Comparative safety of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma: a real-world pharmacovigilance study

Comparative safety of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma: a real-world pharmacovigilance 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 Comparative safety of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma: a real-world pharmacovigilance study Shanshan Xu, Zhihui Song, Dong Wang, Ente Wang, Jiawei Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6426078/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jul, 2025 Read the published version in BMC Cancer → Version 1 posted 11 You are reading this latest preprint version Abstract Background Nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus relatlimab (NIVO-RELA) were approved for treating advanced melanoma. There is no real-world insights into differential adverse eventm (AE) risks across two regimens. Methods We conducted a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database for NIVO-IPI and NIVO-RELA from the fouth quarter (Q4) of 2015 to 2024Q4 by calculating the reporting odds ratios (ROR) and information component (IC) with 95% confidence intervals (ICs). Results In total, 7482 and 185 records were extracted to analyze from FAERS for NIVO-IPI and NIVO-RELA, respectively. NIVO-IPI showed higher significant risks in gastrointestinal (ROR = 1.39), endocrine (ROR = 3.10), hepatobiliary (ROR = 2.32), metabolism and nutrition (ROR = 1.44), and respiratory, thoracic and mediastinal disorders (ROR = 1.18), especially in preferred terms (PTs) of colitis, hypophysitis, pneumonia and hepatitis. NIVO-RELA had elevated risks in cardiac (ROR = 2.84) and vascular disorders (ROR = 2.04), especially in PTs of myocarditis, troponin elevation, and myasthenia gravis. 80% of AEs occurred within 3 months for both regimens. Median time-to-onset was 42 days (NIVO-IPI) vs. 57 days (NIVO-RELA), with no statistical difference ( p = 0.66). Conclusion NIVO-IPI was associated with broader immune-related toxicities, while NIVO-RELA exhibited higher cardiac-specific risks. These findings underscore the need for tailored AE monitoring based on treatment selection. immune checkpoint inhibitor combination therapy heterogeneity FAERS database disproportionality analysis advanced melanoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction In recent years, melanoma has historically been a formidable challenge in oncology, particularly in its advanced stages, defined as unresectable or metastatic disease [ 1 ]. Immune checkpoint inhibitors (ICIs), a class of immunotherapy agents, have significantly improved outcomes for multiple malignancies, including advanced melanoma [ 2 – 6 ]. ICIs are divided into several classes depending on the targets, including programmed cell death protein 1 inhibitor (PD-1), programmed death-ligand 1 inhibitor (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 inhibitor (LAG-3) [ 7 , 8 ]. Ipilimumab, an inhibitor of CTLA-4, was the first agent to be associated with a survival benefit in advanced melanoma, which is although no longer considered a first-line therapy as monotherapy today [ 9 ]. PD-1 inhibitors sucH as pembrolizumab and nivolumab also received the United States (US) Food and Drug Administration (FDA) approval to treat melanoma in recent years. To synergize the efficacy of CTLA-4 and PD-1 inhibitors, FDA approved the nivolumab/ipilimumab combination (NIVO-IPI) in 2015, which has shown better efficacy than monotherapy of ipilimumab or nivolumab [ 10 ]. However, this benefit comes at the cost of a grade 3–4 immune-related adverse events (irAEs) rate of around 60% [ 11 ]. In 2022, the FDA approved a new combination of ICIs, nivolumab/relatlimab (NIVO-RELA). Relatlimab is a first-in-class inhibitor of LAG-3, a surface molecule inhibiting T-lymphocyte proliferation. ELATIVITY-047 study has demonstrated the superiority of NIVO-RELA in the progression-free survival (PFS) over nivolumab monotherapy, and also with less irAEs of grade 3–4[ 12 ]. The National Comprehensive Cancer Network (NCCN) has recommended NIVO-RELA and NIVO-IPI as preferred, category 1, first-line systemic therapy options for unresectable or metastatic melanoma [ 13 ]. Published data about two combination regimens-related adverse events (AEs) are not few but mainly available from clinical trials, and it is possible that the full adverse event (AE) profiles are not accurately represented due to the strict study inclusion criteria, relatively small sample sizes, and the limited follow-up time. NO pharmacovigilance studies of spontaneous reports compared the difference in AE profiles between NIVO-RELA and NIVO-IPI in advanced melanoma. Therefore, this study aimed to explore the differential risk of AEs treated with the two combination regimens by FAERS databases to provide critical insights for improving the prevention and management of AEs in the treatment of advanced melanoma. Additionally, we analyzed the median onset time for AEs across different groups. 2 Methods 2.1. Study design and data sources A retrospective pharmacovigilance study was conducted based on the data retrieved from the FDA Adverse Event Reporting System (FAERS) database. The FAERS database consists of seven data tables: demographic and administrative information (DEMO), drug information (DRUG), the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) coded for the adverse event (REAC), patient outcomes (OUTC), report sources (RPSR), therapy start dates and end dates for reported drugs (THER), and indications for use (INDI). In the FAERS, AEs are coded using the PTs according to the MedDRA Version 26.1, and all AE reports were identified in system organ class (SOC) and preferred term (PT) levels. Due to the arbitrary listing of drugs in the FAERS database, MICROMEDEX was utilized as a reference source, and all generic names, brand names, and research codes were applied (Supplementary Table 1). 2.2 Data extraction FAERS data were downloaded from the fourth quarter (Q4) of 2015 to 2024 Q4 from the FAERS Quarterly Data Extract Files website ( https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html ), because the FDA approved NIVO-IPI for melanoma treatment on September 30, 2015. FAERS data were processed anonymously, and no ethical review was required. We performed data cleaning in three steps before analysis. First, duplicates and multiple cases were excluded using a previously utilized method [ 14 ]. Second, a drug event associated with the combination of nivolumab and ipilimumab or nivolumab and ipilimumab was screened, and only those AE reports with reported roles of one of the drugs as as primary suspect (PS) were included. Finally, we extracted all AEs with the indications of “melanoma”. 2.3 Statistical analysis Disproportionality analysis was used to evaluate the potential relationship between drugs and AEs by calculating the reporting odds ratio (ROR) and information component (IC), which are specific indices used to detect possible associations between drugs and AEs. Calculations for ROR and IC were based on a 2 × 2 contingency table (Supplementary Table 2). The equations and criteria for ROR, IC, and the 95% confidence interval (95% CI) are shown in Supplementary Table 3. Statistical shrinkage (shrinkage parameter = 0.5) was applied to reduce the number of false-positive signals when calculating ROR or IC [ 15 ]. A signal was considered significant if the lower limits of the 95% confidence intervals of ROR (ROR 025 ) or IC (IC 025 ) exceeded predefined thresholds (1 and 0, respectively) in at least three records [ 16 ]. The time-to-onset (TTO) of AEs equals onset date minus therapy start date [ 16 ]. Median and interquartile ranges (IQR) were determined to represent time-to-onset (TTO). Kruskal-Wallis test was used to compare TTO among different two groups. All statistical analyses and graphical representations were conducted using R Studio (version 4.2.0; Boston, MA, United States). 