Prognostic value of Systemic Inflammation Index (SII) in advanced or recurrent endometrial cancer (EC) patients treated with pembrolizumab and lenvatinib: retrospective observational study experience

Prognostic value of Systemic Inflammation Index (SII) in advanced or recurrent endometrial cancer (EC) patients treated with pembrolizumab and lenvatinib: retrospective observational study experience | 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 Prognostic value of Systemic Inflammation Index (SII) in advanced or recurrent endometrial cancer (EC) patients treated with pembrolizumab and lenvatinib: retrospective observational study experience Eleonora Palluzzi, Amedeo Cefaliello, Olga Martelli, Mariagrazia Distefano, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8799000/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background To evaluate the association between baseline Systemic Immune-Inflammation Index (SII) and progression-free survival (PFS) in patients with advanced, recurrent, or metastatic endometrial cancer (EC) treated with pembrolizumab plus lenvatinib (Len-Pem) in a real-world setting. Secondary objectives included assessment of SII in relation to overall survival (OS), adverse events (AEs), treatment discontinuations, dose modifications, and post-progression therapies. Methods This is a monocentric, observational, retrospective/ambispective study including 53 patients with advanced, recurrent, or metastatic mismatch repair proficient (pMMR) EC treated with pembrolizumab-lenvatinib (Len-Pem). Results Fifty-three patients were enrolled, with a median age of 64 years. Median PFS in the overall population was 7.1 months; median OS was 15 months. Patients with baseline SII < 540 had significantly longer PFS (12.5 months) compared to those with SII ≥ 540 (5.5 months; HR 2.94, p = 0.004). Higher SII was also significantly associated with increased risk of specific toxicities, including nausea, anorexia, and vomiting. The Overall Response Rate (ORR) was 42%, and Disease Control Rate (DCR) was 71%. The majority of patients (79%) required lenvatinib dose reductions. Adverse events of any grade were frequent, with fatigue (58%), hypertension (50%), and hypothyroidism (48%) being the most common. Conclusion Our real-world study supports the prognostic role of SII in predicting outcomes and toxicity in EC patients treated with Len-Pem. SII may serve as a cost-effective, accessible biomarker to stratify patients and guide clinical decision-making. Further prospective studies are warranted to validate its clinical utility and to optimize dosing strategies that balance efficacy and tolerability. Systemic Inflammation Index Endometrial Cancer Pembrolizumab Lenvatinib Figures Figure 1 Figure 2 Synopsis We evaluate the association between baseline Systemic Immune-Inflammation Index (SII) and progression-free survival (PFS). This is a monocentric, observational, retrospective/ambispective study. We included 53 patients with advanced, recurrent, or metastatic mismatch repair proficient (pMMR) EC treated with pembrolizumab-lenvatinib (Len-Pem). Our real-world study supports the prognostic role of SII in predicting outcomes and toxicity in EC patients treated with Len-Pem. Introduction Endometrial cancer (EC) is the most common gynaecological cancer in high income countries and its incidence is rising globally ( 1 ), predominantly affecting postmenopausal women. While most cases are diagnosed at an early stage and generally carry a favourable prognosis, approximately 15–20% of patients present with advanced or recurrent disease, which is associated with poor clinical outcomes and limited treatment options ( 1 ). Cytotoxic chemotherapy and radiotherapy offered limited efficacy in these settings, highlighting need for novel therapeutic strategies ( 2 , 3 ). Immune Checkpoint Inhibitors (ICIs) are widely applied for the treatment of various types of malignant tumors and demonstrate clinical benefits for selected patients ( 4 ). ICIs such as pembrolizumab and dostarlimab, have demonstrated remarkable clinical activity, particularly in tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), which are characterized by high mutational burden and increased immunogenicity. However, the majority of endometrial carcinomas is mismatch repair proficient (pMMR) or microsatellite stable (MSS), and these tumors demonstrate limited responsiveness to ICIs monotherapy. The combination of pembrolizumab with lenvatinib, a multitargeted tyrosine kinase inhibitor (TKi), represents a significant advancement in the management of pMMR EC ( 5 ). Despite its clinical efficacy, the combination of Len-Pem at the recommended dosage was associated with significant treatment-related toxicity ( 5 ). Additionally, there were treatment interruptions in 70.2% of patients and Lenvatinib dose reductions in 62.9%, with only 8.9% of patients remaining on lenvatinib for ≥ 6 months without any dose reductions ( 6 ). Therefore, there is the unmeet clinical need to evaluate reliable biomarkers to predict toxicity end efficacy of ICIs therapy and to promote individualized treatment regimens for candidates with immunotherapy. Efficacy of ICIs could to be modulated by several factors such as nutritional status ( 7 ), body mass index ( 8 ), PD-L1 expression ( 9 ), tumor mutation burden, tumor-infiltrating lymphocytes ( 10 ). Systemic Immune Inflammation (SII) index is an inflammation-related indicator and it is calculated based on the peripheral lymphocyte, neutrophil, and platelet counts. This integrated parameter has been considered a good index that reflects the balance of inflammatory and immune status in cancer patients ( 11 ). SII has been investigated as a marker to predict cancer survival in various tumors, such as hepatocellular carcinoma, gastric cancer, germ-cell tumor, and prostate cancer ( 12 ). With regard to lung cancer, the prognostic value of SII was reported in several studies, and most of them showed that SII index could be a biological prognostic biomarker for lung cancer ( 13 , 14 ). Overall, the relationship between SII and survival outcomes in patients treated with ICIs remains uncertain. Few data about SII are available for endometrial cancer, but the role of this inflammatory markerfor immunotherapy has not been studied so far ( 15 – 17 ). Here, we present the analysis to evaluate the effect of SII on ICIs response and prognosis in patients with advanced, recurrent or metastatic EC treated with Len-Pem. Therefore, we aimed to assess the effectiveness and safety of treatment in a real-life experience and to explore the existence of an efficacy-effectiveness gap, comparing registry data with the reference clinical trial. Material and Methods This is an observational, retrospective/ambispective, monocentric study that included advanced, recurrent or metastatic EC patients with Len-Pem combination according to the label. Inclusion criteria were: histologically confirmed endometrial carcinoma; advanced, recurrent, or metastatic disease not amenable to curative treatment; mismatch repair proficient (pMMR) or microsatellite stable (MSS) status; at least one cycle of Len-Pem; Exclusion criteria included: participation in concurrent clinical trial; active infections or uncontrolled comorbidities; prior treatment with immune checkpoint inhibitors Demographic and clinical data were collected at initial diagnosis and at recurrence and recorded in an electronic database (Microsoft Excel) for analysis. The primary objective of the study was to assess the association between the baseline Systemic Immune-Inflammation Index (SII) and clinical outcomes, focusing on progression-free survival (PFS). SII was calculated = (neutrophils count × platelets