks.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eIn the second-line group, 62 patients had measurable lesions according to RECIST version 1.1 at the start of treatment. The ORR was 11.9% in patients who received 240 mg Q2W and 24.0% in those who received 480 mg Q4W (p\u0026thinsp;=\u0026thinsp;0.193). In the later-line group, there were 21 patients. The ORR was 0% in patients who received 240 mg Q2W and 14.3% in those who received 480 mg Q4W (p\u0026thinsp;=\u0026thinsp;0.219). The median follow-up duration was 10.3 months in patients who received 240 mg Q2W and 8.1 months in those who received 480 mg Q4W; median PFS was 1.7 months and 4.1 months, respectively (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35\u0026ndash;1.01; p\u0026thinsp;=\u0026thinsp;0.056) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In the later-line group, the median follow-up duration was 4.0 months in patients who received 240 mg Q2W and 5.8 months in those who received 480 mg Q4W; median PFS was 1.4 months and 1.8 months, respectively (HR 0.58, 95% CI 0.23\u0026ndash;1.46; p\u0026thinsp;=\u0026thinsp;0.25) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). In the second-line group, the median OS was 22.7 months in patients who received 240 mg Q2W as compared with Not Available (NA) in those who received 480 mg Q4W (HR 1.00, 95% CI 11.8-NA; P\u0026thinsp;=\u0026thinsp;0.25) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). In the later-line group, the median OS was 5.6 months in patients who received 240 mg Q2W as compared with 5.7 months in those who received 480 mg Q4W (HR 1.00, 95% CI 1.97-NA; P\u0026thinsp;=\u0026thinsp;0.753) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). There was no significant difference in ORR, PFS, or OS between the fixed dosages of 240 mg Q2W and 480 mg Q4W in either treatment line.\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eSafety was compared between the dosage regimens independent of treatment line. Treatment-related AEs of any grade were observed in 58.3% of patients in the 240 mg Q2W group and in 69.7% of those in the 480 mg Q4W group (Table\u0026nbsp;5). The frequencies of grade 1, 2, 3, and 4 AEs were as follows: rash, 11.9%, 4.8%, 0%, and 0%, respectively, in the 240 mg Q2W group and 3.0%, 3.0%, 0%, and 0% in the 480 mg Q4W group; pruritus, 14.3%, 6.0%, 0%, and 0% in the 240 mg Q2W group and 12.1%, 0%, 0%, and 0% in the 480 mg Q4W group; diarrhea, 3.6%, 4.8%, 1.2%, and 0% in the 240 mg Q2W group and 3.0%, 3.0%, 0%, and 0% in the 480 mg Q4W group; and interstitial pneumonia, 0%, 0%, 3.6%, and 0% in the 240 mg Q2W group and 0%, 9.1%, 6.1%, and 0% in the 480 mg Q4W group. There were no treatment-related deaths in either dosage group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study found no statistically significant differences in efficacy and safety between the 240 mg Q2W and 480 mg Q4W fixed dosages of nivolumab when used as salvage-line monotherapy for advanced ESCC. Nivolumab monotherapy was first approved at a dosage of 2 mg/kg every 3 weeks for melanoma based on the results of a Phase II trial [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Next, a dosage of 3 mg/kg every 2 weeks was approved for lung cancer based on the results of a Phase III trial [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Subsequently, a fixed dosage of 240 mg Q2W became available based on population pharmacokinetics and exposure-response analyses showing comparability of exposure, safety, and efficacy between dosages of 3 mg/kg every 2 weeks and a fixed dosage of 240 mg Q2W [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Finally, a fixed dosage of 480 mg Q4W was approved based on modeling and simulation showing that the benefit-risk of a fixed dosage of 480 mg Q4W was a similar to that of 3 mg/kg Q2W [2]. In this study, since the approval of 480mg Q4W regimen, 480mg Q4W regimen has been predominantly chosen.\u003c/p\u003e \u003cp\u003eA retrospective cohort study of nivolumab as an adjuvant treatment for melanoma compared the duration of therapy and safety of four different dosage (de novo nivolumab 480 mg Q4W, switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3 mg/kg Q2W, de novo nivolumab 3 mg/kg Q2W, and de novo nivolumab 240 mg Q2W) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar and comparable with the safety profile of nivolumab 3 mg/kg Q2W [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In the present study, ORR was 11.9% in patients who received 240 mg Q2W and 24.0% in those who received 480 mg Q4W (p\u0026thinsp;=\u0026thinsp;0.193) in the second-line setting and 0% and 14.3%, respectively (p\u0026thinsp;=\u0026thinsp;0.219) in the later-line setting; the difference according to treatment line was not statistically significant. Median PFS was 1.7 months in patients who received 240 mg Q2W and 4.1 months in those who received 480 mg Q4W as a second-line treatment (HR 0.60, 95% CI 0.35\u0026ndash;1.01; p\u0026thinsp;=\u0026thinsp;0.056]) and 1.4 months and 1.8 months, respectively, in those who received nivolumab as a later-line