Impact of Peritoneal Metastasis on Overall Survival in Patients with Advanced Endometrial Cancer Receiving Lenvatinib plus Pembrolizumab

Impact of Peritoneal Metastasis on Overall Survival in Patients with Advanced Endometrial Cancer Receiving Lenvatinib plus Pembrolizumab | 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 Impact of Peritoneal Metastasis on Overall Survival in Patients with Advanced Endometrial Cancer Receiving Lenvatinib plus Pembrolizumab Shogen Boku, Masato Kita, Tatsuki Ikoma, Tomoyo Yasuda, Nobuhiro Shibata, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8137646/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Purpose: The combination of lenvatinib plus pembrolizumab (LP) is a standard treatment for advanced or recurrent endometrial cancer. However, the optimal starting dose of lenvatinib is debated due to its toxicity profile. This study aimed to evaluate the effectiveness and safety of the LP regimen in a real-world setting and to investigate the impact of the lenvatinib starting dose on survival outcomes. Methods: We conducted a retrospective analysis of 33 patients with advanced or recurrent endometrial cancer treated with the LP regimen at Kansai Medical University Hospital between February 2022 and August 2025. We evaluated the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Prognostic factors for survival were identified using the Kaplan-Meier method and Cox proportional hazards models. Results: The median follow-up was 27.6 months. The ORR was 48.5%, with a median PFS of 6.7 months and a median OS of 21.7 months. Multivariate analysis revealed distinct prognostic factors for PFS and OS. A lenvatinib starting dose of 20 mg was the sole independent predictor for improved PFS (aHR for <20 mg: 5.83; p=0.003). In contrast, the presence of peritoneal metastasis was the sole independent predictor for worse OS (aHR: 7.51; p=0.005). Conclusion: In this real-world analysis, LP therapy was effective and tolerable. We identified distinct prognostic factors for short-term and long-term survival: a 20 mg lenvatinib starting dose was critical for improving PFS. In contrast, peritoneal metastasis was identified as a strong independent predictor of poor OS even in the LP therapy cohort, suggesting a need for further therapeutic development for patients with peritoneal metastasis. Endometrial cancer Lenvatinib Pembrolizumab Starting dose Real-world evidence peritoneal metastasis Figures Figure 1 Figure 2 Introduction Endometrial cancer is a leading gynecologic malignancy, and the prognosis for patients with advanced or recurrent disease remains poor. The phase 3 KEYNOTE-775 trial established the combination of lenvatinib plus pembrolizumab (LP) as a standard of care, demonstrating significant improvements in both progression-free survival (PFS; HR, 0.56) and overall survival (OS; HR, 0.65) compared to chemotherapy [ 1 ]. Despite its pronounced efficacy, the LP regimen was associated with a substantial toxicity burden in the KEYNOTE-775 trial. High rates of adverse events such as hypertension, diarrhea, and hypothyroidism were reported, necessitating dose reductions or interruptions of lenvatinib in a significant proportion of patients. Consequently, the appropriateness of the recommended 20 mg/day starting dose has been debated, and whether to initiate treatment at a reduced dose remains a critical clinical question in real-world practice. In recent years, a growing body of real-world evidence has emerged to address this issue. Multi-institutional reviews and insurance claims analyses from the United States have shown that a 14 mg starting dose is predominant and that variations in the initial dose do not necessarily compromise response rates or survival outcomes [ 2 , 3 ]. In contrast, other retrospective studies suggest that while a lower starting dose may reduce the frequency of dose modifications, it could be associated with inferior PFS after adjusting for factors such as age [ 4 – 6 ]. Systematic reviews and additional real-world studies have consistently supported the dual nature of the LP regimen—its effectiveness and notable toxicity. These studies confirm its feasibility in vulnerable populations, including older adults and patients with an ECOG performance status of 1–2 who would have been ineligible for clinical trials, but also underscore that prospective validation of dosing strategies remains an unmet need [ 7 , 8 ]. In light of this background, we conducted a single-institution retrospective analysis of a real-world cohort in Japan to evaluate the effectiveness and safety of the LP regimen. The primary objective of this study was to exploratively investigate the impact of the lenvatinib starting dose on PFS and OS, thereby generating concrete hypotheses for optimizing initial dosing strategies in real-world settings, taking into account patient backgrounds such as age, sites of metastasis, and performance status. Methods Study Design and Patients This study was a single-center, retrospective cohort study conducted at Kansai Medical University Hospital. We identified patients with advanced or recurrent endometrial cancer who received LP therapy between February 2022 and August 2025. Eligible patients were those who had experienced disease progression after at least one prior platinum-based chemotherapy regimen. This study was approved by the Institutional Review Board of Kansai Medical University Hospital and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study. Data Collection and Assessments We retrospectively collected data from electronic medical records. The collected data included clinical and pathological characteristics, treatment history including the starting dose of lenvatinib, treatment-emergent adverse events (TEAEs), tumor response, and survival status. TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor response was assessed by the attending physician based on imaging studies according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Endpoints The primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from the initiation of LP therapy to disease progression or death from any cause. OS was defined as the time from the initiation of LP therapy to death from any cause. Secondary endpoints were the objective response rate (ORR), defined as the proportion of patients with a complete or partial response, the disease control rate (DCR), defined as the proportion of patients with complete response, partial response, or stable disease, and safety. Statistical Analysis Patient characteristics, effectiveness, and safety data were summarized using descriptive statistics. The median follow-up time was calculated using the reverse Kaplan-Meier method. Survival curves for PFS and OS were estimated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Univariate and multivariate analyses for prognostic factors were performed using the Cox proportional hazards model. A P-value of < 0.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [ 9 ]. Results Patient Characteristics A total of 33 patients treated with lenvatinib plus pembrolizumab were included in this retrospective analysis. The median follow-up time was 27.6 months. Baseline patient and clinical characteristics are detailed in Table 1. For the overall cohort, the median age was 67.4 years, and 17 patients (51.5%) had an ECOG performance status of 0. When stratified by lenvatinib starting dose, patients in the <20 mg group were older and had a poorer performance status compared to the 20 mg group. Specifically, all patients aged ≥75 years (10/10) were in the <20 mg group, and the proportion of patients with an ECOG PS of 0 was substantially higher in the 20 mg group (81.3% vs. 23.5%). The majority of patients (78.8%) received the study treatment for recurrent disease after a median platinum-free interval of 4.0 months. Endometrioid adenocarcinoma was the most frequent histology (63.6%). Treatment Effectiveness For the entire cohort, the objective response rate (ORR) was 48.5% and the disease control rate (DCR) was 87.9% (details in Supplementary Table 1). The median overall survival (OS) for the entire cohort was 21.7 months (95% CI, 18.3 months–not reached), and the median progression-free survival (PFS) was 6.7 months (95% CI, 4.4–10.3 months) (Figure 1). Safety The safety profile is detailed in Table 2. The most frequent treatment-emergent adverse events (TEAEs) of any grade were hypothyroidism (48.5%), hypertension (45.5%), and thrombocytopenia (39.4%). The most common grade ≥3 TEAE was thrombocytopenia (12.1%). Key immune-related