Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer: A retrospective real-world study

Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer: A retrospective real-world study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer: A retrospective real-world study Qi Ding, Yongshuai Wang, Gang Wang, Ruipeng Song, Yubei Sun This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7101973/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immunotherapy in combination with gemcitabine-based chemotherapy has become the standard first-line treatment for advanced biliary tract cancer (BTC). Some small sample studies have shown that immune checkpoint inhibitors (ICIs), when used in combination with lenvatinib and chemotherapy as a first-line therapy, exhibit high BTC antitumour activity. However, real-world data showing the efficacy and safety of durvalumab combined with chemotherapy and lenvatinib are lacking. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib for advanced BTC therapy. Methods We conducted a retrospective analysis of the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib in advanced BTC cancer patients between January 2021 and June 2023. The study endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results Thirty patients with advanced BTC were included in this study, among which 14 (46.7%) received durvalumab combined with lenvatinib plus chemotherapy. For all the patients, the median OS was 11.82 months, the median PFS was 6.23 months, the ORR was 43.4%, and the DCR was 76.7%. Patients who received lenvatinib treatment had a longer median PFS (7.42 vs. 4.98 months, P = 0.875) than did those in the non-lenvatinib group. However, the median OS was shorter in patients in the lenvatinib treatment group (10.60 vs. 14.35 months, P = 0.759). The ORR and DCR in patients receiving lenvatinib were 57.1% and 92.9%, respectively. However, in patients that did not receive lenvatinib, the ORR and DCR were only 31.2% and 62.5%, respectively. All patients experienced adverse events (AEs), but the inclusion of lenvatinib did not increase the risk of AEs. The data are still being updated. Conclusion Durvalumab and gemcitabine-based chemotherapy with or without lenvatinib has been shown to be effective and safe in routine practice. The addition of lenvatinib may improve only the DCR, ORR, and PFS but may not prolong OS. lenvatinib durvalumab gemcitabine-based chemotherapy biliary tract cancer Figures Figure 1 Figure 2 Figure 3 Introduction Biliary tract cancers (BTCs) are an aggressive and heterogeneous group of malignant tumours that originate from the biliary tree. BTCs can be classified as cholangiocarcinoma (CCA) and gallbladder cancer (GBC), the former of which can be further subdivided into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA) [ 1 ] . Although BTCs account for < 1% of all human cancers, the incidence of BTC, especially CCA, has been increasing annually [ 2 ] . Surgical resection is a suitable treatment option for early BTC, but most patients have unresectable tumours or distant metastasis at the time of diagnosis, resulting in a five-year survival rate of only 2%. Although the combination of gemcitabine plus cisplatin (GC) has been the standard palliative chemotherapy for patients with advanced BTC, the objective response rate (ORR) to this treatment is low [ 3 ] . In addition, due to gastrointestinal reactions caused by cisplatin, such as nausea and vomiting, some patients cannot tolerate this regimen. Gemcitabine plus S-1 (GS) reportedly has efficacy that is equal to or better than that of GC along with an acceptable toxicity profile and does not require hydration [ 4 ] . In addition, the combination of gemcitabine plus oxaliplatin (GEMOX) may be a preferred regimen for the treatment of advanced BTC, with a median overall survival (OS) of 9.5 months [ 5 ] . Gemcitabine alone or gemcitabine–oxaliplatin can be considered for patients who are anticipated to poorly tolerate gemcitabine–cisplatin [ 1 ] . However, the overall effect of chemotherapy alone is limited, and few treatment options are available once a patient develops resistance or the disease progresses. Since its advent, immunotherapy has become the first-line standard treatment for advanced BTC. The TOPAZ-1 study demonstrated improvements in OS, ORR and progression-free survival (PFS) with the addition of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) durvalumab to the cisplatin–gemcitabine regimen [ 6 ] . Recently, durvalumab plus gemcitabine and cisplatin was proven to be a first-line treatment by the Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN) in the TOPAZ-1 study. However, a subset of patients who do not benefit from the combination of immunotherapy and chemotherapy remains. In recent years, targeted combination therapy has also become important in anticancer treatment. Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1–3, platelet-derived growth factor receptor (PDGFR) alpha, and fibroblast growth factor receptors (FGFRs) 1–4, and rearranged during transfection (RET) [ 7 ] . Lenvatinib combined with ICIs has been studied in the treatment of various malignant tumours, and this combination has been recommended for patients with endometrial carcinoma who have disease progression after systemic therapy that is not characterized by high microsatellite instability or mismatch repair deficiency and advanced renal cell carcinoma [ 8 , 9 ] . Zhou et al. conducted a phase II clinical trial and demonstrated that toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. The median PFS in this study was 10.0 months and the median OS was 22.5 months, with an ORR of 80% [ 10 ] In addition, some retrospective studies have proven that lenvatinib combined with programmed cell death protein 1 (PD-1)/PD-L1 inhibitors and GEMOX chemotherapy is an effective and tolerable treatment option in patients with advanced BTC [ 11 , 12 ] . Although these studies showed that advanced BTC patients can benefit from immunotherapy combined with targeted therapy and systemic chemotherapy, none of the existing studies have specifically investigated whether adding or omitting lenvatinib to the current standard immunotherapy (durvalumab) and chemotherapy regimen provides incremental clinical benefits. Considering that durvalumab, lenvatinib and chemotherapy have different antitumour mechanisms, combining these three compounds may produce a promising synergistic effect on advanced BTC. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib for advanced BTC in the real world. Materials and methods Study population Between January 2021 and June 2023, patients with advanced BTC who received either durvalumab and gemcitabine-based chemotherapy with or without lenvatinib at The First Affiliated Hospital of University of Science and Technology of China (USTC), were enrolled in this study. The primary eligibility criteria included histologically confirmed BTC and at least one measurable tumour lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria [ 13 ] . A total of 40 patients were screened and enrolled, among which 6 patients received only one cycle of combination treatment, and 4 patients were lost to follow-up (Fig. 1 ). Finally, 30 patients were enrolled in the study. All patients signed the informed consent form. The baseline characteristics of the 30 patients are summarized in Table 1 . Demographics, Eastern Cooperative Oncology Group (ECOG) score, tumour node metastasis classification (TNM) stage, Child‒Pugh score, tumour subtype, cancer antigen 199 (CA19-9) levels, hepatitis B virus (HBV) infection status, site of metastases, differentiated histology and chemotherapy regimens were compiled and recorded. The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (no. 2024-RE-281). Table 1 Patient baseline characteristics ITT (n = 30) durvalumab + chemo (n = 16) durvalumab + lenvatinib+ chemo (n = 14) P Age(years) 61.5 ± 9 62 ± 9 61 ± 9 0.552 Sex 0.696 Male 16 (53.3%) 8 (50.0%) 8 (58.1%) Female 14 (46.7%) 8 (50.0%) 6 (41.9%) ECOG > 0.999 0 2 (6.7%) 1 (6.2%) 1 (7.1%) 1 28 (93.3%) 15 (93.8%) 13 (92.9%) TNM stage 0.186 II 5 (16.7%) 1 (6.2%) 4 (28.6%) III 12 (40.0%) 6 (37.5%) 6 (41.8%) IV 13 (43.3%) 9 (56.3%) 4 (28.6%) Child-Pugh > 0.999 A 27 (90.0%) 14 (87.5%) 13 (92.9%) B 3 (10.0%) 2 (12.5%) 1 (7.1%) Type > 0.999 ICC 17 (56.7%) 9 (56.3%) 8 (58.1%) ECC 3 (10.0%) 2 (12.5%) 1 (7.1%) GBC 10 (33.3%) 5 (31.2%) 5 (35.8%) CA19−9(U/ml) 0.232 ≤ 200 18 (60.0%) 8 (50%) 10 (71.4%) < 200 12 (40.0%) 8 (50%) 4 (28.6%) HBV < 0.001 positive 13 (43.3%) 2 (12.5%) 11 (78.5%) negative 17 (56.7%) 14 (87.5%) 3 (21.5%) Metastasis Lymph node 18 (60.0%) 9 (56.3%) 9 (64.3%) 0.654 Liver 16 (53.3%) 8 (50.0%) 8 (57.1%) 0.696 Bone 4 (13.3%) 2 (12.5%) 2 (14.3%) > 0.999 Peritoneum 4 (6.7%) 2 (6.3%) 2 (7.1%) > 0.999 Others 8 (30.0%) 5 (31.3%) 3 (28.6%) 0.689 Chemotherapy regimens 0.189 GC 21 (70.0%) 12 (75.0%) 9 (64.3%) GS 3 (10.0%) 