count)/lymphocyte count Secondary objectives were correlation of SII with Overall Survival (OS) and toxicities. We also describe efficacy and safety of Len-Pem in intention-to-treat (ITT) population and incidence of adverse events (AEs), as well as treatment discontinuations and dose reductions due to AEs. In addition, data on post progression treatments were collected and analyzed in all patients that experienced a progression during or after Len-Pem. This study was approved by the local institutional ethics committee, and all participants provided written informed consent in accordance with the Declaration of Helsinki. According to standard clinical practice, the recommended starting dose was pembrolizumab 200 mg administered intravenously every 3 weeks, combined with lenvatinib 20 mg orally once daily. Treatment parameters including the number of administered cycles, starting and final maintenance doses of lenvatinib, as well as any dose interruptions, reductions, or permanent discontinuations, were recorded. Adverse Events are recorded according to Common Terminology Criteria for Adverse events (CTCAE) version 5.1. Tumor response and disease progression were assessed according to the response evaluation criteria in solid tumors (RECIST) version 1.1 ( 18 ). PFS was defined as the time interval from the starting date of Pem-Len until disease progression (defined as objective radiological disease progression using modified RECIST version 1.1 or clinical progression) or last contact or death. Patients who did not experience disease progression were censored at the date of the last follow-up visit. OS was defined from the time between the starting date of Pem-Len treatment to death or the last follow up visit for living patients. Disease Control Rate (DCR) was defined as the proportion of patients who, achieve tumor response (partial response (PR) or complete response, (CR) or stable disease (SD) Kaplan-Meier and log-rank analyzes was used to evaluate PFS while, once the assumption of proportionality of risks has been verified, a multivariate Cox proportional hazard model was used to analyze SII for its prognostic relevance. The optimal cut-off values of SII were determined by receiver operating characteristic curves. Median follow-up was calculated according to the inverse Kaplan Meier method p-value for toxicity was calculated with Mann-Whitney non-parametric test. Results Fifty-three EC patients were enrolled at our Institution and treated with Pem-Len combination from November 2022 to April 2024, cut-off date. Patients' characteristics at baseline are shown in Table 1. The median age at time of diagnosis was 64 years (range 48-78). All patients enrolled had stability of Mismatch Repair proteins (pMMR) evaluated with immunohistochemical method. The most common histotypes were serous (38%), endometrioid (28%), mixed (21%), followed by other histotypes (13%). Twenty-six (49%) patients were treated with previous pelvic radiotherapy. Twenty-three (43%) were cared for previous vaginal brachytherapy. Only one patient underwent brachytherapy without a pelvic radiotherapy. Most patients (89%) have received two lines of platinum-based chemotherapy before Len-Pem Adjuvant chemotherapy was counted as one line of therapy. Fourteen patients (26%) had pre-existing autoimmune disease (Table S1). Sites of disease were distributed as follows: 45% visceral, 34% lymph-node, 32% peritoneal and 2% other sites of disease. Most patients (74%) had single sites of disease. Median number of administered cycles was 7 (range 1-23). Fifty-two (98%) patients were evaluable for response, clinical outcomes and toxicities. One patient was not evaluable because only one cycle of treatment has been given due to clinical deterioration. At data cut off analysis 30 pts (57%) were still alive, 22 (42%) have died and 1 (2%) was lost at follow up. Of evaluable patients 33 (64%) discontinued treatment for progression of disease (PD) and 8 (15%) for limiting toxicity. Eleven pts (21%) were still undergoing treatment. Of these, 2 (15%) had oligoprogression regarding only one of disease site, one in lung and one in bone, and they were treated with stereotactic body radiotherapy (SBRT) continuing Len-Pem. Six (11%) out of all patients started with a lower dose of lenvatinib due to clinical conditions. In 5 patients of them dose was further reduced and in 2 treatment was definitively suspended. A lenvatinib dose reduction was necessary in 42 (79%) patients which started with the standard lenvatinib dose: in 19 patients (40%) to 14 mg, in 21 patients (44%) to 10 mg, and in 2 patients (5%) to 8 mg (Table 2). Objective response rate (ORR) was 42% (95% CI ± 1.46) including 38% partial response and 4% complete response. Disease control rate was 71% (95% CI ± 1.13) (Table S2). After a median follow up of 15 months (range: 2–33), median PFS was 7.1 months (95% CI: 4.3-9.9) in the overall population. For patients with endometrioid histology (29%) median PFS was 14.3 months (CI: 4.8-23.8), for that with serous histology (38%) 8.8 months (CI: 0-20.4) and for that with mixed histology (23%) 6.1 months (CI: 5.7-6.5) respectively. Median OS was 15 months (2 – 33). No significant difference in terms of OS was showed in this population. In 42 (79%) patients SII was available at baseline. Median value of baseline SII was 1009 (SD=917). Baseline SII was associated with PFS: the hazard ratio, as the SII increases by 100, was 1.08 (95% CI: 1.03-1.13), p<0.001. We analyzed all possible cut offs of SII in relation to the hazard ratio through Receiver Operating Characteristic (ROC) curves. Eighteen cut offs were significant and the best value to discriminate prognosis was 540 (Figure 1). Eighteen patients had baseline SII 540 (Table 4). The mPFS was 12.5 months (95% CI: NE) for patients with baseline SII ≤ 540 and 5.5 months for patients with SII baseline >540, HR 2.94 (95% CI: 1.35- 6.41), p 0.004 (Figure 2). ORR was 44% for pts with baseline SII ≤ 540, while it was 30% for patients with baseline SII > 540 (Table 3). Subsequent systemic treatment was administered in 30 patients. The most frequently administered regimen was platinum-based chemotherapy (27%) followed by pegylated liposomal doxorubicin (23%), weekly paclitaxel (20%), clinical trial (17%), oral cyclophosphamide (7%) and gemcitabine (7%) respectively. The most frequent adverse events of any grade were: fatigue (58%), hypertension (50%), hypothyroidism (48%), arthralgia (35%), diarrhea (21%), nausea (21%), anemia (21%), followed by proteinuria (13%), anorexia and constipation (12%), vomiting (10%) and weight reduction (6%). Moreover, patients who experienced vomiting, anorexia, or nausea exhibited higher median SII values than those with other toxicities, at 1605.4, 2273.4, and 2008.3, respectively (Table 4). For thirty-one patients are available SII data at the end of treatment. Median SII at the end of treatment was 1374.5 (75 – 1555). There is no statistical difference between baseline and end of treatment SII value (p 0.57). Discussion This real-life observational study supports the prognostic significance of the SII in advanced or recurrent endometrial cancer (EC) patients treated with Len-Pem. Our data demonstrate a statistically significant association between baseline SII and progression-free survival (PFS), with higher SII levels correlating with poorer outcomes. Specifically, patients with SII ≥ 540 exhibited a markedly shorter median PFS (5.5 months) compared to those with SII < 540 (12.5 months), with a hazard ratio of 2.94. This observation suggests that SII may serve as a readily accessible biomarker for early stratification of patients in terms of likely benefit from immunotherapy. We also observed significant associations