3 Results 3.1 Clinical baseline characteristics From 2015 Q4 to 2024 Q4, 19,348,490 AE cases were extracted from the FAERS database. After the data cleaning, 7,482 NIVO-IPI and 185 records of NIVO-RELA were extracted for analysis (Fig. 1 ). Baseline characteristics of patients (cases) are presented in Table 1 . Excluding missing results, most patients were male, with 54.53% and 54.59% in the NIVO-IPI and NIVO-RELA groups, respectively. Regarding age, most patients were under 65 years old in the NIVO-IPI (44.56% <65 vs. 33.07% ≥65), whereas NIVO-RELA showed the opposite trend (28.65% <65 vs. 49.19% ≥65). Patients weighing between 50 and 100 kg (26.90% for NIVO-IPI and 41.08% for NIVO-RELA) accounted for a higher proportion in the available data. Healthcare professionals submitted most cases in both groups, 85.91% and 74.05% in the NIVO-IPI and NIVO-RELA groups. More than half of the cases were submitted by the US and Japan in the NIVO-IPI group and the US submitted 64.86% of AEs in the NIVO-RELA group. The mortality due to AEs was 18.59% in the NIVO-IPI group, a little higher than mortality in the NIVO-RELA group (13.51%). Concerning chronological trends, the proportion of AE reports for NIVO-RELA almost gradually increased from 2018 to 2024. The reported proportion for NIVO-IPI increased year by year from 2015 to 2019 (from 1.46–14.74%), began to decrease from 2020 to 2024. Mortality rates were higher with NIVO-IPI (18.59% vs. 13.51%). Table 1 Clinical characteristics of patients with NIVO-IPI and NIVO-RELA in melanoma from the FAERS database from 2015 Q4 to 2024 Q4. Characteristics NIVO-IPI, n (%) NIVO-RELA, n (%) Number of reports 7482 185 Gender Female 2751 (36.77) 70 (37.84) Male 4080 (54.53) 101 (54.59) Missing 651 (8.70) 14 (7.57) Weight 100 kg 319 (4.26) 6 (3.24) 50ཞ100 kg 2013 (26.90) 76 (41.08) Missing 4969 (66.41) 98 (52.97) Age (years) 85 44 (0.59) 11 (5.95) Missing 1674 (22.37) 41 (22.16) Outcome of adverse events Congenital Anomaly 570 (7.62) 0 (0.00) Died 1391 (18.59) 25 (13.51) Disabled 37 (0.49) 1 (0.54) Hospitalized 2895 (38.69) 70 (37.84) Life-threatening 483 (6.46) 11 (5.95) Other outcomes 2102 (28.09) 33 (17.84) Required Intervention 4 (0.05) 0 (0.00) Missing 570 (7.62) 45 (24.32) Type of reporter [n, (%) ] Healthcare Professional 6428 (85.91) 137 (74.05) Consumer 1049 (14.02) 48 (25.95) Missing 5 (0.07) 0 (0.00) Country [n, (%) ] United States 2734 (36.54) 120 (64.86) Japan 1237 (16.53) 1 (0.54) France 701 (9.37) 13 (7.03) Germany 795 (10.63) 4 (2.16) Australia 291 (3.89) 11 (5.95) Other country 1724 (23.04) 36 (19.46) Reporting year [n, (%) ] 2015 109 (1.46) 0 2016 467 (6.24) 0 2017 806 (10.77) 0 2018 1022 (13.66) 2 (1.08) 2019 1103 (14.74) 11 (5.95) 2020 865 (11.56) 19 (10.27) 2021 962 (12.86) 27 (14.59) 2022 852 (11.39) 21 (12.35) 2023 680 (9.09) 60 (32.43) 2024 616 (8.23) 45 (24.32) 3.2 Disproportionality analysis There were 23 and 18 SOCs with a count greater than three for NIVO-IPI and NIVO-RELA, respectively. The disproportionality analysis results showed that the AEs of NIVO-IPI were over-reported in six SOCs, including gastrointestinal disorders (n = 3,574, ROR = 1.39, 95%CI 1.34–1.45, IC = 0.33, IC 025 = 0.28), endocrine disorders (n = 1,635, ROR = 3.10, 95%CI 2.90–3.30, IC = 1.12, IC 025 = 1.03), hepatobiliary disorders (n = 1,454, ROR = 2.32, 95%CI 2.18–2.48, IC = 0.87, IC 025 = 0.78), metabolism and nutrition disorders (n = 1,207, ROR = 1.44, 95% CI 1.35–1.54, IC = 0.40, IC 025 = 0.30), respiratory, thoracic and mediastinal disorders (n = 1,140, ROR = 1.18, 95%CI 1.11–1.27, IC = 0.19, IC 025 = 0.09), and cardiac disorders (n = 666, ROR = 1.17, 95%CI 1.07–1.27, IC = 0.17, IC 025 = 0.05). For NIVO-RELA, AEs of significant signals were detected in two SOCs, including vascular disorders (n = 13, ROR = 2.04, 95%CI 1.12–3.73, IC = 1.00, IC 025 = 0.15), and cardiac disorders (n = 28, ROR = 2.84, 95%CI 1.82–4.42, IC = 1.44, IC 025 = 0.80) (Fig. 2 A and 2 B). Further analyses conducted at the PT level revealed that there were 1004 PTs with a count greater than three, of which significant signals were noted in 124 PTs of NIVO-IPI (Fig. 3 A). For NIVO-RELA, 27 PTs with a count greater than three were subjected to a disproportionality analysis compared to NIVO-IPI (Fig. 3 B). The results revealed that NIVO-IPI and NIVO-RELA alone shared 2 potential positive PTs, including myocarditis and immune-mediated myocarditis. NIVO-IPI had 122 unique potential positive PTs, while NIVO-RELA had 12 unique potential positive PTs. The most common five positive PTs for NIVO-IPI were colitis, immune-mediated enterocolitis, hypophysitis, hypothyroidism and hepatitis, and the top five PTs with strongest signal strength were immune-mediated hepatic disorder, enterocolitis, immune-mediated enterocolitis, immune-mediated encephalitis and hypopituitarism. For NIVO-RELA, the most common five positive PTs were death, myocarditis, rash, weight decreased and troponin increased. In comparison, the top five PTs with strongest signal strength were troponin increased, immune-mediated myocarditis, myocarditis, myasthenia gravis, and basal cell carcinoma. 3.3 Comparison of time-to-onset More than 80% of related AEs occurred in both groups during the first three months of initiating ICI treatments (Fig. 4 ). The median TTO of total AEs was 42 (18–91) days and 57 (18–89) days in NIVO-IPI and NIVO-RELA groups, respectively. Different combination strategies may not influence the median onset time of total AEs ( p = 0.66) (Fig. 5 ). 4 Discussion To the best of our knowledge, this study is the first pharmacovigilance study to compare the safety profiles of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma based on real-world data from the FAERS database. This study highlights distinct safety profiles in SOC-level and PT-level patterns between NIVO-IPI and NIVO-RELA in extensive sample sizes, providing crucial insights into current clinical practices for treating advanced melanoma. Key findings include: 1) In comparison with NIVO-IPI, NIVO-RELA had a lower incidence of AEs (lower value of IC 025 or ROR 025 for most SOCs and PTs). 