0 (0.0%) 3 (21.4%) Gemcitabine 4 (13.3%) 2 (12.5%) 2 (14.3%) GEMOX 2 (6.7%) 2 (12.5%) 0 (0.0%) Note: Values are presented as the mean ± SD or number (percentage). ITT, intenion-to treat population; ECOG, Eastern Cooperative Oncology Group; TNM, tumour node metastasis classification; ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; CA19−9, cancer antigen 19−9; HBV, hepatitis B virus; GC, gemcitabine/cisplatin; GS, gemcitabine plus S−1; GEMOX, gemcitabine and oxaliplatin. Treatment Durvalumab is administered via a fixed dose of 1000 mg intravenously (IV) every 3 weeks. Lenvatinib was administered orally at a dose of 12 mg (for patients with a body weight ≥ 60 kg) or 8 mg (for patients with a body weight < 60 kg) once a day. The gemcitabine-based chemotherapies were repeated every 3 weeks and included gemcitabine and cisplatin (1000 mg/m 2 gemcitabine and 25 mg/m 2 cisplatin were infused on days 1 and 8), gemcitabine and S-1 (1000 mg/m 2 gemcitabine on days 1 and 8 and S-1 administered orally twice a day for 14 consecutive days dosed according to body surface area (BSA) as follows: BSA < 1.25 m 2 , 80 mg/m 2 ; 1.25 m 2 ≤ BSA < 1.5 m 2 , 100 mg/day; and BSA ≥ 1.5 m 2 , 120 mg/day), and GEMOX (1000 mg/m 2 gemcitabine on days 1 and 8 and 100 mg/m 2 oxaliplatin on day 1). Cisplatin and oxaliplatin were limited to eight cycles; there was no limit to the number of cycles of gemcitabine. Immunotherapy with or without targeted therapy was continued until disease progression or unacceptable toxicity occurred. Outcome assessment and follow-up The clinical objective response was measured using the RECIST v1.1 criteria and evaluated by professional radiologists at the First Affiliated Hospital of USTC [ 13 ] . To assess the tumour growth rate and treatment response, computed tomography (CT)/magnetic resonance imaging (MRI) or positron emission tomography (PET)-CT imaging was performed regularly. The study endpoints were PFS, OS, ORR, disease control rate (DCR), and safety. Safety assessments and grading were recorded from the electronic medical records of patients or collected by the investigators using the Common Terminology Criteria for Adverse Events (version 5.0) as a reference. Subgroup analyses were also performed. Patient follow-ups occurred every 3 months, with the most recent data from September 23, 2024. Statistical analysis Statistical analyses were performed using SPSS v27.0 software (IBM, Armonk, NY, USA) and R software (version 4.2.2). In this study, data up to September 23, 2024 were analysed and were used to generate a summary of baseline characteristics, treatment outcomes and adverse events (AEs). The molecular marker analyses included treated patients whose data were available as of September 23, 2024. PFS and OS were estimated using the Kaplan–Meier method, and the comparisons were performed using the log-rank test. Normally distributed data are expressed as the means ± standard deviations, and an independent sample t test was used for comparisons between groups. Count data are presented as the number of cases (percentages), and comparisons between groups were performed by the chi-square test or Fisher’s exact test. The hazard ratio (HR) and 95% confidence interval (CI) were calculated. A value of P < 0.05 was considered to indicate a significant difference. Results Baseline characteristics of the 30 patients A total of 30 patients with BTC who received durvalumab and gemcitabine-based chemotherapy with or without lenvatinib were included in the study. Fourteen (46.7%) patients had received durvalumab combined with lenvatinib plus chemotherapy. The baseline characteristics and demographics of the 30 patients are summarized in Table 1 . Among the 30 patients with advanced BTC, the ages ranged from 43 to 77 years (mean, 61.5 years), and 53.3% of the patients (16/30) were male. A total of 28 (93.3%) patients had an ECOG performance status of 1, ninety percent of the patients (27/30) had Child‒Pugh stage A disease, and sixty percent (18/30) of the patients had elevated CA19-9 levels (≥ 200 U/mL). Thirteen (43.3%) patients had a history of hepatitis B infection. There were 17 (56.7%) patients with ICC, 3 (10.0%) with extrahepatic cholangiocarcinoma (ECC), and 10 (33.3%) with GBC. In total, 13 (43.3%) patients had TNM stage IV disease. The metastatic distribution among patients was as follows: lymph node metastasis, 18 patients; liver metastasis, 16 patients; bone metastasis, 4 