between higher SII and certain adverse events (AEs), including nausea, anorexia, and vomiting, suggesting a possible link between systemic inflammation and treatment-related toxicities. Our study adds novel insights by exploring the prognostic utility of SII in this therapeutic context. SII has been validated as a prognostic biomarker in several malignancies, including hepatocellular carcinoma, lung, prostate, and gastric cancers ( 19 – 21 ). In lung cancer, higher SII values were associated with poorer outcomes in patients treated with immune checkpoint inhibitors (ICIs), reinforcing the concept that systemic inflammation may counteract immunotherapeutic efficacy ( 22 ). Few studies have evaluated SII in EC, and none has specifically assessed its role in the setting of immunotherapy. Kose et al. reported that high SII correlated with poor survival in EC, albeit in a non-immunotherapy context ( 23 ). Likewise, Cetin et al. found that pre-treatment SII was significantly higher in advanced-stage EC and correlated with lymphovascular invasion and deep myometrial invasion ( 24 ). Our data extend these findings by establishing a correlation between SII and survival outcomes specifically in pMMR EC patients receiving Len-Pem, suggesting that systemic inflammation may be a marker of resistance to immune-modulatory therapy. Cancer-related inflammation is considered a key mechanism in tumor progression, and tumor-induced inflammatory responses can cause corresponding changes in the blood’s neutrophil, lymphocyte, and platelet count. Considering that SII is a systemic marker of host immune function, the association of SII and PFS might be explained by reduced response to immunotherapy in patients with an inflamed possibly exhausted immune status. A low SII value means a reduction of the neutrophil and platelet counts and an increase in lymphocyte count, likely indicating the favorable condition of the immune system. Interestingly, nearly half of the patients in our cohort had received prior pelvic radiotherapy, a factor that could have influenced baseline SII. Radiotherapy has well-documented immunomodulatory effects, including alterations in systemic cytokine levels, bone marrow suppression, and potential lymphopenia ( 25 – 26 ). Although not directly evaluated in this study, it is plausible that prior radiation contributed to higher SII levels via long-term myelosuppressive effects, especially lymphopenia, thus skewing the inflammatory index. Regarding treatment efficacy, our real-world population achieved a median PFS of 7.1 months and an ORR of 42%, consistent with the KEYNOTE-775 trial (median PFS 7.2 months, ORR 31.9%). Subgroup analysis revealed that patients with endometrioid histology had notably longer PFS (14.3 months), suggesting histological subtype plays a substantial role in treatment responsiveness. In our study Disease Control Rate (DCR) (71%) is consistent with prior findings, supporting the external validity of trial data despite differences in population characteristics and treatment management. In our trial, 79% of patients required dose reductions, with some initiating treatment at a reduced dose due to clinical fragility. While KEYNOTE-775 trial did not stratify survival outcomes by dose reduction, emerging real-world data and retrospective analyses suggest that Lenvatinib early dose reductions may not compromise effectiveness if they allow for prolonged treatment exposure and better tolerance. However, we observed a non-significant but numerical shorter PFS in patients requiring early dose modification, warranting further investigation into optimal dosing strategies balancing efficacy and safety. The safety profile observed in this cohort confirms with known adverse event patterns of Len-Pem combination therapy. Notably, toxicities were significant in the population, with fatigue, hypertension, and hypothyroidism being the most frequent. Vomiting, nausea, and anorexia were correlated with higher baseline SII, suggesting that systemic inflammation may also predict susceptibility to adverse events. Among our patients, 26% had pre-existing autoimmune diseases. These patients are traditionally excluded from registration trials due to concerns about immune-related adverse events (irAEs). While our sample is limited, no excess immune-related toxicity was observed in this subgroup, confirming with emerging literature suggesting that pre-existing autoimmune conditions do not necessarily contraindicate ICIs therapy, provided careful monitoring is employed ( 27 ). This study has several limitations. The retrospective, single-center design and relatively small sample size limit the generalizability of our findings. Additionally, missing SII data at baseline (21% of patients) may have introduced selection bias in the survival analysis. Moreover, the SII cut-off value is not standardized, limiting comparability across studies. Although we explored other cut-offs reported in the literature, none showed significant correlation with prognosis in our cohort ( 11 – 13 ). Furthermore, potential confounders—such as comorbidities, tumor burden, and prior treatments were not uniformly controlled or adjusted in the multivariate models. Our analyses suggest that SII may serve as a readily accessible biomarker identifying patients with poor outcome and limited benefit from immunotherapy. Patients with high SII may benefit from closer monitoring, early dose adjustments, or alternative treatment strategies. Furthermore, the association between SII and certain toxicities highlights the potential of SII as a predictive marker for treatment tolerability, which could help guide clinical decision-making and optimize supportive care. Future research should focus on validating these findings in larger, multicentric prospective cohorts and exploring the integration of SII with other immune-related markers, such as PD-L1 expression, tumor-infiltrating lymphocytes, or genomic signatures. Investigating whether interventions that modulate systemic inflammation (e.g., anti-inflammatory agents, nutritional optimization) can enhance the efficacy of ICIs in high-SII patients also represents an area of clinical interest. In conclusion, our findings support the prognostic value of the SII in patients with advanced endometrial cancer treated with Len-Pem, and highlight the challenges of maintaining dose intensity in real-world settings. Future prospective studies are warranted to validate SII as a stratification tool and to explore personalized dose optimization strategies that preserve efficacy while minimizing toxicity. Declarations Conflict of interest : Olga Martelli received travel resources from AstraZeneca, MSD and GSK. Carolina Maria Sassu received honoraria for AstraZeneca, GSK and MSD, declares consultant for AstraZeneca, MSD and GSK. Serena Maria Boccia received honoraria for AbbVie, AstraZeneca, GSK, and received travel resources from AstraZeneca and GSK. Marth received honoraria for AbbVie, AstraZeneca, Biogene, Biontech, Seagen, Eisai, Genmab, GSK, MSD, and declares consultant for AbbVie, AstraZeneca, Biogene, Biontech, Seagen, Eisai, Genmab, GSK, MSD. Anna Fagotti declares an advisory role for GSK, received honoraria for Covidien, Medtronic and Pharmaand, declares consultant for Oncoinvent and received research funding from AstraZeneca and MSD. Francesco Fanfani received honoraria for MSD, GSK and Medtronic, and received travel resources from MSD, GSK and Medtronic. Claudia Marchetti declares an advisory role for AstraZeneca, MSD, Menarini, PharmaMar, GSK, received honoraria for AstraZeneca, MSD, Menarini, PharmaMar, GSK, received research funding from AstraZeneca, MSD, Menarini, PharmaMar, GSK, and received travel resources from AstraZeneca, MSD. Eleonora Palluzzi, Amedeo Cefaliello, Mariagrazia Distefano, Valentina Wager, Laura Vertechy, Giorgia Russo, Luca Romano, Giacomo Corrado, Carolina Bottoni, Diana Giannarelli declares no conflict of interest. Acknowledgements: none References Crosbie EJ, Kitson SJ, McAlpine JN, et al. Endometrial cancer. Lancet. 