2) Patients receiving NIVO-RELA require vigilant monitoring for cardiac and vascular disorders complications, such as myocarditis and hypertension. At the same time, NIVO-IPI warrants attention to hepatic, gastrointestinal, respiratory, endocrine and metabolism complications. There was no significant difference in the time to onset of AEs between two treatment groups. For the clinical characteristics, we found gender differences in the spontaneous reports of NIVO-IPI and NIVO-RELA, with male reports being 1.48 times (4080/2751) and 1.44 times (101/70) that of femalesin the NIVO-IPI and NIVO-RELA groups, respectively. Previous studies have shown that that men have a higher incidence of developing cutaneous melanoma than women and this difference is more evident in older age groups [ 17 ]. There was an age difference between NIVO-IPI and NIVO-RELA, with more proportion in patients under 65 for NIVO-IPI and more proportion in patients above 65 for NIVO-RELA. Previous studies showed consistent safety profiles in patients of different ages in both combination regimens [ 18 – 22 ]. The age differences in our study may need to be confirmed by more data or prospective studies in the future. Moreover, concerning the outcomes of total AEs, our study revealed that NIVO-IPI therapy presented a higher mortality (18.59%), which could stem from its broader immune activation profile, necessitating careful toxicity management. The RELATIVITY-047 and CheckMate 067 trial data showed that NIVO-RELA was associated with fewer grade 3 or 4 AEs (23% vs. 61% for NIVO-IPI) than NIVO-IPI, especially in endocrine, hepatic, renal, and skin [ 23 ]. Our study also showed that NIVO-RELA had a lower risk of incidence of AEs in most SOCs including endocrine, hepatic, gastrointestinal, metabolism, and respiratory. NIVO-IPI showed unique potential positive signals in PTs of colitis, immune-mediated enterocolitis, hypophysitis, hypothyroidism, hepatitis, pneumonitis, type 1 diabetes mellitus, and diabetic ketoacidosis. NIVO-RELA The mechanism of action in enhancing T cell activity of anti-CTLA-4 (ipilimumab) increases the risk of immune-related adverse events (irAEs), and the most common irAEs involving the skin, gastrointestinal tract, liver, and endocrine and nervous systems [ 9 , 24 ]. When combined with anti-PD-1 (nivolumab), the concomitant use results in both a higher incidence, and a broader spectrum of adverse events, because of acting on distinct lymphocyte subtypes and at differentsites. When NIVO-IPI is selected to treat advanced melanoma, AEs including colitis, hepatitis, pneumonitis, type 1 diabetes mellitus, and diabetic ketoacidosis should be closely monitored. NIVO-RELA related AE reports were much less than NIVO-IPI, which might be related to its not widely used in clinic. The disproportionality analysis also showed NIVO-RELA had a lower risk of incidence of AEs compared to NIVO-IPI. A double-blind, randomized trial found the most common categories of irAEs that occurred in the NIVO-RELA group were hypothyroidism or thyroiditis, rash, and diarrhea or colitis [ 12 ]. Our study found that NIVO-RELA had a higher AE risk of vascular disorders and cardiac disorders, especially in PTs of myocarditis and hypertension. NIVO-RELA also had some unique potential positive PTs, such as troponin increased, myasthenia gravis, chest pain, and pleural effusion. Patients who develop myasthenia gravis during ICI treatment typically have a higher risk of myasthenic crisis than those with classical autoimmune myasthenia gravis, as well as a higher risk of myositis [ 25 ]. Myocarditis and myositis was the common cause of treatment-related death [ 26 , 27 ]. Hussein et al. [ 12 ] found myocarditis occurred in 1.7% of the patients in the NIVO-RELA group and 0.6% of those in the nivolumab group. They also found AEs of troponin elevation (12% of the patients) were observed more commonly than myocarditis events in the NIVO-RELA group. In addition, Patients may develop complications such as myositis or myasthenia gravis, which may also be associated with myocarditis [ 28 ]. So when NIVO-RELA is selected, the serum creatine kinase and troponin levels should be monitored, and their elevation should raise the suspicion of myositis and/or myocarditis [ 27 ]. We did not find the AE risk of hypothyroidism, thyroiditis, rash, diarrhea and colitis was more higher in NIVO-RELA than that of NIVO-IPI, which may be due to too little data in the NIVO-RELA group. The TTO indicated that most AEs occurred within the three months after both groups started the ICI combination therapy. Studies have shown that most AEs related to ICI occurred ranging from 2.2 to 14.8 weeks after the initiation of treatment [ 29 ]. The study also showed that the TTO of all-grade irAEs in the NIVO-IPI group was 6 weeks, consistent with our study (median TTO = 42 days). Although the median TTO of NIVO-RELA was longer than that of NIVO-IPI (57 vs. 42 days), there was no significant difference observed between the two groups. Despite the valuable insights gained, our study must acknowledge several limitations. First, due to the spontaneous and incomplete reporting, the FAERS database is subject to inherent biases (e.g., incomplete documentation with 86% missing gender data in the AI group). Second, the small number of cases receiving NIVO-RELA in the database may influence the results, necessitating further validation through additional studies. Third, the lack of clinical details (e.g., prior therapies) limits causal inference. Fourth, differences in baseline characteristics (e.g., age, gender, indication) between treatment groups were not fully adjusted. Fifth, due to the wide combination of ICIs with other anti-cancer drugs, such as targeted therapy agents, chemotherapeutic drugs, biologics, etc., it is difficult to rule out the effect of these drugs on the results. Finally, the disproportionate analysis cannot quantify absolute risks but identifies signals requiring further validation. ​ 5 Conclusion The real-world study highlights distinct safety profiles between NIVO-IPI and NIVO-RELA, informing risk-stratified treatment decisions. NIVO-IPI poses broader multi-organ toxicities, especially with higher AE risk of endocrine, hepatobiliary, gastrointestinal, metabolism and respiratory toxicities, while the cardiac risk of NIVO-RELA necessitates targeted surveillance. Our findings may be valuable for the selection and clinical management of NIVO-IPI and NIVO-REL. Further research is critical to optimize monitoring protocols and mechanistic understanding for better risk management. Abbreviations ICIs Immune checkpoint inhibitors NIVO-IPI Nivolumab plus ipilimumab NIVO-RELA Nivolumab plus relatlimab FDA Food and Drug Administration AE Adverse event FAERS Food and Drug Administration Adverse Event Reporting System PD-1 Programmed cell death protein 1 inhibitor PD-L1 Programmed death-ligand 1 inhibitor CTLA-4 Cytotoxic T-lymphocyte-associated protein 4 LAG-3 Lymphocyte activation gene 3 inhibitor PFS Progression-free survival NCCN National Comprehensive Cancer Network PS Primary suspected PT Preferred term SOC System organ class MedDRA Medical Dictionary for Regulatory Activities ROR Reporting odds ratio CI Confidence interval IC Information component TTO Time-to-onset Declarations Supplementary Materials Supplemental materials for this article are available online. Acknowledgements The authors thank all the contributors of the FAERS database. Author contributions SX: Methodology; Formal analysis; Investigation; Data acquisition; Interpretation of results; Writing original draft; Literature review and implementation of the study. JW: Conceptualization; Supervision and processing analysis. ZS: Formal analysis, Interpretation of results; Contributed to the design and implementation of the study; Interpretation of results. EW and DW: Methodology; Data checking and interpretation of results. All authors contributed to the article and approved the submitted version. Funding This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data Availability Statement Data are available by contact with the correspondence authors. Ethics approval and consent to participate Not applicable. Ethical approval was not required for this study because we used the FAERS database, which is a free open-access database. Consent for publication Not applicable. 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Med (Baltim). 2017;96(50):e9262. 10.1097/MD.0000000000009262 . Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789–801. 10.1056/NEJMoa1802357 . Suzuki S, Ishikawa N, Konoeda F, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89(11):1127–34. 