patients; and peritoneal metastasis, 4 patients. Some patients presented with multiple metastatic sites. The patients had received different types of chemotherapy. Among the patients in the durvalumab and lenvatinib groups, 9 patients received gemcitabine and cisplatin, 2 patients received gemcitabine alone, and 3 patients received gemcitabine and S-1. Among patients in the durvalumab group, 12 patients received gemcitabine and cisplatin, 2 patinets received gemcitabine alone, and 2 patients received GEMOX. Treatment and efficacy Until the last follow-up date, only one patient had no disease progression and was still receiving maintenance treatment. All patients underwent complete radiological evaluation (Table 2 ). Overall, 17 (56.7%) patients had a decrease in the target tumour size from baseline. Thirteen (43.4%) patients achieved an objective response. Among these 13 patients, 2 (3.5%) achieved a complete response (CR), and 11 (36.7%) achieved a partial response (PR). In total, 10 (33.3%) patients exhibited stable disease (SD), and seven (23.3%) patients exhibited progressive disease (PD). Therefore, the total ORR was 43.4% (95% CI: 25.4–62.2), and the DCR was 76.7% (95% CI: 60.6–92.7). The survival outcomes of the enrolled patients were also investigated. For all the patients, the median PFS was 6.23 months (95% CI: 4.6–8.43) (Fig. 2 A) and the median OS was 11.82 months (95% CI: 8.76 - NA) (Fig. 3 A). Table 2 Confirmed anti-tumour activity (evaluated by RECIST 1.1) Tumor response,n(%) ITT (n = 30) durvalumab + chemo (n = 16) durvalumab + lenvatinib + chemo (n = 14) P CR 2 (6.7%) 1 (6.2%) 1 (7.1%) - PR 11 (36.7%) 4 (25.0%) 7 (50.0%) - SD 10 (33.3%) 5 (31.3%) 5 (35.8%) - PD 7 (23.3%) 6 (37.5%) 1 (7.1%) - ORR (95% CI) 43.4% (24.5–62.2) 31.2% (5.7–56.8) 57.1% (27.5–86.8) 0.269 DCR (95% CI) 76.7% (60.6–92.7) 62.5% (35.9–89.1) 92.9% (77.4−108.3) 0.086 Note: Values are presented as percentage. RECIST, Response Evaluation Criteria in Solid Tumors; ITT, intenion-to treat population; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response; DCR, disease control rate; CI, confidence interval. The baseline characteristics of the lenvatinib treatment group compared with the non-lenvatinib treatment group are summarized in Table 1 , and no significant differences in baseline characteristics, except for HBV infection status, were found between the two groups. When patients were stratified by treatment method, Kaplan–Meier survival curves and log-rank tests revealed that patients who received lenvatinib treatment had longer median PFS (7.42 vs. 4.98 months, P = 0.875; Fig. 2 B) than did those in the non-lenvatinib treatment group; however, the difference was not significant. Nevertheless, the median OS was shorter in patients in the lenvatinib treatment group (10.60 vs. 14.35 months, P = 0.759; Fig. 3 B). The ORR and DCR in patients receiving lenvatinib were 57.1% and 92.9%, respectively. However, the ORR and DCR of patients who did not receive lenvatinib were only 31.2% and 62.5%, respectively (Table 2 ). Safety AEs were reported in all 30 (100%) patients throughout treatment (Table 3 ). Most AEs were mild, well tolerated, and controlled during combination treatment. The most common AEs (of any grade) were anaemia (76.7%), thrombocytopenia (56.6%), and transaminitis (53.3%). The addition of lenvatinib did not increase the risk of AEs. Notably, two patients developed acute cerebral infarction after receiving just one cycle of combination therapy with durvalumab, lenvatinib, and chemotherapy, leading to treatment discontinuation. Table 3 Summary of the AEs in patients. AEs,n(%) ITT (n = 30) durvalumab+ chemo (n = 16) durvalumab + lenvatinib + chemo(n = 14) P Anemia 23 (76.7%) 13 (81.3%) 10 (71.4%) 0.675 Thrombocytopenia 17 (56.6%) 12 (75.0%) 5 (35.7%) 0.030 Neutropenia 13 (43.3%) 8 (50.0%) 5 (35.7%) 0.431 Elevated ALT 12 (40%) 10 (62.5%) 2 (14.3%) 0.007 Elevates AST 16 (53.3%) 10 (62.5%) 6 (42.9%) 0.282 Creatinine elevation 4 (13.3%) 3 (18.8%) 1 (7.1%) 0.602 Nausea 11 (36.7%) 4 (25%) 7 (50.0%) 0.156 Pruritus 4 (13.3%) 2 (12.5%) 2 (14.3%) > 0.999 Constipation 3 (10%) 1 (6.3%) 2 (14.3%) 0.586 Rash 3 (10%) 2 (12.5%) 1 (7.1%) > 0.999 Note: Values are presented as percentage. AEs, adverse events; ITT, intenion-to treat population; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Discussion BTC is a highly malignant and lethal cancer type with a low response rate and a poor prognosis. This is the first