adverse events (irAEs) included adrenal insufficiency (9.1%), myositis (6.1%), and pneumonitis (3.0%). Prognostic Factor Analysis We performed univariate and multivariate analyses to identify prognostic factors for response and survival. When stratified by the lenvatinib starting dose, the ORR was numerically higher in the 20 mg group compared to the <20 mg group (56.3% vs 41.2%), though the difference was not statistically significant (p=0.715) (Supplementary Table 1). Progression-Free Survival In the univariate analysis, a lenvatinib starting dose of 20 mg was significantly associated with longer PFS (median 21.6 vs 4.9 months; p=0.001) (Figure 2A). Notably, the presence of peritoneal metastasis, which was a strong predictor for OS, was not associated with PFS (p=0.844). Additionally, patients aged ≥75 years showed a trend toward shorter PFS (p=0.087). The full univariate analysis results are shown in Supplementary Table 2. To adjust for potential confounders, a multivariate analysis was performed including the starting dose and age, as age often influences the choice of starting dose. The analysis confirmed that a lenvatinib starting dose of 20 mg was the sole independent predictor of improved PFS (aHR for dose <20 mg: 5.83, 95% CI 1.84–18.43; p=0.003) (Table 3). Overall Survival In the univariate analysis for OS, peritoneal metastasis (p=0.003), lung metastasis (p=0.003), and age ≥75 years (p=0.020) were significantly associated with shorter OS (details in Supplementary Table 3). Patients starting lenvatinib at 20 mg showed a non-significant trend toward longer OS (median 27.4 vs 19.9 months; p=0.187) (Figure 2B). In the exploratory multivariate analysis, which included clinically relevant factors, peritoneal metastasis was identified as the sole independent prognostic factor for worse OS (aHR 7.51; 95% CI, 1.87–30.25; p=0.005) (Table 4). Discussion This real-world study shows that lenvatinib plus pembrolizumab (LP) achieves high disease control in advanced or recurrent endometrial cancer and suggests the starting dose of lenvatinib impacts progression-free survival (PFS). Our results support the external validity of the well-established efficacy and safety profile from the pivotal KEYNOTE-775 trial [ 1 ]. Additionally, our findings offer new insights into how initial dosing strategies affect clinical outcomes in routine practice. Our finding that a 20 mg starting dose of lenvatinib independently predicted better PFS may be explained by the "vascular normalization window." Anti-VEGF drugs like lenvatinib can temporarily normalize tumor blood vessels for a few days after starting treatment. This process improves oxygen levels and allows more immune cells (effector T cells) to enter the tumor [ 10 – 12 ]. We hypothesize that giving a full dose of lenvatinib during this short window enhances the initial priming effect of the ICI, which helps suppress early progression and leads to a better response. Preclinical data support this, showing that lenvatinib remodels the tumor microenvironment to boost the effect of anti-PD-1 antibodies [ 13 ]. Therefore, starting with a higher dose likely achieves both vascular normalization and immune priming more effectively. The importance of sufficient drug levels early in treatment—the "quality of initial exposure"—is also supported by other studies. For instance, a Japanese multi-center study found that a relative dose intensity (RDI) of ≥ 50% in the first 8 weeks was linked to better PFS and OS, highlighting the need for adequate drug exposure early on [ 6 ]. In contrast, other real-world studies report that starting doses of 14 mg or less are common and do not show a significant loss of effectiveness in unadjusted analyses [ 2 – 4 , 7 ]. This discrepancy highlights a key clinical challenge: balancing an effective dose with managing side effects. Our findings support a "start high, then adjust" strategy: begin with 20 mg under close monitoring and reduce the dose quickly if toxicity occurs. This approach aims to utilize the early therapeutic window while maintaining long-term treatment. However, this strategy must be individualized for vulnerable patients, such as the elderly or those with poor performance status, where a lower starting dose may be safer. In terms of safety, the profile of treatment-emergent adverse events, including hypertension, proteinuria, and hypothyroidism, was consistent with previous reports [ 1 , 14 ]. The toxicity profile in our cohort, where 51.5% started at < 20 mg, underscores the necessity of proactive toxicity management (e.g., monitoring, dose modifications, and supportive care) according to established guidelines [ 15 – 17 ] to maintain treatment feasibility. For overall survival (OS), the strong effect of the starting dose seen for PFS was not observed. Instead, our multivariate analysis identified peritoneal metastasis as a powerful, independent predictor of worse OS. This creates a notable contrast, as peritoneal metastasis did not affect short-term outcomes like PFS in our cohort. This finding aligns with the clinical understanding that factors related to tumor biology and burden, such as the site of metastasis, are major drivers of long-term outcomes, potentially outweighing the impact of the initial dosing strategy seen in PFS [ 2 – 4 , 6 , 7 ]. The dilution of the starting dose effect on OS may also be attributed to the heterogeneity of subsequent therapies. Our multivariate analysis, which confirmed peritoneal metastasis as an independent prognostic factor for OS, highlights its critical role in determining long-term outcomes in this population. Large-scale studies show the lung is the most common site of distant metastasis [ 18 , 19 ], but the prognosis varies. In contrast, peritoneal carcinomatosis generally indicates a poor prognosis, although this can depend on whether the cancer is confined to the peritoneum [ 20 ]. For patients with a low tumor volume, surgery (CRS), sometimes combined with other treatments like HIPEC, may improve survival [ 21 , 22 ]. Together, these findings show that even within the same advanced stage, different patterns of metastasis have different biological behaviors and treatment options. This highlights the need for treatment strategies that are specific to the site of metastasis. Our study has several limitations. As a retrospective study from a single center with a small number of patients, it is subject to potential selection bias, information bias, and unmeasured confounding factors. Specifically, the multivariate analysis for OS was limited by a small number of events (n = 12), resulting in a low events-per-variable (EPV) ratio of 4. This increases the risk of overfitting, and therefore, the results must be interpreted with particular caution. A key limitation is "confounding by indication," meaning the physician's choice of starting dose was likely influenced by their assessment of the patient's overall health or frailty. Therefore, we must be cautious when inferring a direct cause-and-effect relationship between the dose and outcomes. Future prospective trials are needed to compare a fixed 20 mg starting dose against an individualized lower-dose strategy. Such trials should stratify patients by factors like age, platinum-free interval, metastatic sites, and performance status [ 5 , 6 ]. Conclusion In this single-center retrospective analysis in Japan, the combination therapy of lenvatinib plus pembrolizumab demonstrated favorable effectiveness and a tolerable safety profile. While the lenvatinib starting dose was a critical predictor for progression-free survival, our analysis revealed that the presence of peritoneal metastasis was the sole independent prognostic factor for poor overall survival. Notably, as peritoneal metastasis did not significantly impact PFS, these findings suggest that LP therapy should be appropriately initiated even in this patient subgroup with a poor long-term prognosis. Declarations Acknowledgements We thank Yoshimi Shinomiya and Yuki Inoue for their assistance with data management. Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests: Shogen Boku reports receiving honoraria from MSD K.K. Nobuhiro Shibata reports receiving honoraria from Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Company, Limited, and Chugai Pharmaceutical Co., Ltd. Masashi Kanai reports holding unlisted stock in Therabiopharma Co., Ltd. He has also received honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Guardant Health Japan. The other authors have no COI to be disclosed. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Shogen Boku. The first draft of the manuscript was written by Shogen Boku and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Kansai Medical University Hospital (Approval No. 2025268). Clinical trial number: Not applicable. Consent to Participate: The requirement for informed consent was waived by the Institutional Review Board due to the retrospective nature of the study. References Makker V, Colombo N, Casado Herraez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 2022;386(5):437-48. https://doi.org/10.1056/NEJMoa2108330 Corr BR, Thomas SM, Haight PJ, et al. Evaluation of the combination lenvatinib and pembrolizumab in endometrial cancer; a real world multi-institutional review of practice patterns, efficacy and tolerability. Gynecol Oncol 2025;201:69-75. https://doi.org/10.1016/j.ygyno.2025.08.008 Ta QD, Do C, Sharma K, et al. Reduced dosing of lenvatinib with pembrolizumab for advanced endometrial cancer. Gynecol Oncol 2025;196:36-41. https://doi.org/10.1016/j.ygyno.2025.03.034 Barbi M, Lee CS, Rahman H, Cheng KL, John VS. Toxicity and efficacy of lenvatinib plus pembrolizumab in advanced endometrial cancer: a real-world retrospective analysis. Front Oncol 2025;15:1622253. https://doi.org/10.3389/fonc.2025.1622253 How JA, Patel S, Fellman B, et al. Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer. Gynecol Oncol 2021;162(1):24-31. https://doi.org/10.1016/j.ygyno.2021.04.034 Nagase Y, Nakagawa S, Kobayashi M, et al. Prognostic factors of lenvatinib plus pembrolizumab therapy for advanced or recurrent endometrial cancer: analysis of a multicenter cohort study in Japan. Int J Clin Oncol 2025. Online ahead of print. https://doi.org/10.1007/s10147-025-02842-x Wada K, Lopes G, Guntupalli SR, et al. Real-world utilization, effectiveness, and safety of lenvatinib and pembrolizumab for the treatment of advanced endometrial cancer in the USA. Future Oncol 2024;20(11):737-51. https://doi.org/10.2217/fon-2023-0870 Pawsey A, MacDonald D, Bolton L, et al. 235O Real-world outcomes of pembrolizumab plus lenvatinib in older patients with relapsed endometrial cancer. Ann Oncol 2025;35(Suppl 5):S235. https://doi.org/10.1016/j.annonc.2024.03.245 Kanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow Transpl 2013;48:452–8. https://doi.org/10.1038/bmt.2012.244 Magnussen AL, Mills IG. Vascular normalisation as the stepping stone into tumour microenvironment transformation. Br J Cancer 2021;125(8):1117-1128. https://doi.org/10.1038/s41416-021-01501-8 Chatterjee S, Heukamp LC, Siobal M, et al. Transient antiangiogenic treatment improves delivery of cytotoxic therapy in NSCLC models. Cancer Res 2014;74(10):2816-2824. https://doi.org/10.1158/0008-5472.CAN-13-2611 Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013;73(10):2943-2948. https://doi.org/10.1158/0008-5472.CAN-12-4319 Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates interferon signaling and reduces tumor-associated macrophages. PLoS One 2019;14(2):e0212513. https://doi.org/10.1371/journal.pone.0212513 Schlumberger M, Jarzab B, Cabanillas ME, et al. Lenvatinib for Radioiodine-Refractory Thyroid Cancer: A Review of Safety and Toxicity Management. Eur J Cancer 2019;121:174-85. https://doi.org/10.1016/j.ejca.2019.08.019 Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-68. https://doi.org/10.1200/JCO.2017.77.6385 Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv119-42. https://doi.org/10.1093/annonc/mdx225 Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5(1):95. https://doi.org/10.1186/s40425-017-0295-9 Capozzi VA, Rosati A, Sozzi G, et al. Optimal management for stage IVB endometrial cancer. Cancers (Basel) 2023;15(20):5023. https://doi.org/10.3390/cancers15205023 Li J, Kong X, Tang M, et al. Patterns of distant metastases in patients with endometrial carcinoma: a SEER-based analysis. J Clin Oncol 2019;37(15_suppl):e17109. https://doi.org/10.1200/JCO.2019.37.15_suppl.e17109 Li H, Wu X, Cheng X. Prognostic value of different metastatic sites for patients with FIGO stage IVB endometrial cancer: a retrospective cohort study. Int J Gynecol Cancer 2020;30(9):1287-93. https://doi.org/10.1136/ijgc-2020-001358 Panczel I, Varga A, Komm M, et al. Survival difference of endometrial cancer patients with peritoneal carcinomatosis treated with cytoreductive surgery with or without HIPEC: a systematic review. Cancers (Basel) 2024;16(11):1991. https://doi.org/10.3390/cancers16111991 Lolis ED, Theodoropoulos GE, Somarakis A, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from endometrial cancer: updated evidence. In Vivo 2025;39(5):2832-43. https://doi.org/10.21873/invivo.13456 Tables Table 1: Baseline Patient and Clinical Characteristics by Lenvatinib Starting Dose Characteristic All Patients (N=33) Lenvatinib 20 mg (n=16) Lenvatinib <20 mg (n=17) Patient Demographics Age (years), median (range) 67.4 (44.4 - 82.8) 60.0 (44.4 - 70.7) 76.7 (54.3 - 82.8) ≥75 years, n (%) 10 (30.3) 0 (0.0) 10 (58.8) BMI (kg/m²), median (range) 22.8 (14.5 - 41.0) 27.3 (16.6 - 41.0) 21.8 (14.5 - 28.7) ECOG Performance Status, n (%) 0 17 (51.5) 13 (81.3) 4 (23.5) 1 15 (45.5) 3 (18.8) 12 (70.6) 2 1 (3.0) 0 (0.0) 1 (5.9) Tumor and Treatment History FIGO Stage at initial diagnosis, n (%) I 7 (21.2) 4 (25.0) 3 (17.6) II 5 (15.2) 1 (6.3) 4 (23.5) III 9 (27.3) 3 (18.8) 6 (35.3) IV 12 (36.4) 8 (50.0) 4 (23.5) Disease status at LP therapy initiation, n (%) Primary unresectable disease 7 (21.2) 4 (25.0) 3 (17.6) Recurrent disease 26 (78.8) 12 (75.0) 14 (82.4) Number of prior chemotherapy regimens, n (%) 1 21 (63.6) 12 (75.0) 9 (52.9) ≥2 12 (36.4) 4 (25.0) 8 (47.1) Platinum-free interval (months), median (range) 4.0 (0 - 71) 6.1 (1.0 - 28.0) 4.1 (0 - 71.0) Pathological Features Histology, n (%) Endometrioid adenocarcinoma 21 (63.6) 11 (68.8) 10 (58.8) Adenocarcinoma, NOS 2 (6.1) 1 (6.3) 1 (5.9) Dedifferentiated carcinoma 3 (9.1) 1 (6.3) 2 (11.8) Other 7 (21.2) 3 (18.8) 4 (23.5) MMR/MSI Status, n (%) dMMR/MSI-High 4 (12.1) 3 (18.8) 1 (5.9) Metastatic Sites at LP therapy initiation, n (%) * Local/Regional 5 (15.2) 3 (18.8) 2 (11.8) Lymph node 11 (33.3) 7 (43.8) 4 (23.5) Peritoneum 11 (33.3) 4 (25.0) 7 (41.2) Lung 11 (33.3) 6 (37.5) 5 (29.4) Liver 3 (9.1) 1 (6.3) 2 (11.8) Bone 4 (12.1) 3 (18.8) 1 (5.9) Baseline Laboratory Values eGFR (mL/min/1.73m²), median (range) 61.0 (20 - 111) 63.0 (50 - 103) 60.0 (20 - 111) CRP (mg/dL), median (range) 0.28 (0.02 - 6.5) 0.33 (0.02 - 3.98) 0.14 (0.05 - 6.5) Albumin (g/dL), median (range) 4.2 (3.2 - 4.7) 4.3 (3.4 - 4.7) 3.9 (3.2 - 4.6) Abbreviations: BMI, body mass index; CRP, C-reactive protein; dMMR, mismatch repair deficient; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; FIGO, International Federation of Gynecology and Obstetrics; LP, lenvatinib plus pembrolizumab; MSI, microsaurikellite instability; NOS, not otherwise specified. *Patients may have more than one site of metastasis. Table 2: Treatment-Emergent Adverse Events Adverse Event All Grades, n (%) Grade ≥3, n (%) Hypothyroidism 16 (48.5) 0 (0.0) Hypertension 15 (45.5) 1 (3.0) Thrombocytopenia 13 (39.4) 4 (12.1) Proteinuria 12 (36.4) 1 (3.0) Decreased appetite 12 (36.4) 1 (3.0) Fatigue/Asthenia 10 (30.3) 1 (3.0) Stomatitis/Oral mucositis 8 (24.2) 2 (6.1) Dysphonia 7 (21.2) 0 (0.0) Peripheral neuropathy 7 (21.2) 0 (0.0) Arthralgia 6 (18.2) 0 (0.0) Hand-foot syndrome 6 (18.2) 0 (0.0) Hepatic dysfunction 6 (18.2) 2 (6.1) Nausea 6 (18.2) 0 (0.0) Edema 6 (18.2) 0 (0.0) Anemia 5 (15.2) 2 (6.1) Diarrhea 5 (15.2) 0 (0.0) Renal impairment 5 (15.2) 0 (0.0) Rash 5 (15.2) 0 (0.0) Adrenal insufficiency 3 (9.1) 0 (0.0) Leukopenia 2 (6.1) 2 (6.1) Myositis/CPK increase 2 (6.1) 1 (3.0) Enteritis 2 (6.1) 0 (0.0) Pneumonitis 1 (3.0) 0 (0.0) Table lists all reported adverse events. Table 3: Multivariate Analysis of Prognostic Factors for Progression-Free Survival Characteristic Adjusted Hazard Ratio (aHR) 95% CI P-value Lenvatinib starting dose <20 mg (vs. 20 mg) 5.83 1.84–18.43 0.003 Age ≥75 years (vs. <75) 0.76 0.27–2.11 0.593 ECOG PS ≥1 (vs. 0) 0.79 0.34–1.86 0.589 Abbreviations: aHR, adjusted Hazard Ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status. Table 4: Multivariate Analysis of Prognostic Factors for Overall Survival Characteristic Adjusted Hazard Ratio (aHR) 95% CI P-value Peritoneal metastasis (Present vs. Absent) 7.51 1.87–30.25 0.005 Age ≥75 years (vs. <75) 4.83 0.85–27.46 0.076 Lenvatinib starting dose <20 mg (vs. 20 mg) 1.04 0.18–5.93 0.963 Abbreviations: aHR, adjusted Hazard Ratio; CI, confidence Additional Declarations Competing interest reported. Shogen Boku reports receiving honoraria from MSD K.K. Nobuhiro Shibata reports receiving honoraria from Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Company, Limited, and Chugai Pharmaceutical Co., Ltd. Masashi Kanai reports holding unlisted stock in Therabiopharma Co., Ltd. He has also received honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Guardant Health Japan. The other authors have no COI to be disclosed. Supplementary Files supplementaryTable.