10.1212/WNL.0000000000004359 . Martin Huertas R, Saavedra Serrano C, Perna C, et al. Cardiac toxicity of immune-checkpoint inhibitors: a clinical case of nivolumab-induced myocarditis and review of the evidence and new challenges. Cancer Manag Res. 2019;11:4541–8. 10.2147/CMAR.S185202 . Tang SQ, Tang LL, Mao YP, et al. The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: a pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat. 2021;53(2):339–54. 10.4143/crt.2020.790 . Additional Declarations No competing interests reported. Supplementary Files supplymental.docx Cite Share Download PDF Status: Published Journal Publication published 19 Jul, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 02 Jun, 2025 Reviews received at journal 26 May, 2025 Reviewers agreed at journal 26 May, 2025 Reviews received at journal 13 May, 2025 Reviewers agreed at journal 13 May, 2025 Reviewers agreed at journal 09 May, 2025 Reviewers invited by journal 07 May, 2025 Editor invited by journal 07 May, 2025 Editor assigned by journal 15 Apr, 2025 Submission checks completed at journal 15 Apr, 2025 First submitted to journal 11 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6426078","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":454531577,"identity":"b89a63a4-4fc6-4dc2-bffe-d875de3d6a3a","order_by":0,"name":"Shanshan Xu","email":"","orcid":"","institution":"Beijing Tongren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Xu","suffix":""},{"id":454531578,"identity":"f66285df-473f-4e18-8ae2-40d84f3493f5","order_by":1,"name":"Zhihui Song","email":"","orcid":"","institution":"Beijing Tongren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhihui","middleName":"","lastName":"Song","suffix":""},{"id":454531579,"identity":"357bffce-e6b9-412b-a4d6-6b547ce9454a","order_by":2,"name":"Dong Wang","email":"","orcid":"","institution":"Beijing Tongren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"","lastName":"Wang","suffix":""},{"id":454531580,"identity":"9237b4b0-0d7c-4608-93af-09a336f33d85","order_by":3,"name":"Ente Wang","email":"","orcid":"","institution":"Beijing Tongren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ente","middleName":"","lastName":"Wang","suffix":""},{"id":454531581,"identity":"7e66bcdd-95d3-4561-b5c2-652dfd775db8","order_by":4,"name":"Jiawei Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIie3PvQrCMBSG4QOCU6WbJBTqLUQCRUHwVprFKTh3rFS6iaviTXQSx1MKukRcBRfBxaFDxVX8m3TRZhTMMwQC30sIgGH8KgIdy7YjxCLQT3ounSxFOlH672ScoeRZbaixZat1dmzHFRGiKrAWQsOuY0mi+r0WjatiEI0SpAtoTmf+98RD6TE6t0QE6wSbCny2K0s2+TMhIga5x8epkWwl39M54xZIwFQn6W5zD+jVdwlZsjRUpPwvdCz5maib1d1Eh/Ml6DRspyR5qDrkdSGfd28qp0JrZxiG8bfuPSxNVOYSsd4AAAAASUVORK5CYII=","orcid":"","institution":"Beijing Tongren Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jiawei","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-04-11 07:53:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6426078/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6426078/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-14546-6","type":"published","date":"2025-07-19T16:05:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82651288,"identity":"5fa34971-149f-43cb-bfed-81695b7959e3","added_by":"auto","created_at":"2025-05-13 17:19:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":227190,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of AE reports selection for NIVO-IPI and NIVO-RELA in melanoma.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/099420c7c3cf176031b6fcbb.jpg"},{"id":82650180,"identity":"5bea5a30-f8c5-4318-a904-1be7163a24ee","added_by":"auto","created_at":"2025-05-13 17:03:10","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":293635,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of SOC in terms of ROR (95% CI) (2A) and IC\u003csub\u003e025\u003c/sub\u003e (2B) between two therapeutic regimens in the FAERS database.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/071f7218404176279159ba97.jpg"},{"id":82650176,"identity":"7fb82e95-2040-4db3-99e0-1b70fa6bc960","added_by":"auto","created_at":"2025-05-13 17:03:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":154699,"visible":true,"origin":"","legend":"\u003cp\u003eA) The heatmap of ROR\u003csub\u003e025\u003c/sub\u003e and IC\u003csub\u003e025\u003c/sub\u003e for 124 PTs with significant signal of NIVO-IPI (with cases no less than 3) in the FAERS database. B) Comparison of 27 PTs with a count greater than three of NIVO-RELA to NIVO-IPI regarding ROR\u003csub\u003e025\u003c/sub\u003e and IC\u003csub\u003e025\u003c/sub\u003e in the FAERS database.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/4d0513b541d03f81aacde495.jpg"},{"id":82650179,"identity":"4f60fc26-5974-4aaf-b153-c73d03cbcb60","added_by":"auto","created_at":"2025-05-13 17:03:10","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":294335,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of time to onset of AEs between two therapeutic regimens.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/88de4a9a23529314ecd79ee6.jpg"},{"id":82651291,"identity":"92c5eca9-65f6-4026-920e-ac944e8d3786","added_by":"auto","created_at":"2025-05-13 17:19:10","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":35666,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative distribution curves of the onset time of total AE cases after treatment in two therapeutic regimens.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/cf426c594c0869ace3e96c6f.jpg"},{"id":88506092,"identity":"153a04e6-bb39-4119-87bd-17466228ae59","added_by":"auto","created_at":"2025-08-07 07:30:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1751075,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/4cf7d197-35f8-4524-af08-3e399d81e59f.pdf"},{"id":82650175,"identity":"28539a99-d8ea-493f-aef1-7ae07e6c8417","added_by":"auto","created_at":"2025-05-13 17:03:10","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":22430,"visible":true,"origin":"","legend":"","description":"","filename":"supplymental.docx","url":"https://assets-eu.researchsquare.com/files/rs-6426078/v1/df4b9e5fa634f233392ba208.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative safety of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma: a real-world pharmacovigilance study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eIn recent years, melanoma has historically been a formidable challenge in oncology, particularly in its advanced stages, defined as unresectable or metastatic disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Immune checkpoint inhibitors (ICIs), a class of immunotherapy agents, have significantly improved outcomes for multiple malignancies, including advanced melanoma [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. ICIs are divided into several classes depending on the targets, including programmed cell death protein 1 inhibitor (PD-1), programmed death-ligand 1 inhibitor (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 inhibitor (LAG-3) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIpilimumab, an inhibitor of CTLA-4, was the first agent to be associated with a survival benefit in advanced melanoma, which is although no longer considered a first-line therapy as monotherapy today [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. PD-1 inhibitors sucH as pembrolizumab and nivolumab also received the United States (US) Food and Drug Administration (FDA) approval to treat melanoma in recent years. To synergize the efficacy of CTLA-4 and PD-1 inhibitors, FDA approved the nivolumab/ipilimumab combination (NIVO-IPI) in 2015, which has shown better efficacy than monotherapy of ipilimumab or