2022;399:1412-1428. doi: 10.1016/S0140-6736(22)00323-3. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023;388:2145-2158. doi: 10.1056/NEJMoa2216334. Green AK , Makker V. Novel therapy in endometrial cancer: How much will we pay?. Gynecol Oncol. 2021 Aug;162(2):243-244. doi: 10.1016/j.ygyno.2021.07.012. Junyan Kou, Jing Huang, Jun Li1, et al Systemic immune‑inflammation index predicts prognosis and responsiveness to immunotherapy in cancer patients: a systematic review and meta‑analysis. Clin Exp Med. 2023 Nov;23(7):3895-3905. doi: 10.1007/s10238-023-01035-y. Makker V., et al. 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Frontiers in Oncology, 13, 1201500. https://doi.org/10.3389/fonc.2023.1201500 Fillon, M. (2019). Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease. CA: A Cancer Journal for Clinicians, 70(1), 3–4. DOI: 10.3322/caac.21587 Tables Tables 1 to 4 are available in the Supplementary Files section. Supplementary Files Tables.docx Supplementary.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-8799000","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587572910,"identity":"1855c154-111a-48f8-9573-201c7dad6ff8","order_by":0,"name":"Eleonora 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Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Mariagrazia","middleName":"","lastName":"Distefano","suffix":""},{"id":587572914,"identity":"77aed2d0-264d-43ae-a38d-8f42125e3a27","order_by":4,"name":"Carolina Maria Sassu","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"Maria","lastName":"Sassu","suffix":""},{"id":587572915,"identity":"b3ad276e-62d4-40e4-a5d0-9d0a3c7b70a5","order_by":5,"name":"Valentina Weger","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Weger","suffix":""},{"id":587572916,"identity":"d649fcba-bcb2-45af-a88a-7c458b250586","order_by":6,"name":"Serena Maria Boccia","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Serena","middleName":"Maria","lastName":"Boccia","suffix":""},{"id":587572917,"identity":"ddea5bc4-fb05-4cfc-83c5-0aa665da73eb","order_by":7,"name":"Laura Vertechy","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Vertechy","suffix":""},{"id":587572918,"identity":"a905bf3e-9c53-401a-83b6-c2e7c291a088","order_by":8,"name":"Giorgia Russo","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Giorgia","middleName":"","lastName":"Russo","suffix":""},{"id":587572919,"identity":"5d74b8eb-15c2-4c52-9930-75dae7bcfa43","order_by":9,"name":"Luca Romano","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Romano","suffix":""},{"id":587572920,"identity":"911c3b5e-3a02-4dcf-997e-eab56b690bf5","order_by":10,"name":"Giacomo Corrado","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Giacomo","middleName":"","lastName":"Corrado","suffix":""},{"id":587572921,"identity":"ef7f30b2-73bf-4df7-b7f5-a0167745dbda","order_by":11,"name":"Carolina Bottoni","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"","lastName":"Bottoni","suffix":""},{"id":587572922,"identity":"a2859ffa-27a0-4e01-8214-42350e91f8bf","order_by":12,"name":"Diana Giannarelli","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Diana","middleName":"","lastName":"Giannarelli","suffix":""},{"id":587572923,"identity":"c35449b4-e387-438a-9a52-0cd6948f3b10","order_by":13,"name":"Christian Marth","email":"","orcid":"","institution":"Policlinico Universitario Agostino Gemelli Unita Operativa Complessa di Ginecologia Oncologica","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Marth","suffix":""},{"id":587572924,"identity":"62e153aa-02df-478c-a2b5-16858700ed2c","order_by":14,"name":"Anna Fagotti","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Fagotti","suffix":""},{"id":587572925,"identity":"b1cea09b-dc9f-4851-b7b7-d434683eaa8a","order_by":15,"name":"Francesco Fanfani","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Fanfani","suffix":""},{"id":587572926,"identity":"80a8d85d-a7c0-4e76-b886-b278f1302903","order_by":16,"name":"Claudia Marchetti","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Marchetti","suffix":""}],"badges":[],"createdAt":"2026-02-05 15:50:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8799000/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8799000/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102593721,"identity":"586fbd8f-ead4-4605-a3c5-e07ece1bce3c","added_by":"auto","created_at":"2026-02-13 11:51:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91362,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of all possible cut offs of Systemic Inflammation Index (SII) in relation to the hazard ratio (HR).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8799000/v1/bd165e17ba5ebca2c0cdc224.png"},{"id":102593724,"identity":"8a2929e5-7df8-4ed3-b0c6-88ea05e6b76a","added_by":"auto","created_at":"2026-02-13 11:51:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35089,"visible":true,"origin":"","legend":"\u003cp\u003eProgression Free Survival based on SII value\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8799000/v1/ba62b726ef2d97f9fa8c83be.png"},{"id":106414690,"identity":"8a337c84-4b55-4782-8cb7-41b2849371b4","added_by":"auto","created_at":"2026-04-08 10:22:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":608765,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8799000/v1/6c090b72-4115-4b38-843b-8fd63d0748eb.pdf"},{"id":102593723,"identity":"e3894553-1faf-418e-8967-3223caa4d3b2","added_by":"auto","created_at":"2026-02-13 11:51:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32961,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8799000/v1/92264e39630d2fd8d7525d2d.docx"},{"id":103049359,"identity":"af84eef7-68ef-445d-aaf4-7cda426259d5","added_by":"auto","created_at":"2026-02-20 07:40:16","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":48500,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8799000/v1/1466a48036ed0f9ac969ec1a.docx"}],"financialInterests":"","formattedTitle":"Prognostic value of Systemic Inflammation Index (SII) in advanced or recurrent endometrial cancer (EC) patients treated with pembrolizumab and lenvatinib: retrospective observational study experience","fulltext":[{"header":"Synopsis","content":"\u003cp\u003eWe evaluate the association between baseline Systemic Immune-Inflammation Index (SII) and progression-free survival (PFS). This is a monocentric, observational, retrospective/ambispective study. We included 53 patients with advanced, recurrent, or metastatic mismatch repair proficient (pMMR) EC treated with pembrolizumab-lenvatinib (Len-Pem). Our real-world study supports the prognostic role of SII in predicting outcomes and toxicity in EC patients treated with Len-Pem.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eEndometrial cancer (EC) is the most common gynaecological cancer in high income countries and its incidence is rising globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), predominantly affecting postmenopausal women. While most cases are diagnosed at an early stage and generally carry a favourable prognosis, approximately 15\u0026ndash;20% of patients present with advanced or recurrent disease, which is associated with poor clinical outcomes and limited treatment options (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Cytotoxic chemotherapy and radiotherapy offered limited efficacy in these settings, highlighting need for novel therapeutic strategies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImmune Checkpoint Inhibitors (ICIs) are widely applied for the treatment of various types of malignant tumors and demonstrate clinical benefits for selected patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). ICIs such as pembrolizumab and dostarlimab, have demonstrated remarkable clinical activity, particularly in tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), which are characterized by high mutational burden and increased immunogenicity.