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Dec, 2025 Reviews received at journal 10 Dec, 2025 Reviews received at journal 07 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviewers invited by journal 01 Dec, 2025 Editor assigned by journal 18 Nov, 2025 Submission checks completed at journal 18 Nov, 2025 First submitted to journal 17 Nov, 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. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8137646","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":554627524,"identity":"3b7a7289-65d8-4077-9dbc-97c6732a834f","order_by":0,"name":"Shogen Boku","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shogen","middleName":"","lastName":"Boku","suffix":""},{"id":554627525,"identity":"51edbdd2-ba07-471b-9dc4-c4e4e8ea5a94","order_by":1,"name":"Masato Kita","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Kita","suffix":""},{"id":554627526,"identity":"cb374f67-5ebe-4b78-bd26-91ec6dcff26c","order_by":2,"name":"Tatsuki Ikoma","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tatsuki","middleName":"","lastName":"Ikoma","suffix":""},{"id":554627527,"identity":"36851522-1514-40de-97e2-89c43e79bd48","order_by":3,"name":"Tomoyo Yasuda","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomoyo","middleName":"","lastName":"Yasuda","suffix":""},{"id":554627528,"identity":"69dc0a88-0201-460b-9f49-31538a9e667b","order_by":4,"name":"Nobuhiro Shibata","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nobuhiro","middleName":"","lastName":"Shibata","suffix":""},{"id":554627529,"identity":"2e5f27b1-a385-48a6-ab3b-1f6a265a2267","order_by":5,"name":"Hiroshi Shiraga","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Shiraga","suffix":""},{"id":554627530,"identity":"dd143d8f-e65f-4418-a349-82891e2c8cc2","order_by":6,"name":"Yusuke Butsuhara","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Butsuhara","suffix":""},{"id":554627531,"identity":"daaba1a3-a487-46fc-ae69-767c5ee57473","order_by":7,"name":"Hiromi Murata","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hiromi","middleName":"","lastName":"Murata","suffix":""},{"id":554627532,"identity":"d8f61f07-ab0f-410c-b38a-95997993cd3a","order_by":8,"name":"Tomomi Mizokami","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomomi","middleName":"","lastName":"Mizokami","suffix":""},{"id":554627533,"identity":"886b419d-e86a-4c4e-88c6-45c8247ae66a","order_by":9,"name":"Hidetaka Okada","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hidetaka","middleName":"","lastName":"Okada","suffix":""},{"id":554627534,"identity":"5cad56ef-a9f9-48bf-964f-0807fde407c9","order_by":10,"name":"Masashi Kanai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACCRCRACLY22BiB4jVwnOMFC0QVhqRDpNsP3vwwwOGbfbyM5+lbuZhsJNnYDyL3xppnrxkiQSG24kbbqcdu83DkGzYwHAuAa8WOYYcA5CWBAPp9DagFmag8jMG+LXwvzH+AdQCdNhxkJZ6wlqkJXLMQLYwNtxgAznsMGEtkjPemFkkGAD9ciYt7eYcg+OGbYT8InE+x/jmjwqgw9qPmd14U1Etzy9BIMQgwACJwSZxhggdqIC/h2Qto2AUjIJRMLwBADMEQ79bse8xAAAAAElFTkSuQmCC","orcid":"","institution":"Kansai Medical University","correspondingAuthor":true,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Kanai","suffix":""}],"badges":[],"createdAt":"2025-11-17 16:23:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8137646/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8137646/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97653031,"identity":"c216795a-c9fe-4262-ad0c-60746f868b38","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.LEN.PEM.DO.docx","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/e22f57f09ea99082698095c7.docx"},{"id":97674213,"identity":"9270b537-1d7f-4c2a-b38d-0464f058875f","added_by":"auto","created_at":"2025-12-08 09:42:38","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1487610,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.1.tif","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/1223704f4ed7c839863ebd21.tif"},{"id":97653037,"identity":"f12e2850-544d-460e-a416-38767e28d3dc","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":25662,"visible":true,"origin":"","legend":"","description":"","filename":"table14.docx","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/63f2ca276f0a70e1944e2021.docx"},{"id":97674944,"identity":"a24f2a49-3f10-4f38-802c-c7a66fd00de7","added_by":"auto","created_at":"2025-12-08 09:44:56","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2741628,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.2.tif","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/e5a85910826695aef71eea88.tif"},{"id":97674520,"identity":"0196076c-9a57-4e0b-810a-2235ed7b316f","added_by":"auto","created_at":"2025-12-08 09:43:31","extension":"json","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11889,"visible":true,"origin":"","legend":"","description":"","filename":"c8a6624243af4ad38cda5cc394bca970.json","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/674cd4c75018dad77ced75d9.json"},{"id":97673732,"identity":"50f14562-a75b-4727-ad93-69af0aad461d","added_by":"auto","created_at":"2025-12-08 09:41:12","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":24324,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/369f8f554f6580760836dd20.docx"},{"id":97653041,"identity":"ceec2f5d-4f52-4a5d-a58a-edb0b647f364","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94171,"visible":true,"origin":"","legend":"","description":"","filename":"c8a6624243af4ad38cda5cc394bca9701enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/43db265dc78a92536c561ff3.xml"},{"id":97653042,"identity":"6782cdee-b7c5-4705-a379-aae391e377d9","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"tif","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1487610,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.1.tif","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/f068808eb5bd4db164d10d48.tif"},{"id":97653047,"identity":"85a0633b-ad06-4497-b0c4-260bd4749585","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"tif","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2741628,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.2.tif","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/9c6933d13e9e73205fd7edde.tif"},{"id":97653040,"identity":"dc351992-2468-4741-acfa-76fc8878f523","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":155452,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/1c0f80f84226235781e6703a.png"},{"id":97674679,"identity":"9219fdff-6a9c-4b40-a999-89aa0295057a","added_by":"auto","created_at":"2025-12-08 09:43:48","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":260393,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/9c8d9ac8cf6b0d077289c958.png"},{"id":97653045,"identity":"6fb6d374-6177-4020-89ae-cffa4afab7ca","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":93435,"visible":true,"origin":"","legend":"","description":"","filename":"c8a6624243af4ad38cda5cc394bca9701structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/bafceac6e341f58dca2c24a9.xml"},{"id":97653044,"identity":"60e45309-668b-445b-bd31-d9ae55197067","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":103618,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/27171639aef33e13eb66f0d6.html"},{"id":97653038,"identity":"56cd80d2-77bc-496a-bdbb-be117d5789d0","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":363278,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for (A) progression-free survival and (B) overall survival in the entire cohort (N=33). The numbers of patients at risk at each time point are shown below the x-axis.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/4b8c27b994163605aa9d8a85.png"},{"id":97653039,"identity":"f2109e41-7f0c-4916-bb35-97b2ac4f30cd","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1239991,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for (A) progression-free survival and (B) overall survival, stratified by the starting dose of lenvatinib. The numbers of patients at risk at each time point are shown below the x-axis.