nivolumab [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, this benefit comes at the cost of a grade 3\u0026ndash;4 immune-related adverse events (irAEs) rate of around 60% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In 2022, the FDA approved a new combination of ICIs, nivolumab/relatlimab (NIVO-RELA). Relatlimab is a first-in-class inhibitor of LAG-3, a surface molecule inhibiting T-lymphocyte proliferation. ELATIVITY-047 study has demonstrated the superiority of NIVO-RELA in the progression-free survival (PFS) over nivolumab monotherapy, and also with less irAEs of grade 3\u0026ndash;4[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The National Comprehensive Cancer Network (NCCN) has recommended NIVO-RELA and NIVO-IPI as preferred, category 1, first-line systemic therapy options for unresectable or metastatic melanoma [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePublished data about two combination regimens-related adverse events (AEs) are not few but mainly available from clinical trials, and it is possible that the full adverse event (AE) profiles are not accurately represented due to the strict study inclusion criteria, relatively small sample sizes, and the limited follow-up time. NO pharmacovigilance studies of spontaneous reports compared the difference in AE profiles between NIVO-RELA and NIVO-IPI in advanced melanoma. Therefore, this study aimed to explore the differential risk of AEs treated with the two combination regimens by FAERS databases to provide critical insights for improving the prevention and management of AEs in the treatment of advanced melanoma. Additionally, we analyzed the median onset time for AEs across different groups.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design and data sources\u003c/h2\u003e \u003cp\u003eA retrospective pharmacovigilance study was conducted based on the data retrieved from the FDA Adverse Event Reporting System (FAERS) database. The FAERS database consists of seven data tables: demographic and administrative information (DEMO), drug information (DRUG), the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) coded for the adverse event (REAC), patient outcomes (OUTC), report sources (RPSR), therapy start dates and end dates for reported drugs (THER), and indications for use (INDI).\u003c/p\u003e \u003cp\u003eIn the FAERS, AEs are coded using the PTs according to the MedDRA Version 26.1, and all AE reports were identified in system organ class (SOC) and preferred term (PT) levels. Due to the arbitrary listing of drugs in the FAERS database, MICROMEDEX was utilized as a reference source, and all generic names, brand names, and research codes were applied (Supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data extraction\u003c/h2\u003e \u003cp\u003eFAERS data were downloaded from the fourth quarter (Q4) of 2015 to 2024 Q4 from the FAERS Quarterly Data Extract Files website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\u003c/span\u003e\u003cspan address=\"https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), because the FDA approved NIVO-IPI for melanoma treatment on September 30, 2015. FAERS data were processed anonymously, and no ethical review was required. We performed data cleaning in three steps before analysis. First, duplicates and multiple cases were excluded using a previously utilized method [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Second, a drug event associated with the combination of nivolumab and ipilimumab or nivolumab and ipilimumab was screened, and only those AE reports with reported roles of one of the drugs as as primary suspect (PS) were included. Finally, we extracted all AEs with the indications of \u0026ldquo;melanoma\u0026rdquo;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eDisproportionality analysis was used to evaluate the potential relationship between drugs and AEs by calculating the reporting odds ratio (ROR) and information component (IC), which are specific indices used to detect possible associations between drugs and AEs. Calculations for ROR and IC were based on a 2 \u0026times; 2 contingency table (Supplementary Table\u0026nbsp;2). The equations and criteria for ROR, IC, and the 95% confidence interval (95% CI) are shown in Supplementary Table\u0026nbsp;3. Statistical shrinkage (shrinkage parameter\u0026thinsp;=\u0026thinsp;0.5) was applied to reduce the number of false-positive signals when calculating ROR or IC [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A signal was considered significant if the lower limits of the 95% confidence intervals of ROR (ROR\u003csub\u003e025\u003c/sub\u003e) or IC (IC\u003csub\u003e025\u003c/sub\u003e) exceeded predefined thresholds (1 and 0, respectively) in at least three records [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The time-to-onset (TTO) of AEs equals onset date minus therapy start date [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Median and interquartile ranges (IQR) were determined to represent time-to-onset (TTO). Kruskal-Wallis test was used to compare TTO among different two groups. All statistical analyses and graphical representations were conducted using R Studio (version 4.2.0; Boston, MA, United States).\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Clinical baseline characteristics\u003c/h2\u003e \u003cp\u003eFrom 2015 Q4 to 2024 Q4, 19,348,490 AE cases were extracted from the FAERS database. After the data cleaning, 7,482 NIVO-IPI and 185 records of NIVO-RELA were extracted for analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Baseline characteristics of patients (cases) are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Excluding missing results, most patients were male, with 54.53% and 54.59% in the NIVO-IPI and NIVO-RELA groups, respectively. Regarding age, most patients were under 65 years old in the NIVO-IPI (44.56% \u0026lt;65 vs. 33.07% \u0026ge;65), whereas NIVO-RELA showed the opposite trend (28.65% \u0026lt;65 vs. 49.19% \u0026ge;65). Patients weighing between 50 and 100 kg (26.90% for NIVO-IPI and 41.08% for NIVO-RELA) accounted for a higher proportion in the available data. Healthcare professionals submitted most cases in both groups, 85.91% and 74.05% in the NIVO-IPI and NIVO-RELA groups. More than half of the cases were submitted by the US and Japan in the NIVO-IPI group and the US submitted 64.86% of AEs in the NIVO-RELA group. The mortality due to AEs was 18.59% in the NIVO-IPI group, a little higher than mortality in the NIVO-RELA group (13.51%). Concerning chronological trends, the proportion of AE reports for NIVO-RELA almost gradually increased from 2018 to 2024. The reported proportion for NIVO-IPI increased year by year from 2015 to 2019 (from 1.46\u0026ndash;14.74%), began to decrease from 2020 to 2024. Mortality rates were higher with NIVO-IPI (18.59% vs. 13.51%).\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\u003eClinical characteristics of patients with NIVO-IPI and NIVO-RELA in melanoma from the FAERS database from 2015 Q4 to 2024 Q4.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNIVO-IPI, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNIVO-RELA, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of reports\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2751 (36.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (37.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4080 (54.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101 (54.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e651 (8.