treatment (HR 0.58, 95% CI 0.23\u0026ndash;1.46; p\u0026thinsp;=\u0026thinsp;0.25). Although there was no statistically significant difference between the two fixed dosages, 480 mg Q4W showed a trend of slightly better efficacy. This finding may reflect differences in patient background characteristics or differences in the timing of standard treatment. This is the first study to demonstrate the efficacy and safety of nivolumab at these dosages for advanced ESCC, and its findings are similar to those in melanoma and other solid and hematological tumors [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e], [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur finding of no significant difference in AEs between the two dosages of nivolumab is consistent with a previous report [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Interstitial pneumonia cases tended to be more frequent in patients who received 480 mg Q4W. However, chart review revealed that patients who developed interstitial pneumonia had pre-existing poor lung function because of underlying collagen disease or chronic obstructive pulmonary disease. When there was evidence of pneumonia and an increased oxygen demand, there was a tendency to administer steroids early before the pneumonia became severe. This could reflect implementation of methods to manage immune-related AEs potentially caused by nivolumab.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, it had a single-center retrospective cohort design and included a number of patients with poor PS who were started on nivolumab third-line or later-line treatment immediately after the drug received regulatory approval for use in this setting. In several studies of nivolumab in patients with various types of cancer, subgroup analyses in Japanese patients have identified more cases with good PS and an association between PS and overall survival [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Patients with better PS are more likely to receive further treatment. Our present findings indicate that the efficacy and safety of the two currently approved fixed dosages of nivolumab were comparable when used as monotherapy in patients with advanced ESCC. Moreover, they are based on real-world data and confirm that the dosages of nivolumab that have been used up to now are safe and effective.\u003c/p\u003e \u003cp\u003eIn conclusion, the two fixed dosages of nivolumab monotherapy currently approved for patients with advanced ESCC were comparable in terms of efficacy and safety.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eKK reports funding to the institution from Merck Sharp \u0026amp; Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKK, YM, and SY contributed to the conception, design, and planning of the study; all authors contributed to the acquisition of data; YM, and SY contributed to the analysis of data; YM, SY, and YK contributed to the interpretation of results; all authors contributed to the drafting, or critical review and revision of the manuscript; all authors approved the final version to be submitted.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eIndividual participant data underpinning the results reported in this article will be shared, after de-identification, with investigators whose proposed data usage has been approved. Proposals for data access should be directed to [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCancer Information Service. Cancer statistics in Japan. https://ganjoho.jp/reg_stat/statistics/stat/cancer/4_esophagus.html Accessed 30 Jan 2023. \u003c/li\u003e\n\u003cli\u003eCancer Statics. NATIONAL CANCER INSTITUTE https://seer.cancer.gov/statfacts/html/esoph.html Accessed 15 Feb 2023.\u003c/li\u003e\n\u003cli\u003eWatanabe M, Tachimori Y, Oyama T, et al. Comprehensive registry of esophageal cancer in Japan, 2013. Esophagus. 2021;18(1):1-24.\u003c/li\u003e\n\u003cli\u003eOze I, Charvat H, Matsuo K, et al. Does cigarette smoking and alcohol drinking have interaction for the risk of esophageal cancer? Cancer Med. 2019; 8(14): 6414-6425.\u003c/li\u003e\n\u003cli\u003eYousef F, Cardwell C, Cantwell MM, et al. The incidence of esophageal cancer and high-grade dysplasia in Barrett\u0026apos;s esophagus: a systematic review and meta-analysis. Am J Epidemiol. 2008; 168(3): 237-49.\u003c/li\u003e\n\u003cli\u003eLagergren J, Bergstr\u0026ouml;m R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999; 340(11): 825-31.\u003c/li\u003e\n\u003cli\u003eNakamura Y, Kitano S, Takahashi A, et al. Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 2016; 7: 77404-15.\u003c/li\u003e\n\u003cli\u003eKitagawa Y, Ishihara R, Ishikawa H, et al. Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 1. Esophagus. 2023; 20: 343-372. \u003c/li\u003e\n\u003cli\u003eKitagawa Y, Ishihara R, Ishikawa H, et al. Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 2. Esophagus. 2023; 20: 373-389. \u003c/li\u003e\n\u003cli\u003eDoki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022; 3; 386(5): 449-462.\u003c/li\u003e\n\u003cli\u003eSun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021; 28; 398(10302): 759-771.