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/6b555e796afd057a1ea2f7b7.png"},{"id":97678806,"identity":"9ac08932-e739-4ecb-95f8-d5f66ef0f0a5","added_by":"auto","created_at":"2025-12-08 09:56:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2459989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/245c8c76-1129-4567-b033-0083d723d141.pdf"},{"id":97653033,"identity":"996896dd-6fe6-43a2-99c4-ab3752e1cbf5","added_by":"auto","created_at":"2025-12-08 06:45:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24324,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-8137646/v1/0fc38cc2cd8c532fd4bd4b12.docx"}],"financialInterests":"Competing interest reported. Shogen Boku reports receiving honoraria from MSD K.K. Nobuhiro Shibata reports receiving honoraria from Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Company, Limited, and Chugai Pharmaceutical Co., Ltd. Masashi Kanai reports holding unlisted stock in Therabiopharma Co., Ltd. He has also received honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Guardant Health Japan. The other authors have no COI to be disclosed.","formattedTitle":"Impact of Peritoneal Metastasis on Overall Survival in Patients with Advanced Endometrial Cancer Receiving Lenvatinib plus Pembrolizumab","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometrial cancer is a leading gynecologic malignancy, and the prognosis for patients with advanced or recurrent disease remains poor. The phase 3 KEYNOTE-775 trial established the combination of lenvatinib plus pembrolizumab (LP) as a standard of care, demonstrating significant improvements in both progression-free survival (PFS; HR, 0.56) and overall survival (OS; HR, 0.65) compared to chemotherapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite its pronounced efficacy, the LP regimen was associated with a substantial toxicity burden in the KEYNOTE-775 trial. High rates of adverse events such as hypertension, diarrhea, and hypothyroidism were reported, necessitating dose reductions or interruptions of lenvatinib in a significant proportion of patients. Consequently, the appropriateness of the recommended 20 mg/day starting dose has been debated, and whether to initiate treatment at a reduced dose remains a critical clinical question in real-world practice. In recent years, a growing body of real-world evidence has emerged to address this issue. Multi-institutional reviews and insurance claims analyses from the United States have shown that a 14 mg starting dose is predominant and that variations in the initial dose do not necessarily compromise response rates or survival outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, other retrospective studies suggest that while a lower starting dose may reduce the frequency of dose modifications, it could be associated with inferior PFS after adjusting for factors such as age [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Systematic reviews and additional real-world studies have consistently supported the dual nature of the LP regimen\u0026mdash;its effectiveness and notable toxicity. These studies confirm its feasibility in vulnerable populations, including older adults and patients with an ECOG performance status of 1\u0026ndash;2 who would have been ineligible for clinical trials, but also underscore that prospective validation of dosing strategies remains an unmet need [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In light of this background, we conducted a single-institution retrospective analysis of a real-world cohort in Japan to evaluate the effectiveness and safety of the LP regimen. The primary objective of this study was to exploratively investigate the impact of the lenvatinib starting dose on PFS and OS, thereby generating concrete hypotheses for optimizing initial dosing strategies in real-world settings, taking into account patient backgrounds such as age, sites of metastasis, and performance status.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design and Patients\u003c/p\u003e\u003cp\u003eThis study was a single-center, retrospective cohort study conducted at Kansai Medical University Hospital. We identified patients with advanced or recurrent endometrial cancer who received LP therapy between February 2022 and August 2025. Eligible patients were those who had experienced disease progression after at least one prior platinum-based chemotherapy regimen. This study was approved by the Institutional Review Board of Kansai Medical University Hospital and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\u003cp\u003eData Collection and Assessments\u003c/p\u003e\u003cp\u003eWe retrospectively collected data from electronic medical records. The collected data included clinical and pathological characteristics, treatment history including the starting dose of lenvatinib, treatment-emergent adverse events (TEAEs), tumor response, and survival status. TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor response was assessed by the attending physician based on imaging studies according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e\u003cp\u003eEndpoints\u003c/p\u003e\u003cp\u003eThe primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from the initiation of LP therapy to disease progression or death from any cause. OS was defined as the time from the initiation of LP therapy to death from any cause. Secondary endpoints were the objective response rate (ORR), defined as the proportion of patients with a complete or partial response, the disease control rate (DCR), defined as the proportion of patients with complete response, partial response, or stable disease, and safety.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003ePatient characteristics, effectiveness, and safety data were summarized using descriptive statistics. The median follow-up time was calculated using the reverse Kaplan-Meier method. Survival curves for PFS and OS were estimated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Univariate and multivariate analyses for prognostic factors were performed using the Cox proportional hazards model. A P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 patients treated with lenvatinib plus pembrolizumab were included in this retrospective analysis. The median follow-up time was 27.6 months. Baseline patient and clinical characteristics are detailed in Table 1. For the overall cohort, the median age was 67.4 years, and 17 patients (51.5%) had an ECOG performance status of 0. When stratified by lenvatinib starting dose, patients in the \u0026lt;20 mg group were older and had a poorer performance status compared to the 20 mg group. Specifically, all patients aged \u0026ge;75 years (10/10) were in the \u0026lt;20 mg group, and the proportion of patients with an ECOG PS of 0 was substantially higher in the 20 mg group (81.3% vs. 23.5%). The majority of patients (78.8%) received the study treatment for recurrent disease after a median platinum-free interval of 4.0 months. Endometrioid adenocarcinoma was the most frequent histology (63.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Effectiveness\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the entire cohort, the objective response rate (ORR) was 48.5% and the disease control rate (DCR) was 87.9% (details in Supplementary Table 1). The median overall survival (OS) for the entire cohort was 21.7 months (95% CI, 18.3 months\u0026ndash;not reached), and the median progression-free survival (PFS) was 6.7 months (95% CI, 4.4\u0026ndash;10.3 months) (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe safety profile is detailed in Table 2. The most frequent treatment-emergent adverse events (TEAEs) of any grade were hypothyroidism (48.5%), hypertension (45.5%), and thrombocytopenia (39.4%). The most common grade \u0026ge;3 TEAE was thrombocytopenia (12.1%). Key immune-related adverse events (irAEs) included adrenal insufficiency (9.1%), myositis (6.1%), and pneumonitis (3.0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic Factor Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed univariate and multivariate analyses to identify prognostic factors for response and survival. When stratified by the lenvatinib starting dose, the ORR was numerically higher in the 20 mg group compared to the \u0026lt;20 mg group (56.3% vs 41.2%), though the difference was not statistically significant (p=0.715) (Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProgression-Free Survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the univariate analysis, a lenvatinib starting dose of 20 mg was significantly associated with longer PFS (median 21.6 vs 4.9 months; p=0.001) (Figure 2A). Notably, the presence of peritoneal metastasis, which was a strong predictor for OS, was not associated with PFS (p=0.844). Additionally, patients