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (7.57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;50 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e181 (2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (2.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e319 (4.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50ཞ100 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2013 (26.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (41.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4969 (66.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98 (52.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18ཞ64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3292 (44.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (28.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65ཞ85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2430 (32.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (43.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (0.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1674 (22.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (22.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome of adverse events\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Anomaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e570 (7.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDied\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1391 (18.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (13.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisabled\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalized\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2895 (38.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (37.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e483 (6.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2102 (28.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (17.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRequired Intervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (0.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e570 (7.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (24.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of reporter [n, (%) ]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealthcare Professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6428 (85.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137 (74.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsumer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1049 (14.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (25.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCountry [n, (%) ]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2734 (36.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120 (64.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1237 (16.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e701 (9.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (7.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e795 (10.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e291 (3.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther country\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1724 (23.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (19.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReporting year [n, (%) ]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109 (1.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e467 (6.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e806 (10.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1022 (13.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1103 (14.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e865 (11.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (10.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e962 (12.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (14.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e852 (11.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (12.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e680 (9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (32.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e616 (8.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (24.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Disproportionality analysis\u003c/h2\u003e \u003cp\u003eThere were 23 and 18 SOCs with a count greater than three for NIVO-IPI and NIVO-RELA, respectively. The disproportionality analysis results showed that the AEs of NIVO-IPI were over-reported in six SOCs, including gastrointestinal disorders (n\u0026thinsp;=\u0026thinsp;3,574, ROR\u0026thinsp;=\u0026thinsp;1.39, 95%CI 1.34\u0026ndash;1.45, IC\u0026thinsp;=\u0026thinsp;0.33, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.28), endocrine disorders (n\u0026thinsp;=\u0026thinsp;1,635, ROR\u0026thinsp;=\u0026thinsp;3.10, 95%CI 2.90\u0026ndash;3.30, IC\u0026thinsp;=\u0026thinsp;1.12, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.03), hepatobiliary disorders (n\u0026thinsp;=\u0026thinsp;1,454, ROR\u0026thinsp;=\u0026thinsp;2.32, 95%CI 2.18\u0026ndash;2.48, IC\u0026thinsp;=\u0026thinsp;0.87, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.78), metabolism and nutrition disorders (n\u0026thinsp;=\u0026thinsp;1,207, ROR\u0026thinsp;=\u0026thinsp;1.44, 95% CI 1.35\u0026ndash;1.54, IC\u0026thinsp;=\u0026thinsp;0.40, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.30), respiratory, thoracic and mediastinal disorders (n\u0026thinsp;=\u0026thinsp;1,140, ROR\u0026thinsp;=\u0026thinsp;1.18, 95%CI 1.11\u0026ndash;1.27, IC\u0026thinsp;=\u0026thinsp;0.19, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.09), and cardiac disorders (n\u0026thinsp;=\u0026thinsp;666, ROR\u0026thinsp;=\u0026thinsp;1.17, 95%CI 1.07\u0026ndash;1.27, IC\u0026thinsp;=\u0026thinsp;0.17, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.05). For NIVO-RELA, AEs of significant signals were detected in two SOCs, including vascular disorders (n\u0026thinsp;=\u0026thinsp;13, ROR\u0026thinsp;=\u0026thinsp;2.04, 95%CI 1.12\u0026ndash;3.73, IC\u0026thinsp;=\u0026thinsp;1.00, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.15), and cardiac disorders (n\u0026thinsp;=\u0026thinsp;28, ROR\u0026thinsp;=\u0026thinsp;2.84, 95%CI 1.82\u0026ndash;4.42, IC\u0026thinsp;=\u0026thinsp;1.44, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.80) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eFurther analyses conducted at the PT level revealed that there were 1004 PTs with a count greater than three, of which significant signals were noted in 124 PTs of NIVO-IPI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). For NIVO-RELA, 27 PTs with a count greater than three were subjected to a disproportionality analysis compared to NIVO-IPI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The results revealed that NIVO-IPI and NIVO-RELA alone shared 2 potential positive PTs, including myocarditis and immune-mediated myocarditis. NIVO-IPI had 122 unique potential positive PTs, while NIVO-RELA had 12 unique potential positive PTs. The most common five positive PTs for NIVO-IPI were colitis, immune-mediated enterocolitis, hypophysitis, hypothyroidism and hepatitis, and the top five PTs with strongest signal strength were immune-mediated hepatic disorder, enterocolitis, immune-mediated enterocolitis, immune-mediated encephalitis and hypopituitarism. For NIVO-RELA, the most common five positive PTs were death, myocarditis, rash, weight decreased and troponin increased. In comparison, the top five PTs with strongest signal strength were troponin increased, immune-mediated myocarditis, myocarditis, myasthenia gravis, and basal cell carcinoma.