\u003c/p\u003e \u003cp\u003eHowever, the majority of endometrial carcinomas is mismatch repair proficient (pMMR) or microsatellite stable (MSS), and these tumors demonstrate limited responsiveness to ICIs monotherapy. The combination of pembrolizumab with lenvatinib, a multitargeted tyrosine kinase inhibitor (TKi), represents a significant advancement in the management of pMMR EC (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite its clinical efficacy, the combination of Len-Pem at the recommended dosage was associated with significant treatment-related toxicity (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Additionally, there were treatment interruptions in 70.2% of patients and Lenvatinib dose reductions in 62.9%, with only 8.9% of patients remaining on lenvatinib for \u0026ge;\u0026thinsp;6 months without any dose reductions (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Therefore, there is the unmeet clinical need to evaluate reliable biomarkers to predict toxicity end efficacy of ICIs therapy and to promote individualized treatment regimens for candidates with immunotherapy.\u003c/p\u003e \u003cp\u003eEfficacy of ICIs could to be modulated by several factors such as nutritional status (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), body mass index (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), PD-L1 expression (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), tumor mutation burden, tumor-infiltrating lymphocytes (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Systemic Immune Inflammation (SII) index is an inflammation-related indicator and it is calculated based on the peripheral lymphocyte, neutrophil, and platelet counts. This integrated parameter has been considered a good index that reflects the balance of inflammatory and immune status in cancer patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). SII has been investigated as a marker to predict cancer survival in various tumors, such as hepatocellular carcinoma, gastric cancer, germ-cell tumor, and prostate cancer (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). With regard to lung cancer, the prognostic value of SII was reported in several studies, and most of them showed that SII index could be a biological prognostic biomarker for lung cancer (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Overall, the relationship between SII and survival outcomes in patients treated with ICIs remains uncertain. Few data about SII are available for endometrial cancer, but the role of this inflammatory markerfor immunotherapy has not been studied so far (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHere, we present the analysis to evaluate the effect of SII on ICIs response and prognosis in patients with advanced, recurrent or metastatic EC treated with Len-Pem. Therefore, we aimed to assess the effectiveness and safety of treatment in a real-life experience and to explore the existence of an efficacy-effectiveness gap, comparing registry data with the reference clinical trial.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eThis is an observational, retrospective/ambispective, monocentric study that included advanced, recurrent or metastatic EC patients with Len-Pem combination according to the label.\u003c/p\u003e \u003cp\u003eInclusion criteria were: histologically confirmed endometrial carcinoma; advanced, recurrent, or metastatic disease not amenable to curative treatment; mismatch repair proficient (pMMR) or microsatellite stable (MSS) status; at least one cycle of Len-Pem; Exclusion criteria included: participation in concurrent clinical trial; active infections or uncontrolled comorbidities; prior treatment with immune checkpoint inhibitors\u003c/p\u003e \u003cp\u003eDemographic and clinical data were collected at initial diagnosis and at recurrence and recorded in an electronic database (Microsoft Excel) for analysis.\u003c/p\u003e \u003cp\u003eThe primary objective of the study was to assess the association between the baseline Systemic Immune-Inflammation Index (SII) and clinical outcomes, focusing on progression-free survival (PFS). SII was calculated = (neutrophils count \u0026times; platelets count)/lymphocyte count\u003c/p\u003e \u003cp\u003eSecondary objectives were correlation of SII with Overall Survival (OS) and toxicities. We also describe efficacy and safety of Len-Pem in intention-to-treat (ITT) population and incidence of adverse events (AEs), as well as treatment discontinuations and dose reductions due to AEs. In addition, data on post progression treatments were collected and analyzed in all patients that experienced a progression during or after Len-Pem.\u003c/p\u003e \u003cp\u003e This study was approved by the local institutional ethics committee, and all participants provided written informed consent in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eAccording to standard clinical practice, the recommended starting dose was pembrolizumab 200 mg administered intravenously every 3 weeks, combined with lenvatinib 20 mg orally once daily. Treatment parameters including the number of administered cycles, starting and final maintenance doses of lenvatinib, as well as any dose interruptions, reductions, or permanent discontinuations, were recorded. Adverse Events are recorded according to Common Terminology Criteria for Adverse events (CTCAE) version 5.1. Tumor response and disease progression were assessed according to the response evaluation criteria in solid tumors (RECIST) version 1.1 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePFS was defined as the time interval from the starting date of Pem-Len until disease progression (defined as objective radiological disease progression using modified RECIST version 1.1 or clinical progression) or last contact or death. Patients who did not experience disease progression were censored at the date of the last follow-up visit. OS was defined from the time between the starting date of Pem-Len treatment to death or the last follow up visit for living patients. Disease Control Rate (DCR) was defined as the proportion of patients who, achieve tumor response (partial response (PR) or complete response, (CR) or stable disease (SD)\u003c/p\u003e \u003cp\u003eKaplan-Meier and log-rank analyzes was used to evaluate PFS while, once the assumption of proportionality of risks has been verified, a multivariate Cox proportional hazard model was used to analyze SII for its prognostic relevance. The optimal cut-off values of SII were determined by receiver operating characteristic curves. Median follow-up was calculated according to the inverse Kaplan Meier method p-value for toxicity was calculated with Mann-Whitney non-parametric test.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-three EC patients were enrolled at our Institution and treated with Pem-Len combination from November 2022 to April 2024, cut-off date. Patients\u0026apos; characteristics at baseline are shown in Table 1.\u003c/p\u003e\n\u003cp\u003eThe median age at time of diagnosis was 64 years (range 48-78). All patients enrolled had stability of Mismatch Repair proteins (pMMR) evaluated with immunohistochemical method. The most common histotypes were serous (38%), endometrioid (28%), mixed (21%), followed by other histotypes (13%). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwenty-six (49%) patients were treated with previous pelvic radiotherapy. Twenty-three (43%) were cared for previous vaginal brachytherapy. Only one patient underwent brachytherapy without a pelvic radiotherapy. Most patients (89%) have received two lines of platinum-based chemotherapy before Len-Pem Adjuvant chemotherapy was counted as one line of therapy. Fourteen patients (26%) had pre-existing autoimmune disease (Table S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSites of disease were distributed as follows: 45% visceral, 34% lymph-node, 32% peritoneal and 2% other sites of disease. Most patients (74%) had single sites of disease. Median number of administered cycles was 7 (range 1-23).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFifty-two (98%) patients were evaluable for response, clinical outcomes and toxicities. One patient was not evaluable because only one cycle of treatment has been given due to clinical deterioration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt data cut off analysis 30 pts (57%) were still alive, 22 (42%) have died and 1 (2%) was lost at follow up. \u0026nbsp;Of evaluable patients 33 (64%) discontinued treatment for progression of disease (PD) and 8 (15%) for limiting toxicity. Eleven pts (21%) were still undergoing treatment. Of these, 2 (15%) had oligoprogression regarding only one of disease site, one in lung and one in bone, and they were treated with stereotactic body radiotherapy (SBRT) continuing Len-Pem.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSix (11%) out of all patients started with a lower dose of lenvatinib due to clinical conditions. In 5 patients of them dose was further reduced and in 2 treatment was definitively suspended. A lenvatinib dose reduction was necessary in 42 (79%) patients which started with the standard lenvatinib dose: in 19 patients (40%) to 14 mg, in 21 patients (44%) to 10 mg, and in 2 patients (5%) to 8 mg (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eObjective response rate (ORR) was 42% (95% CI \u0026plusmn; 1.46) including 38% \u0026nbsp; partial response and 4% \u0026nbsp;complete response. Disease control rate was 71% (95% CI \u0026plusmn; 1.13) (Table S2). After a median follow up of 15 months (range: 2\u0026ndash;33), median PFS was 7.1 months (95% CI: 4.3-9.9) in the overall population. For patients with endometrioid histology (29%) median PFS was 14.3 months (CI: 4.8-23.8), for that with serous histology (38%) 8.8 months (CI: 0-20.4) and for that with mixed histology (23%) 6.1 months (CI: 5.7-6.5) respectively. Median OS was 15 months (2 \u0026ndash; 33). No significant difference in terms of OS was showed in this population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 42 (79%) patients SII was available at baseline. Median value of baseline SII was 1009 (SD=917). Baseline SII was associated with PFS: the hazard ratio, as the SII increases by 100, was 1.08 (95% CI: 1.03-1.13), p\u0026lt;0.001. We analyzed all possible cut offs of SII in relation to the hazard ratio through Receiver Operating Characteristic (ROC) curves. Eighteen cut offs were significant and the best value to discriminate prognosis was 540 (Figure 1). Eighteen patients had baseline SII \u0026lt; 540, 24 patients had SII \u0026gt; 540 (Table 4). The mPFS was 12.5 months (95% CI: NE) for patients with baseline SII \u0026le; 540 and 5.5 months for patients with SII baseline \u0026gt;540, HR 2.94 (95% CI: 1.35- 6.41), p 0.004 (Figure 2). ORR was 44% for pts with baseline SII \u0026le; 540, while it was 30% for patients with baseline SII \u0026gt; 540 (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubsequent systemic treatment was administered in 30 patients. The most frequently administered regimen was platinum-based chemotherapy (27%) followed by pegylated liposomal doxorubicin (23%), weekly paclitaxel (20%), clinical trial (17%), oral cyclophosphamide (7%) and gemcitabine (7%) respectively.\u003c/p\u003e\n\u003cp\u003eThe most frequent adverse events of any grade were: fatigue (58%), hypertension (50%), hypothyroidism (48%), arthralgia (35%), diarrhea (21%), nausea (21%), anemia (21%), followed by proteinuria (13%), anorexia and constipation (12%), vomiting (10%) and weight reduction (6%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMoreover, patients who experienced vomiting, anorexia, or nausea exhibited higher median SII values than those with other toxicities, at 1605.4, 2273.4, and 2008.3, respectively (Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor thirty-one patients are available SII data at the end of treatment. Median SII at the end of treatment was 1374.5 (75 \u0026ndash; 1555). There is no statistical difference between baseline and end of treatment SII value (p 0.57). \u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis real-life observational study supports the prognostic significance of the SII in advanced or recurrent endometrial cancer (EC) patients treated with Len-Pem. Our data demonstrate a statistically significant association between baseline SII and progression-free survival (PFS), with higher SII levels correlating with poorer outcomes. Specifically, patients with SII\u0026thinsp;\u0026ge;\u0026thinsp;540 exhibited a markedly shorter median PFS (5.5 months) compared to those with SII\u0026thinsp;\u0026lt;\u0026thinsp;540 (12.5 months), with a hazard ratio of 2.94. This observation suggests that SII may serve as a readily accessible biomarker for early stratification of patients in terms of likely benefit from immunotherapy. We also observed significant associations between higher SII and certain adverse events (AEs), including nausea, anorexia, and vomiting, suggesting a possible link between systemic inflammation and treatment-related toxicities.\u003c/p\u003e \u003cp\u003eOur study adds novel insights by exploring the prognostic utility of SII in this therapeutic context. SII has been validated as a prognostic biomarker in several malignancies, including hepatocellular carcinoma, lung, prostate, and gastric cancers (\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In lung cancer, higher SII values were associated with poorer outcomes in patients treated with immune checkpoint inhibitors (ICIs), reinforcing the concept that systemic inflammation may counteract immunotherapeutic efficacy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFew studies have evaluated SII in EC, and none has specifically assessed its role in the setting of immunotherapy. Kose et al. reported that high SII correlated with poor survival in EC, albeit in a non-immunotherapy context (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Likewise, Cetin et al. found that pre-treatment SII was significantly higher in advanced-stage EC and correlated with lymphovascular invasion and deep myometrial invasion (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Our data extend these findings by establishing a correlation between SII and survival outcomes specifically in pMMR EC patients receiving Len-Pem, suggesting that systemic inflammation may be a marker of resistance to immune-modulatory therapy. Cancer-related inflammation is considered a key mechanism in tumor progression, and tumor-induced inflammatory responses can cause corresponding changes in the blood\u0026rsquo;s neutrophil, lymphocyte, and platelet count. Considering that SII is a systemic marker of host immune function, the association of SII and PFS might be explained by reduced response to immunotherapy in patients with an inflamed possibly exhausted immune status. A low SII value means a reduction of the neutrophil and platelet counts and an increase in lymphocyte count, likely indicating the favorable condition of the immune system.