aged \u0026ge;75 years showed a trend toward shorter PFS (p=0.087). The full univariate analysis results are shown in Supplementary Table 2. To adjust for potential confounders, a multivariate analysis was performed including the starting dose and age, as age often influences the choice of starting dose. The analysis confirmed that a lenvatinib starting dose of 20 mg was the sole independent predictor of improved PFS (aHR for dose \u0026lt;20 mg: 5.83, 95% CI 1.84\u0026ndash;18.43; p=0.003) (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall Survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the univariate analysis for OS, peritoneal metastasis (p=0.003), lung metastasis (p=0.003), and age \u0026ge;75 years (p=0.020) were significantly associated with shorter OS (details in Supplementary Table 3). Patients starting lenvatinib at 20 mg showed a non-significant trend toward longer OS (median 27.4 vs 19.9 months; p=0.187) (Figure 2B). In the exploratory multivariate analysis, which included clinically relevant factors, peritoneal metastasis was identified as the sole independent prognostic factor for worse OS (aHR 7.51; 95% CI, 1.87\u0026ndash;30.25; p=0.005) (Table 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis real-world study shows that lenvatinib plus pembrolizumab (LP) achieves high disease control in advanced or recurrent endometrial cancer and suggests the starting dose of lenvatinib impacts progression-free survival (PFS). Our results support the external validity of the well-established efficacy and safety profile from the pivotal KEYNOTE-775 trial [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Additionally, our findings offer new insights into how initial dosing strategies affect clinical outcomes in routine practice. Our finding that a 20 mg starting dose of lenvatinib independently predicted better PFS may be explained by the \"vascular normalization window.\" Anti-VEGF drugs like lenvatinib can temporarily normalize tumor blood vessels for a few days after starting treatment. This process improves oxygen levels and allows more immune cells (effector T cells) to enter the tumor [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. We hypothesize that giving a full dose of lenvatinib during this short window enhances the initial priming effect of the ICI, which helps suppress early progression and leads to a better response. Preclinical data support this, showing that lenvatinib remodels the tumor microenvironment to boost the effect of anti-PD-1 antibodies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, starting with a higher dose likely achieves both vascular normalization and immune priming more effectively. The importance of sufficient drug levels early in treatment\u0026mdash;the \"quality of initial exposure\"\u0026mdash;is also supported by other studies. For instance, a Japanese multi-center study found that a relative dose intensity (RDI) of \u0026ge;\u0026thinsp;50% in the first 8 weeks was linked to better PFS and OS, highlighting the need for adequate drug exposure early on [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In contrast, other real-world studies report that starting doses of 14 mg or less are common and do not show a significant loss of effectiveness in unadjusted analyses [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This discrepancy highlights a key clinical challenge: balancing an effective dose with managing side effects. Our findings support a \"start high, then adjust\" strategy: begin with 20 mg under close monitoring and reduce the dose quickly if toxicity occurs. This approach aims to utilize the early therapeutic window while maintaining long-term treatment. However, this strategy must be individualized for vulnerable patients, such as the elderly or those with poor performance status, where a lower starting dose may be safer. In terms of safety, the profile of treatment-emergent adverse events, including hypertension, proteinuria, and hypothyroidism, was consistent with previous reports [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The toxicity profile in our cohort, where 51.5% started at \u0026lt;\u0026thinsp;20 mg, underscores the necessity of proactive toxicity management (e.g., monitoring, dose modifications, and supportive care) according to established guidelines [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] to maintain treatment feasibility. For overall survival (OS), the strong effect of the starting dose seen for PFS was not observed. Instead, our multivariate analysis identified peritoneal metastasis as a powerful, independent predictor of worse OS. This creates a notable contrast, as peritoneal metastasis did not affect short-term outcomes like PFS in our cohort. This finding aligns with the clinical understanding that factors related to tumor biology and burden, such as the site of metastasis, are major drivers of long-term outcomes, potentially outweighing the impact of the initial dosing strategy seen in PFS [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The dilution of the starting dose effect on OS may also be attributed to the heterogeneity of subsequent therapies. Our multivariate analysis, which confirmed peritoneal metastasis as an independent prognostic factor for OS, highlights its critical role in determining long-term outcomes in this population. Large-scale studies show the lung is the most common site of distant metastasis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], but the prognosis varies. In contrast, peritoneal carcinomatosis generally indicates a poor prognosis, although this can depend on whether the cancer is confined to the peritoneum [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. For patients with a low tumor volume, surgery (CRS), sometimes combined with other treatments like HIPEC, may improve survival [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Together, these findings show that even within the same advanced stage, different patterns of metastasis have different biological behaviors and treatment options. This highlights the need for treatment strategies that are specific to the site of metastasis. Our study has several limitations. As a retrospective study from a single center with a small number of patients, it is subject to potential selection bias, information bias, and unmeasured confounding factors. Specifically, the multivariate analysis for OS was limited by a small number of events (n\u0026thinsp;=\u0026thinsp;12), resulting in a low events-per-variable (EPV) ratio of 4. This increases the risk of overfitting, and therefore, the results must be interpreted with particular caution. A key limitation is \"confounding by indication,\" meaning the physician's choice of starting dose was likely influenced by their assessment of the patient's overall health or frailty. Therefore, we must be cautious when inferring a direct cause-and-effect relationship between the dose and outcomes. Future prospective trials are needed to compare a fixed 20 mg starting dose against an individualized lower-dose strategy. Such trials should stratify patients by factors like age, platinum-free interval, metastatic sites, and performance status [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this single-center retrospective analysis in Japan, the combination therapy of lenvatinib plus pembrolizumab demonstrated favorable effectiveness and a tolerable safety profile. While the lenvatinib starting dose was a critical predictor for progression-free survival, our analysis revealed that the presence of peritoneal metastasis was the sole independent prognostic factor for poor overall survival. Notably, as peritoneal metastasis did not significantly impact PFS, these findings suggest that LP therapy should be appropriately initiated even in this patient subgroup with a poor long-term prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Yoshimi Shinomiya and Yuki Inoue for their assistance with data management.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e Shogen Boku reports receiving honoraria from MSD K.K. Nobuhiro Shibata reports receiving honoraria from Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Company, Limited, and Chugai Pharmaceutical Co., Ltd. Masashi Kanai reports holding unlisted stock in Therabiopharma Co., Ltd. He has also received honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Guardant Health Japan. The other authors have no COI to be disclosed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Shogen Boku. The first draft of the manuscript was written by Shogen Boku and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Kansai Medical University Hospital (Approval No. 2025268).