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Comparison of time-to-onset\u003c/h2\u003e \u003cp\u003eMore than 80% of related AEs occurred in both groups during the first three months of initiating ICI treatments (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The median TTO of total AEs was 42 (18\u0026ndash;91) days and 57 (18\u0026ndash;89) days in NIVO-IPI and NIVO-RELA groups, respectively. Different combination strategies may not influence the median onset time of total AEs (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.66) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eTo the best of our knowledge, this study is the first pharmacovigilance study to compare the safety profiles of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma based on real-world data from the FAERS database. This study highlights distinct safety profiles in SOC-level and PT-level patterns between NIVO-IPI and NIVO-RELA in extensive sample sizes, providing crucial insights into current clinical practices for treating advanced melanoma. Key findings include: 1) In comparison with NIVO-IPI, NIVO-RELA had a lower incidence of AEs (lower value of IC\u003csub\u003e025\u003c/sub\u003e or ROR\u003csub\u003e025\u003c/sub\u003e for most SOCs and PTs). 2) Patients receiving NIVO-RELA require vigilant monitoring for cardiac and vascular disorders complications, such as myocarditis and hypertension. At the same time, NIVO-IPI warrants attention to hepatic, gastrointestinal, respiratory, endocrine and metabolism complications. There was no significant difference in the time to onset of AEs between two treatment groups.\u003c/p\u003e \u003cp\u003eFor the clinical characteristics, we found gender differences in the spontaneous reports of NIVO-IPI and NIVO-RELA, with male reports being 1.48 times (4080/2751) and 1.44 times (101/70) that of femalesin the NIVO-IPI and NIVO-RELA groups, respectively. Previous studies have shown that that men have a higher incidence of developing cutaneous melanoma than women and this difference is more evident in older age groups [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. There was an age difference between NIVO-IPI and NIVO-RELA, with more proportion in patients under 65 for NIVO-IPI and more proportion in patients above 65 for NIVO-RELA. Previous studies showed consistent safety profiles in patients of different ages in both combination regimens [\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The age differences in our study may need to be confirmed by more data or prospective studies in the future. Moreover, concerning the outcomes of total AEs, our study revealed that NIVO-IPI therapy presented a higher mortality (18.59%), which could stem from its broader immune activation profile, necessitating careful toxicity management.\u003c/p\u003e \u003cp\u003eThe RELATIVITY-047 and CheckMate 067 trial data showed that NIVO-RELA was associated with fewer grade 3 or 4 AEs (23% vs. 61% for NIVO-IPI) than NIVO-IPI, especially in endocrine, hepatic, renal, and skin [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our study also showed that NIVO-RELA had a lower risk of incidence of AEs in most SOCs including endocrine, hepatic, gastrointestinal, metabolism, and respiratory. NIVO-IPI showed unique potential positive signals in PTs of colitis, immune-mediated enterocolitis, hypophysitis, hypothyroidism, hepatitis, pneumonitis, type 1 diabetes mellitus, and diabetic ketoacidosis. NIVO-RELA The mechanism of action in enhancing T cell activity of anti-CTLA-4 (ipilimumab) increases the risk of immune-related adverse events (irAEs), and the most common irAEs involving the skin, gastrointestinal tract, liver, and endocrine and nervous systems [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. When combined with anti-PD-1 (nivolumab), the concomitant use results in both a higher incidence, and a broader spectrum of adverse events, because of acting on distinct lymphocyte subtypes and at differentsites. When NIVO-IPI is selected to treat advanced melanoma, AEs including colitis, hepatitis, pneumonitis, type 1 diabetes mellitus, and diabetic ketoacidosis should be closely monitored.\u003c/p\u003e \u003cp\u003eNIVO-RELA related AE reports were much less than NIVO-IPI, which might be related to its not widely used in clinic. The disproportionality analysis also showed NIVO-RELA had a lower risk of incidence of AEs compared to NIVO-IPI. A double-blind, randomized trial found the most common categories of irAEs that occurred in the NIVO-RELA group were hypothyroidism or thyroiditis, rash, and diarrhea or colitis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Our study found that NIVO-RELA had a higher AE risk of vascular disorders and cardiac disorders, especially in PTs of myocarditis and hypertension. NIVO-RELA also had some unique potential positive PTs, such as troponin increased, myasthenia gravis, chest pain, and pleural effusion. Patients who develop myasthenia gravis during ICI treatment typically have a higher risk of myasthenic crisis than those with classical autoimmune myasthenia gravis, as well as a higher risk of myositis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Myocarditis and myositis was the common cause of treatment-related death [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Hussein et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] found myocarditis occurred in 1.7% of the patients in the NIVO-RELA group and 0.6% of those in the nivolumab group. They also found AEs of troponin elevation (12% of the patients) were observed more commonly than myocarditis events in the NIVO-RELA group. In addition, Patients may develop complications such as myositis or myasthenia gravis, which may also be associated with myocarditis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. So when NIVO-RELA is selected, the serum creatine kinase and troponin levels should be monitored, and their elevation should raise the suspicion of myositis and/or myocarditis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We did not find the AE risk of hypothyroidism, thyroiditis, rash, diarrhea and colitis was more higher in NIVO-RELA than that of NIVO-IPI, which may be due to too little data in the NIVO-RELA group.\u003c/p\u003e \u003cp\u003eThe TTO indicated that most AEs occurred within the three months after both groups started the ICI combination therapy. Studies have shown that most AEs related to ICI occurred ranging from 2.2 to 14.8 weeks after the initiation of treatment [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The study also showed that the TTO of all-grade irAEs in the NIVO-IPI group was 6 weeks, consistent with our study (median TTO\u0026thinsp;=\u0026thinsp;42 days). Although the median TTO of NIVO-RELA was longer than that of NIVO-IPI (57 vs. 42 days), there was no significant difference observed between the two groups.