\u003c/p\u003e \u003cp\u003eInterestingly, nearly half of the patients in our cohort had received prior pelvic radiotherapy, a factor that could have influenced baseline SII. Radiotherapy has well-documented immunomodulatory effects, including alterations in systemic cytokine levels, bone marrow suppression, and potential lymphopenia (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Although not directly evaluated in this study, it is plausible that prior radiation contributed to higher SII levels via long-term myelosuppressive effects, especially lymphopenia, thus skewing the inflammatory index.\u003c/p\u003e \u003cp\u003eRegarding treatment efficacy, our real-world population achieved a median PFS of 7.1 months and an ORR of 42%, consistent with the KEYNOTE-775 trial (median PFS 7.2 months, ORR 31.9%). Subgroup analysis revealed that patients with endometrioid histology had notably longer PFS (14.3 months), suggesting histological subtype plays a substantial role in treatment responsiveness. In our study Disease Control Rate (DCR) (71%) is consistent with prior findings, supporting the external validity of trial data despite differences in population characteristics and treatment management.\u003c/p\u003e \u003cp\u003eIn our trial, 79% of patients required dose reductions, with some initiating treatment at a reduced dose due to clinical fragility. While KEYNOTE-775 trial did not stratify survival outcomes by dose reduction, emerging real-world data and retrospective analyses suggest that Lenvatinib early dose reductions may not compromise effectiveness if they allow for prolonged treatment exposure and better tolerance. However, we observed a non-significant but numerical shorter PFS in patients requiring early dose modification, warranting further investigation into optimal dosing strategies balancing efficacy and safety.\u003c/p\u003e \u003cp\u003eThe safety profile observed in this cohort confirms with known adverse event patterns of Len-Pem combination therapy. Notably, toxicities were significant in the population, with fatigue, hypertension, and hypothyroidism being the most frequent. Vomiting, nausea, and anorexia were correlated with higher baseline SII, suggesting that systemic inflammation may also predict susceptibility to adverse events.\u003c/p\u003e \u003cp\u003eAmong our patients, 26% had pre-existing autoimmune diseases. These patients are traditionally excluded from registration trials due to concerns about immune-related adverse events (irAEs). While our sample is limited, no excess immune-related toxicity was observed in this subgroup, confirming with emerging literature suggesting that pre-existing autoimmune conditions do not necessarily contraindicate ICIs therapy, provided careful monitoring is employed (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations. The retrospective, single-center design and relatively small sample size limit the generalizability of our findings. Additionally, missing SII data at baseline (21% of patients) may have introduced selection bias in the survival analysis. Moreover, the SII cut-off value is not standardized, limiting comparability across studies. Although we explored other cut-offs reported in the literature, none showed significant correlation with prognosis in our cohort (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Furthermore, potential confounders\u0026mdash;such as comorbidities, tumor burden, and prior treatments were not uniformly controlled or adjusted in the multivariate models.\u003c/p\u003e \u003cp\u003eOur analyses suggest that SII may serve as a readily accessible biomarker identifying patients with poor outcome and limited benefit from immunotherapy.\u003c/p\u003e \u003cp\u003ePatients with high SII may benefit from closer monitoring, early dose adjustments, or alternative treatment strategies. Furthermore, the association between SII and certain toxicities highlights the potential of SII as a predictive marker for treatment tolerability, which could help guide clinical decision-making and optimize supportive care.\u003c/p\u003e \u003cp\u003eFuture research should focus on validating these findings in larger, multicentric prospective cohorts and exploring the integration of SII with other immune-related markers, such as PD-L1 expression, tumor-infiltrating lymphocytes, or genomic signatures. Investigating whether interventions that modulate systemic inflammation (e.g., anti-inflammatory agents, nutritional optimization) can enhance the efficacy of ICIs in high-SII patients also represents an area of clinical interest.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings support the prognostic value of the SII in patients with advanced endometrial cancer treated with Len-Pem, and highlight the challenges of maintaining dose intensity in real-world settings. Future prospective studies are warranted to validate SII as a stratification tool and to explore personalized dose optimization strategies that preserve efficacy while minimizing toxicity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e:\u003c/h2\u003e\n\u003cp\u003eOlga Martelli received travel resources from AstraZeneca, MSD and GSK. Carolina Maria Sassu received honoraria for AstraZeneca, GSK and MSD, declares consultant for AstraZeneca, MSD and GSK. Serena Maria Boccia received honoraria for AbbVie, AstraZeneca, GSK, and received travel resources from AstraZeneca and GSK. Marth received honoraria for AbbVie, AstraZeneca, Biogene, Biontech, Seagen, Eisai, Genmab, GSK, MSD, and declares consultant for AbbVie, AstraZeneca, Biogene, Biontech, Seagen, Eisai, Genmab, GSK, MSD. Anna Fagotti declares an advisory role for GSK, received honoraria for Covidien, Medtronic and Pharmaand, declares consultant for Oncoinvent and received research funding from AstraZeneca and MSD. Francesco Fanfani received honoraria for MSD, GSK and Medtronic, and received travel resources from MSD, GSK and Medtronic. Claudia Marchetti declares an advisory role for AstraZeneca, MSD, Menarini, PharmaMar, GSK, received honoraria for AstraZeneca, MSD, Menarini, PharmaMar, GSK, received research funding from AstraZeneca, MSD, Menarini, PharmaMar, GSK, and received travel resources from AstraZeneca, MSD. Eleonora Palluzzi, Amedeo Cefaliello, Mariagrazia Distefano, Valentina Wager, Laura Vertechy, Giorgia Russo, Luca Romano, Giacomo Corrado, Carolina Bottoni, Diana Giannarelli declares no conflict of interest.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003enone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCrosbie EJ, Kitson SJ, McAlpine JN, et al. Endometrial cancer. Lancet. 2022;399:1412-1428. doi: 10.1016/S0140-6736(22)00323-3.\u003c/li\u003e\n\u003cli\u003eMirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023;388:2145-2158. doi: 10.1056/NEJMoa2216334.\u003c/li\u003e\n\u003cli\u003eGreen AK , Makker V. Novel therapy in endometrial cancer: How much will we pay?. Gynecol Oncol. 2021 Aug;162(2):243-244. doi: 10.1016/j.ygyno.2021.07.012.\u003c/li\u003e\n\u003cli\u003eJunyan Kou, Jing Huang, Jun Li1, et al Systemic immune‑inflammation index predicts prognosis and responsiveness to immunotherapy in cancer patients: a systematic review and meta‑analysis. Clin Exp Med. 2023 Nov;23(7):3895-3905. doi: 10.1007/s10238-023-01035-y. \u003c/li\u003e\n\u003cli\u003eMakker V., et al. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. J Clin Oncol. 2023 Jun 1;41(16):2904-2910. doi: 10.1200/JCO.22.02152.\u003c/li\u003e\n\u003cli\u003eJeffrey A How.