\u003c/li\u003e\n\u003cli\u003eKato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATT RACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 1506-17. \u003c/li\u003e\n\u003cli\u003eKojima T, Shah MA, Muro K, et al. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020; 10; 38(35): 4138-4148.\u003c/li\u003e\n\u003cli\u003eYamamoto S, Kawakami H, Kii T, et al. Randomized phase II study of docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma refractory to fluoropyrimidine- and platinum-based chemotherapy: OGSG1201. Eur J Cancer. 2021; 154: 307-315.\u003c/li\u003e\n\u003cli\u003eZhao X, Ivaturi V, Gopalakrishnan M, et al. A model-based exposure\u0026ndash;response (E\u0026ndash;R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types. Cancer Res 2017; 77(13 Supplement): abstract CT101.\u003c/li\u003e\n\u003cli\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026apos;EZR\u0026apos; for medical statistics. Bone Marrow Transplant. 2013; 48(3): 452-8.\u003c/li\u003e\n\u003cli\u003eYamazaki N, Kiyohara Y, et al. Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study. Cancer Sci. 2017 Jun;108(6):1223-1230.\u003c/li\u003e\n\u003cli\u003eOya Y, Yoshida T, Kuroda H, et al. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small- cell lung cancer. Oncotarget. 2017; 8: 103117-28.\u003c/li\u003e\n\u003cli\u003eZhao X, Suryawanshi S, Hruska M, et al. Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol 2017; 28(8): 2002-2008. \u003c/li\u003e\n\u003cli\u003eSamlowski W, Robert NJ, Chen L, et al. Real-World nivolumab dosing patterns and safety outcomes in patients receiving adjuvant therapy for melanoma. Cancer Med. 2023; 12(3): 2378-2388.\u003c/li\u003e\n\u003cli\u003eBi Y, Liu J, Furmanski B, et al. Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective. Ann Oncol. 2019 Apr 1; 30(4): 644-651.\u003c/li\u003e\n\u003cli\u003eLong GV, Tykodi SS, et al. Assessment of nivolumab exposure and clinical safety of 480\u0026thinsp;mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018 1; 29(11): 2208-2213.\u003c/li\u003e\n\u003cli\u003eTakahashi, M, Kato, K, Okada, M, et al\u003cem\u003e.\u003c/em\u003e Nivolumab versus chemotherapy in Japanese patients with advanced esophageal squamous cell carcinoma: a subgroup analysis of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3). Esophagus 2021; 18, 90-99.\u003c/li\u003e\n\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":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"esophageal cancer, esophageal squamous cell carcinoma, nivolumab, chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4304600/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4304600/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line(n=85) or later-line(n=32) nivolumab monotherapy at our institution between January 2016 and December 2021.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics in the second-line group were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2, 34/61/5% vs 54/42/4%; prior FP, 81.3 vs. 42.3%. Those in the later-line group were as follows: PS 0/1/2, 28/60/12% vs. 14/86/0%; prior FP, 60.0 vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p=0.19) and 0 vs. 14.3% in the later-line group (p=0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35-1.01, p=0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23-1.46, p=0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of salvage-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma: Comparison of 240 mg versus 480 mg doses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-02 19:42:45","doi":"10.21203/rs.3.rs-4304600/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-12T21:44:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-10T14:56:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-08T13:02:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"249430693121819025684886083992929695793","date":"2024-05-06T02:06:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199435798342268141682430423381292675077","date":"2024-05-01T02:26:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-01T01:35:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-01T01:32:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-25T09:42:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2024-04-22T08:54:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"034ed7cd-aaf8-48e9-8ca7-04c75e045d46","owner":[],"postedDate":"May 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-01T16:18:43+00:00","versionOfRecord":{"articleIdentity":"rs-4304600","link":"https://doi.org/10.1007/s12029-024-01092-w","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2024-07-15 15:57:26","publishedOnDateReadable":"July 15th, 2024"},"versionCreatedAt":"2024-05-02 19:42:45","video":"","vorDoi":"10.1007/s12029-024-01092-w","vorDoiUrl":"https://doi.org/10.1007/s12029-024-01092-w","workflowStages":[]},"version":"v1","identity":"rs-4304600","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4304600","identity":"rs-4304600","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}