\u003c/p\u003e \u003cp\u003eDespite the valuable insights gained, our study must acknowledge several limitations. First, due to the spontaneous and incomplete reporting, the FAERS database is subject to inherent biases (e.g., incomplete documentation with 86% missing gender data in the AI group). Second, the small number of cases receiving NIVO-RELA in the database may influence the results, necessitating further validation through additional studies. Third, the lack of clinical details (e.g., prior therapies) limits causal inference. Fourth, differences in baseline characteristics (e.g., age, gender, indication) between treatment groups were not fully adjusted. Fifth, due to the wide combination of ICIs with other anti-cancer drugs, such as targeted therapy agents, chemotherapeutic drugs, biologics, etc., it is difficult to rule out the effect of these drugs on the results. Finally, the disproportionate analysis cannot quantify absolute risks but identifies signals requiring further validation. ​\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThe real-world study highlights distinct safety profiles between NIVO-IPI and NIVO-RELA, informing risk-stratified treatment decisions. NIVO-IPI poses broader multi-organ toxicities, especially with higher AE risk of endocrine, hepatobiliary, gastrointestinal, metabolism and respiratory toxicities, while the cardiac risk of NIVO-RELA necessitates targeted surveillance. Our findings may be valuable for the selection and clinical management of NIVO-IPI and NIVO-REL. Further research is critical to optimize monitoring protocols and mechanistic understanding for better risk management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eICIs Immune checkpoint inhibitors\u003c/p\u003e\n\u003cp\u003eNIVO-IPI Nivolumab plus ipilimumab\u003c/p\u003e\n\u003cp\u003eNIVO-RELA Nivolumab plus relatlimab\u003c/p\u003e\n\u003cp\u003eFDA Food and Drug Administration\u003c/p\u003e\n\u003cp\u003eAE Adverse event\u003c/p\u003e\n\u003cp\u003eFAERS Food and Drug Administration Adverse Event Reporting System\u003c/p\u003e\n\u003cp\u003ePD-1 Programmed cell death protein 1 inhibitor\u003c/p\u003e\n\u003cp\u003ePD-L1 Programmed death-ligand 1 inhibitor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCTLA-4 Cytotoxic T-lymphocyte-associated protein 4\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLAG-3 Lymphocyte activation gene 3 inhibitor\u003c/p\u003e\n\u003cp\u003ePFS Progression-free survival\u003c/p\u003e\n\u003cp\u003eNCCN National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003ePS Primary suspected\u003c/p\u003e\n\u003cp\u003ePT Preferred term\u003c/p\u003e\n\u003cp\u003eSOC System organ class\u003c/p\u003e\n\u003cp\u003eMedDRA Medical Dictionary for Regulatory Activities\u003c/p\u003e\n\u003cp\u003eROR Reporting odds ratio\u003c/p\u003e\n\u003cp\u003eCI Confidence interval\u003c/p\u003e\n\u003cp\u003eIC Information component\u003c/p\u003e\n\u003cp\u003eTTO Time-to-onset\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplemental materials for this article are available online.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the contributors of the FAERS database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSX: Methodology; Formal analysis; Investigation; Data acquisition; Interpretation of results; Writing original draft; Literature review and implementation of the study. JW: Conceptualization; Supervision and processing analysis. ZS: Formal analysis, Interpretation of results; Contributed to the design and implementation of the study; Interpretation of results. EW and DW: Methodology; Data checking and interpretation of results. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available by contact with the correspondence authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Ethical approval was not required for this study because we used the FAERS database, which is a free open-access database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLong GV, Swetter SM, Menzies AM, et al. Cutaneous melanoma. 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The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: a pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat. 2021;53(2):339\u0026ndash;54. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4143/crt.2020.790\u003c/span\u003e\u003cspan address=\"10.4143/crt.2020.790\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"immune checkpoint inhibitor, combination therapy, heterogeneity, FAERS database, disproportionality analysis, advanced melanoma","lastPublishedDoi":"10.21203/rs.3.rs-6426078/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6426078/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus relatlimab (NIVO-RELA) were approved for treating advanced melanoma. There is no real-world insights into differential adverse eventm (AE) risks across two regimens.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database for NIVO-IPI and NIVO-RELA from the fouth quarter (Q4) of 2015 to 2024Q4 by calculating the reporting odds ratios (ROR) and information component (IC) with 95% confidence intervals (ICs).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 7482 and 185 records were extracted to analyze from FAERS for NIVO-IPI and NIVO-RELA, respectively. NIVO-IPI showed higher significant risks in gastrointestinal (ROR\u0026thinsp;=\u0026thinsp;1.39), endocrine (ROR\u0026thinsp;=\u0026thinsp;3.10), hepatobiliary (ROR\u0026thinsp;=\u0026thinsp;2.32), metabolism and nutrition (ROR\u0026thinsp;=\u0026thinsp;1.44), and respiratory, thoracic and mediastinal disorders (ROR\u0026thinsp;=\u0026thinsp;1.18), especially in preferred terms (PTs) of colitis, hypophysitis, pneumonia and hepatitis. NIVO-RELA had elevated risks in cardiac (ROR\u0026thinsp;=\u0026thinsp;2.84) and vascular disorders (ROR\u0026thinsp;=\u0026thinsp;2.04), especially in PTs of myocarditis, troponin elevation, and myasthenia gravis. 80% of AEs occurred within 3 months for both regimens. Median time-to-onset was 42 days (NIVO-IPI) vs. 57 days (NIVO-RELA), with no statistical difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.66).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eNIVO-IPI was associated with broader immune-related toxicities, while NIVO-RELA exhibited higher cardiac-specific risks. These findings underscore the need for tailored AE monitoring based on treatment selection.\u003c/p\u003e","manuscriptTitle":"Comparative safety of nivolumab plus ipilimumab versus nivolumab plus relatlimab in advanced melanoma: a real-world pharmacovigilance study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 17:03:05","doi":"10.21203/rs.3.rs-6426078/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-02T05:21:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-26T12:19:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64874902872446006576141563973924672473","date":"2025-05-26T10:46:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-13T11:28:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141635927594492580231712112252232243229","date":"2025-05-13T10:12:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224163645916888334200095668938533339066","date":"2025-05-10T00:28:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-08T00:25:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-07T15:46:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-16T00:46:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-16T00:45:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-04-11T07:49:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8f0d51c1-fe7e-4a50-8e23-d14f4f62f564","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-07T07:13:57+00:00","versionOfRecord":{"articleIdentity":"rs-6426078","link":"https://doi.org/10.1186/s12885-025-14546-6","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-07-19 16:05:01","publishedOnDateReadable":"July 19th, 2025"},"versionCreatedAt":"2025-05-13 17:03:05","video":"","vorDoi":"10.1186/s12885-025-14546-6","vorDoiUrl":"https://doi.org/10.1186/s12885-025-14546-6","workflowStages":[]},"version":"v1","identity":"rs-6426078","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6426078","identity":"rs-6426078","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}