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u0026nbsp;\u003c/strong\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u003c/strong\u003e The requirement for informed consent was waived by the Institutional Review Board due to the retrospective nature of the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMakker V, Colombo N, Casado Herraez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 2022;386(5):437-48. https://doi.org/10.1056/NEJMoa2108330\u003c/li\u003e\n \u003cli\u003eCorr BR, Thomas SM, Haight PJ, et al. Evaluation of the combination lenvatinib and pembrolizumab in endometrial cancer; a real world multi-institutional review of practice patterns, efficacy and tolerability. Gynecol Oncol 2025;201:69-75. https://doi.org/10.1016/j.ygyno.2025.08.008\u003c/li\u003e\n \u003cli\u003eTa QD, Do C, Sharma K, et al. Reduced dosing of lenvatinib with pembrolizumab for advanced endometrial cancer. Gynecol Oncol 2025;196:36-41. https://doi.org/10.1016/j.ygyno.2025.03.034\u003c/li\u003e\n \u003cli\u003eBarbi M, Lee CS, Rahman H, Cheng KL, John VS. Toxicity and efficacy of lenvatinib plus pembrolizumab in advanced endometrial cancer: a real-world retrospective analysis. Front Oncol 2025;15:1622253. https://doi.org/10.3389/fonc.2025.1622253\u003c/li\u003e\n \u003cli\u003eHow JA, Patel S, Fellman B, et al. Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer. Gynecol Oncol 2021;162(1):24-31. https://doi.org/10.1016/j.ygyno.2021.04.034\u003c/li\u003e\n \u003cli\u003eNagase Y, Nakagawa S, Kobayashi M, et al. Prognostic factors of lenvatinib plus pembrolizumab therapy for advanced or recurrent endometrial cancer: analysis of a multicenter cohort study in Japan. Int J Clin Oncol 2025. Online ahead of print. https://doi.org/10.1007/s10147-025-02842-x\u003c/li\u003e\n \u003cli\u003eWada K, Lopes G, Guntupalli SR, et al. Real-world utilization, effectiveness, and safety of lenvatinib and pembrolizumab for the treatment of advanced endometrial cancer in the USA. Future Oncol 2024;20(11):737-51. https://doi.org/10.2217/fon-2023-0870\u003c/li\u003e\n \u003cli\u003ePawsey A, MacDonald D, Bolton L, et al. 235O Real-world outcomes of pembrolizumab plus lenvatinib in older patients with relapsed endometrial cancer. Ann Oncol 2025;35(Suppl 5):S235. https://doi.org/10.1016/j.annonc.2024.03.245\u003c/li\u003e\n \u003cli\u003eKanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow Transpl 2013;48:452\u0026ndash;8. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n \u003cli\u003eMagnussen AL, Mills IG. Vascular normalisation as the stepping stone into tumour microenvironment transformation. Br J Cancer 2021;125(8):1117-1128. https://doi.org/10.1038/s41416-021-01501-8\u003c/li\u003e\n \u003cli\u003eChatterjee S, Heukamp LC, Siobal M, et al. Transient antiangiogenic treatment improves delivery of cytotoxic therapy in NSCLC models. Cancer Res 2014;74(10):2816-2824. https://doi.org/10.1158/0008-5472.CAN-13-2611\u003c/li\u003e\n \u003cli\u003eHuang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013;73(10):2943-2948. https://doi.org/10.1158/0008-5472.CAN-12-4319\u003c/li\u003e\n \u003cli\u003eKato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates interferon signaling and reduces tumor-associated macrophages. PLoS One 2019;14(2):e0212513. https://doi.org/10.1371/journal.pone.0212513\u003c/li\u003e\n \u003cli\u003eSchlumberger M, Jarzab B, Cabanillas ME, et al. Lenvatinib for Radioiodine-Refractory Thyroid Cancer: A Review of Safety and Toxicity Management. Eur J Cancer 2019;121:174-85. https://doi.org/10.1016/j.ejca.2019.08.019\u003c/li\u003e\n \u003cli\u003eBrahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-68. https://doi.org/10.1200/JCO.2017.77.6385\u003c/li\u003e\n \u003cli\u003eHaanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv119-42. https://doi.org/10.1093/annonc/mdx225\u003c/li\u003e\n \u003cli\u003ePuzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5(1):95. https://doi.org/10.1186/s40425-017-0295-9\u003c/li\u003e\n \u003cli\u003eCapozzi VA, Rosati A, Sozzi G, et al. Optimal management for stage IVB endometrial cancer. Cancers (Basel) 2023;15(20):5023. https://doi.org/10.3390/cancers15205023\u003c/li\u003e\n \u003cli\u003eLi J, Kong X, Tang M, et al. Patterns of distant metastases in patients with endometrial carcinoma: a SEER-based analysis. J Clin Oncol 2019;37(15_suppl):e17109. https://doi.org/10.1200/JCO.2019.37.15_suppl.e17109\u003c/li\u003e\n \u003cli\u003eLi H, Wu X, Cheng X. Prognostic value of different metastatic sites for patients with FIGO stage IVB endometrial cancer: a retrospective cohort study. Int J Gynecol Cancer 2020;30(9):1287-93. https://doi.org/10.1136/ijgc-2020-001358\u003c/li\u003e\n \u003cli\u003ePanczel I, Varga A, Komm M, et al. Survival difference of endometrial cancer patients with peritoneal carcinomatosis treated with cytoreductive surgery with or without HIPEC: a systematic review. Cancers (Basel) 2024;16(11):1991. https://doi.org/10.3390/cancers16111991\u003c/li\u003e\n \u003cli\u003eLolis ED, Theodoropoulos GE, Somarakis A, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from endometrial cancer: updated evidence. In Vivo 2025;39(5):2832-43. https://doi.org/10.21873/invivo.13456\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Baseline Patient and Clinical Characteristics by Lenvatinib Starting Dose\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Patients (N=33)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib 20 mg (n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib \u0026lt;20 mg (n=17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient Demographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAge (years), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e67.4 (44.4 - 82.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e60.0 (44.4 - 70.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e76.7 (54.3 - 82.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026ge;75 years, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e10 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBMI (kg/m\u0026sup2;), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e22.8 (14.5 - 41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e27.3 (16.6 - 41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e21.8 (14.5 - 28.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eECOG Performance Status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e17 (51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e13 (81.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e15 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e12 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor and Treatment History\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eFIGO Stage at initial diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e9 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e6 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e12 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDisease status at LP therapy initiation, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Primary unresectable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Recurrent disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e26 (78.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e12 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e14 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eNumber of prior chemotherapy regimens, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e21 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e12 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026ge;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e12 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e8 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePlatinum-free interval (months), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.0 (0 - 71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e6.1 (1.0 - 28.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.1 (0 - 71.