\u003csup\u003e \u003c/sup\u003e, Shrina Patel\u003csup\u003e \u003c/sup\u003e, Bryan Fellman. et al. \u003csup\u003e \u003c/sup\u003eToxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer Gynecol Oncol doi: 10.1016/j.ygyno.2021.04.034. \u003c/li\u003e\n\u003cli\u003eChen L, Sun H, Zhao R, et al. Controlling nutritional status (CONUT) predicts survival in gastric cancer patients with immune checkpoint inhibitor (PD-1/PD-L1) outcomes. Front Pharmacol. 2022;13:836958. \u003c/li\u003e\n\u003cli\u003eAhmed M, von Itzstein MS, Sheffield T, et al. Associa tion between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2021;9:102425. \u003c/li\u003e\n\u003cli\u003eDeng H, Zhao Y, Cai X, et al. PD-L1 expression and tumor mutation burden as pathological response biomarkers of neo adjuvant immunotherapy for early-stage non-small cell lung cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2022;170:103582. \u003c/li\u003e\n\u003cli\u003eLi F, Li C, Cai X, et al. The association between CD8+ tumor infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis. E Clin Med. 2021;41:101134.\u003c/li\u003e\n\u003cli\u003eHu B, Yang XR, Xu Y, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20:6212\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eYi Zhang, Bo Chen, Lijuan Wang, et al. Systemic immune-inflammation index is a promising noninvasive marker to predict survival of lung cancer: A meta-analysis Meta-Analysis Medicine (Baltimore) . 2019 Jan;98(3):e13788. doi: 10.1097/MD.0000000000013788.\u003c/li\u003e\n\u003cli\u003eTong YS, Tan J, Zhou XL, et al. Systemic immune-inflammation index predicting chemoradiation resistance and poor outcome in patients with stage III non-small cell lung cancer. J Transl Med 2017;15:221\u003c/li\u003e\n\u003cli\u003eYan Wang et al. Prognostic and clinicopathological significance of Systemic Immune-Inflammation Index in cancer patients receiving immune checkpoint inhibitors: a meta-analysis. 2022, Annals of Medicine. https://doi.org/10.1080/07853890.2023.2181983\u003c/li\u003e\n\u003cli\u003eHuang Y, et al. Postoperative Systemic Immune-Inflammation Index (SII): A Superior Prognostic Factor of Endometrial Cancer.; Front Surg. 2021 doi: 10.3389/fsurg.2021.704235\u003c/li\u003e\n\u003cli\u003eMatsubara S, et al. . Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer. PLoS One. 2021 doi.org/10.1371/journal.pone.0248871\u003c/li\u003e\n\u003cli\u003eJi P, et al Prognostic value of pretreatment systemic immune-inflammation index in patients with endometrial cancer: a meta-analysis. Biomark Med. 2024 doi: 10.2217/bmm-2023-0629.\u003c/li\u003e\n\u003cli\u003eE A Eisenhauer, P Therasse et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eur J Cancer, 2009 Jan; 45(2):228-47.doi: 10.1016/j.ejca.2008. 10.026.\u003c/li\u003e\n\u003cli\u003eFu S, Liu Y, Dong Q, Sun W, Xiao X. Prognostic value of the systemic immune-inflammation index in patients with non-small-cell lung cancer: A meta-analysis. Cancer Manag Res. 2020;12:12967\u0026ndash;12981.\u003c/li\u003e\n\u003cli\u003eDeng Q, He B, Liu X, Zhang J, Peng Y, Pan Y, et al. Prognostic value of pre-operative inflammatory response biomarkers in gastric cancer patients and the construction of a predictive model. Oncotarget. 2016;7(30):48870\u0026ndash;48881.\u003c/li\u003e\n\u003cli\u003eGuo W, Lu X, Liu Q, Zhang T, Li P, Qiao W, et al. Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for breast cancer patients: An updated meta-analysis of 17,079 individuals. PLoS One. 2016;11(7):e0158839.\u003c/li\u003e\n\u003cli\u003eDiem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. J Thorac Oncol. 2017;12(2):208\u0026ndash;218.\u003c/li\u003e\n\u003cli\u003eKose S, Cetin B, Ozyurt S, Naldoken S. Prognostic role of systemic immune inflammation index in patients with endometrial cancer. Eur J Gynaecol Oncol. 2020;41(1):87\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eCetin B, Simsek T, Kose S, Asoglu MR. Prognostic significance of systemic immune-inflammation index in endometrial cancer: a retrospective study. Int J Clin Oncol. 2023;28(3):463\u0026ndash;470.\u003c/li\u003e\n\u003cli\u003eLadbury, C. J., Rusthoven, C. G., Camidge, D. R., Kavanagh, B. D., \u0026amp; Nath, S. K. (2019). Impact of radiation dose to circulating lymphocytes on survival in non-small cell lung cancer. Journal of Thoracic Oncology, 14(4), 558\u0026ndash;566. https://doi.org/10.1016/j.jtho.2018.12.006\u003c/li\u003e\n\u003cli\u003eXie, L., \u0026amp; Zhang, H. (2023). The radiosensitivity of lymphocytes and the clinical significance of radiation-induced lymphopenia in cancer treatment. Frontiers in Oncology, 13, 1201500. https://doi.org/10.3389/fonc.2023.1201500\u003c/li\u003e\n\u003cli\u003eFillon, M. (2019). Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease. CA: A Cancer Journal for Clinicians, 70(1), 3\u0026ndash;4. DOI: 10.3322/caac.21587\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Systemic Inflammation Index, Endometrial Cancer, Pembrolizumab, Lenvatinib","lastPublishedDoi":"10.21203/rs.3.rs-8799000/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8799000/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo evaluate the association between baseline Systemic Immune-Inflammation Index (SII) and progression-free survival (PFS) in patients with advanced, recurrent, or metastatic endometrial cancer (EC) treated with pembrolizumab plus lenvatinib (Len-Pem) in a real-world setting. Secondary objectives included assessment of SII in relation to overall survival (OS), adverse events (AEs), treatment discontinuations, dose modifications, and post-progression therapies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a monocentric, observational, retrospective/ambispective study including 53 patients with advanced, recurrent, or metastatic mismatch repair proficient (pMMR) EC treated with pembrolizumab-lenvatinib (Len-Pem).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFifty-three patients were enrolled, with a median age of 64 years. Median PFS in the overall population was 7.1 months; median OS was 15 months. Patients with baseline SII\u0026thinsp;\u0026lt;\u0026thinsp;540 had significantly longer PFS (12.5 months) compared to those with SII\u0026thinsp;\u0026ge;\u0026thinsp;540 (5.5 months; HR 2.94, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Higher SII was also significantly associated with increased risk of specific toxicities, including nausea, anorexia, and vomiting. The Overall Response Rate (ORR) was 42%, and Disease Control Rate (DCR) was 71%. The majority of patients (79%) required lenvatinib dose reductions. Adverse events of any grade were frequent, with fatigue (58%), hypertension (50%), and hypothyroidism (48%) being the most common.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur real-world study supports the prognostic role of SII in predicting outcomes and toxicity in EC patients treated with Len-Pem. SII may serve as a cost-effective, accessible biomarker to stratify patients and guide clinical decision-making. Further prospective studies are warranted to validate its clinical utility and to optimize dosing strategies that balance efficacy and tolerability.\u003c/p\u003e","manuscriptTitle":"Prognostic value of Systemic Inflammation Index (SII) in advanced or recurrent endometrial cancer (EC) patients treated with pembrolizumab and lenvatinib: retrospective observational study experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-13 11:51:26","doi":"10.21203/rs.3.rs-8799000/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9bf91d81-77cc-4896-96a0-f7266efcb656","owner":[],"postedDate":"February 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T07:48:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-13 11:51:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8799000","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8799000","identity":"rs-8799000","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}