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological Features\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eHistology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Endometrioid adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e21 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e11 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Adenocarcinoma, NOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Dedifferentiated carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMMR/MSI Status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;dMMR/MSI-High\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic Sites at LP therapy initiation, n (%)\u003c/strong\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Local/Regional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Peritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e5 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline Laboratory Values\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eeGFR (mL/min/1.73m\u0026sup2;), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e61.0 (20 - 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e63.0 (50 - 103)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e60.0 (20 - 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCRP (mg/dL), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.28 (0.02 - 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.33 (0.02 - 3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.14 (0.05 - 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAlbumin (g/dL), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.2 (3.2 - 4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.3 (3.4 - 4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3.9 (3.2 - 4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: BMI, body mass index; CRP, C-reactive protein; dMMR, mismatch repair deficient; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; FIGO, International Federation of Gynecology and Obstetrics; LP, lenvatinib plus pembrolizumab; MSI, microsaurikellite instability; NOS, not otherwise specified.\u003c/p\u003e\n\u003cp\u003e*Patients may have more than one site of metastasis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Treatment-Emergent Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Grades, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade \u0026ge;3, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e16 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e15 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e13 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e12 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e12 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eFatigue/Asthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e10 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eStomatitis/Oral mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e8 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eDysphonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePeripheral neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eArthralgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eHand-foot syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eHepatic dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eEdema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eRenal impairment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAdrenal insufficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eMyositis/CPK increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eEnteritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePneumonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable\u003c/em\u003e lists all reported adverse \u003cem\u003eevents.\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Multivariate Analysis of Prognostic Factors for Progression-Free Survival\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted Hazard Ratio (aHR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib starting dose \u0026lt;20 mg (vs. 20 mg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.84\u0026ndash;18.43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAge \u0026ge;75 years (vs. \u0026lt;75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.27\u0026ndash;2.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eECOG PS \u0026ge;1 (vs. 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.34\u0026ndash;1.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.589\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e aHR, adjusted Hazard Ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Multivariate Analysis of Prognostic Factors for Overall Survival\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted Hazard Ratio (aHR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePeritoneal metastasis (Present vs. Absent)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e7.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.87\u0026ndash;30.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAge \u0026ge;75 years (vs. \u0026lt;75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.85\u0026ndash;27.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eLenvatinib starting dose \u0026lt;20 mg (vs. 20 mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.18\u0026ndash;5.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.963\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e aHR, adjusted Hazard Ratio; CI, confidence\u0026nbsp;\u003c/p\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":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometrial cancer, Lenvatinib, Pembrolizumab, Starting dose, Real-world evidence, peritoneal metastasis","lastPublishedDoi":"10.21203/rs.3.rs-8137646/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8137646/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e The combination of lenvatinib plus pembrolizumab (LP) is a standard treatment for advanced or recurrent endometrial cancer. However, the optimal starting dose of lenvatinib is debated due to its toxicity profile. This study aimed to evaluate the effectiveness and safety of the LP regimen in a real-world setting and to investigate the impact of the lenvatinib starting dose on survival outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a retrospective analysis of 33 patients with advanced or recurrent endometrial cancer treated with the LP regimen at Kansai Medical University Hospital between February 2022 and August 2025. We evaluated the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Prognostic factors for survival were identified using the Kaplan-Meier method and Cox proportional hazards models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The median follow-up was 27.6 months. The ORR was 48.5%, with a median PFS of 6.7 months and a median OS of 21.7 months. Multivariate analysis revealed distinct prognostic factors for PFS and OS. A lenvatinib starting dose of 20 mg was the sole independent predictor for improved PFS (aHR for \u0026lt;20 mg: 5.83; p=0.003). In contrast, the presence of peritoneal metastasis was the sole independent predictor for worse OS (aHR: 7.51; p=0.005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In this real-world analysis, LP therapy was effective and tolerable. We identified distinct prognostic factors for short-term and long-term survival: a 20 mg lenvatinib starting dose was critical for improving PFS. In contrast, peritoneal metastasis was identified as a strong independent predictor of poor OS even in the LP therapy cohort, suggesting a need for further therapeutic development for patients with peritoneal metastasis.\u003c/p\u003e","manuscriptTitle":"Impact of Peritoneal Metastasis on Overall Survival in Patients with Advanced Endometrial Cancer Receiving Lenvatinib plus Pembrolizumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 06:45:38","doi":"10.21203/rs.3.rs-8137646/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-16T13:25:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-10T06:28:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-07T06:37:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170081062941982273866323249862912078698","date":"2025-12-01T23:05:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220593245103405700632356682935590091916","date":"2025-12-01T22:16:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-01T10:11:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-18T11:08:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-18T11:06:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2025-11-17T16:12:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"03443346-270f-40cb-aa5a-10696e134407","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-12T09:27:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 06:45:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8137646","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8137646","identity":"rs-8137646","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}