retrospective analysis of the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib in advanced BTC patients and represents a potentially shifting approach to improving the response to immunotherapy. In particular, the combination of durvalumab plus gemcitabine-based chemotherapy with lenvatinib is promising. Patients who received durvalumab plus gemcitabine-based chemotherapy with lenvatinib had longer PFS (7.42 vs. 4.98 months) than patients who received durvalumab plus gemcitabine-based chemotherapy without lenvatinib did. However, no significant improvement in OS was observed with lenvatinib versus without lenvatinib (10.60 vs. 14.35 months, P = 0.759). In addition, this study demonstrated that durvalumab combined with gemcitabine-based chemotherapy and lenvatinib was well tolerated. In this study, the total ORR was 43.4%, which was higher than that reported in the TOPAZ-1 study, with an ORR of 26.7% [ 6 ] . Moreover, patients receiving durvalumab plus lenvatinib with gemcitabine-based chemotherapy achieved an ORR of approximately 57.1% and a DCR of approximately 92.9%. In the Leap-005 study, the ORR of lenvatinib plus pembrolizumab treatment reached only 10%, and the DCR was 68% [ 14 ] . In a real-world cohort study that included 103 patients who received PD-1 blockade plus lenvatinib for advanced intrahepatic cholangiocarcinoma, the ORR was 18.4%, and the DCR was 80.6% [ 15 ] . Recently, a phase II study in which patients received toripalimab combined with lenvatinib and GEMOX for ICC exhibited an ORR of 80.0% and a DCR of 93.3% [ 10 ] . A growing body of evidence suggests that ICIs can improve treatment efficacy in advanced BTC patients. Moreover, the combination of lenvatinib and ICIs may further improve treatment efficacy. Lenvatinib has been demonstrated to have immunomodulatory activity in in vivo and in vitro studies, and the antitumour activity of lenvatinib and can be enhanced by combination therapy with ICIs [ 16 ] . Targeted therapy can reduce the immunosuppressive effects mediated by vascular endothelial growth factor (VEGF) in tumours and their microenvironments. Reversing VEGF-related immunosuppression and promoting T-cell infiltration into tumours enhances the efficacy of anti-PD-1 and anti-PD-L1 therapies. Lenvatinib can eliminate cancer cells via its direct antitumour activity and by inducing immunogenic cell death while also reducing the number of cells targeted and killed by immune cells, thereby improving immunotherapy effectiveness [ 17 ] . Indeed, lenvatinib strongly inhibits VEGFRs and FGFRs, both of which play crucial immunosuppressive roles in immune responses [ 18 ] . However, the PFS and OS reported in our study were lower than the median PFS and OS reported in the TOPAZ-1 trial [ 6 ] and in similar real-world studies [ 19 , 20 ] . The possible reasons for this discrepancy may include the following. First, durvalumab dose reduction: owing to China's earlier drug donation policy, the dose of durvalumab in this study was 1000 mg, which is lower than the approved label dose (1500 mg). Second, in real-world settings in China, patients generally have worse baseline characteristics, with ECOG 1 status accounting for the vast majority (93.3%), whereas in the TOPAZ-1 study [ 6 ] , only approximately half (50.9%) of patients had an ECOG PS score of 1. Finally, the chemotherapy regimen in our study was less intensive than that in TOPAZ-1 [ 6 ] , with only two-thirds of patients receiving the combination of gemcitabine plus cisplatin. These factors may have collectively contributed to the inferior survival outcomes observed in our study. Moreover, in our subgroup analysis, the addition of lenvatinib improved only the ORR and DCR and modestly prolonged PFS, but these changes failed to translate into an improvement in OS. This finding aligns with the results of the LEAP-011 trial, which compared pembrolizumab plus lenvatinib with pembrolizumab monotherapy as a first-line treatment for advanced urothelial carcinoma [ 21 ] . These data suggest that while lenvatinib combination therapy may enhance early efficacy markers (ORR and DCR) and marginally prolong PFS, it does not confer a survival advantage, which is consistent with our real-world findings. In our study, although nearly all patients experienced AEs of varying severity, no fatal AEs were observed. Among all patients, the most common adverse reactions were myelosuppression, manifested as anaemia (76.7%), and thrombocytopenia (56.6%), which are likely associated with the chemotherapeutic agents [ 22 ] . The addition of lenvatinib did not significantly increase treatment-related AEs in patients, which is consistent with findings from other studies [ 23 , 24 ] . However, notably, two patients receiving combination therapy (immunotherapy plus targeted therapy and chemotherapy) developed acute cerebral thrombosis after just one treatment cycle, leading to treatment discontinuation. Although lenvatinib, an antiangiogenic agent, is associated with a relatively low risk of thromboembolic events [ 25 ] , this combination regimen still requires rigorous screening and close monitoring for thrombosis risk. This study has several limitations. First, this was a single-centre retrospective study with a small sample size; therefore, the results should be interpreted with caution. Larger scale, multicentre prospective studies are needed to validate these findings in the future. Second, the chemotherapy regimens were not uniform, although all were standard treatments, and dedicated prospective studies are needed to compare outcomes among different drug regimens. Third, our study population exclusively comprised Chinese patients, and the findings may not be directly generalizable to Western cohorts. Despite these limitations, as a real-world study, our findings provide valuable insights for designing future clinical trials and informing treatment strategies in clinical practice. Conclusions Durvalumab and gemcitabine-based chemotherapy with or without lenvatinib has been shown to be effective and safe in routine practice. However, the addition of lenvatinib may improve only the DCR, ORR, and PFS but may not prolong OS. Hence, larger prospective cohort studies need to be conducted to confirm the necessity and feasibility of adding lenvatinib to ICI and chemotherapy regimens. Abbreviations BTC, biliary tract cancer; ICIs, immune checkpoint inhibitors; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; DCR, disease control rate; HR, hazard ratio; CI, confidence interval; CCA, cholangiocarcinoma; GBC, gallbladder cancer; ICC, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma; dCCA, distal cholangiocarcinoma; GC, gemcitabine/cisplatin; GS, gemcitabine plus S-1; GEMOX, gemcitabine plus oxaliplatin; PD-L1, programmed death-ligand 1; FDA, Food and Drug Administraion; NCCN, National Comprehensive Cancer Network; VEGFRs, vascular endothelial growth factor receptors; PDGFR, platelet-derived growth factor receptor; FGFRs, fibroblast growth factor receptors; RET, rearranged during transfection; PD-1, programmed cell death protein 1; USTC, University of Science and Technology of China; RECIST, Response Evaluation Criteria in Solid Tumors; ECOG, Eastern Cooperative Oncology Group; TNM, tumor node metastasisclassification; CA19-9, cancer antigen 19-9; IV, intravenously; BSA, body surface area; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; ECC, extrahepatic cholangiocarcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; HBV, hepatitis B virus; AEs, adverse events; VEGF, vascular endothelial growth factor. Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (no. 2024-RE-281) and accordance with the Declaration of Helsinki. All patients signed the informed consent form. Consent for publication Not applicable Data Availability Statement The dataset generated during the present study can be obtained from the corresponding author with a reasonable request. Conflict of interest disclosure The authors declare no financial interests or personal relationships which may be considered as potential competing interests in this work. Funding This work was supported by the National Natural Science Foundation of China (No. 82272700). Authors' contributions Conception and design: QD, YS; Administrative support: GW, RS, YS; Provision of study materials or patients: QD; Collection and assembly of data: QD; Data analysis and interpretation: QD, YW; Manuscript writing: All authors; Final approval of manuscript: All authors. Acknowledgment We thank all the patients and their families for their participation and thank Ms. Shanshan Chen from AstraZeneca medical affairs for her contribution in terms of material support. References Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127–40. 10.1016/j.annonc.2022.10.506 . Edeline J, Lamarca A. Practicalities accessing precision medicine in biliary tract cancer. Lancet Gastroenterol Hepatol. 2023;8(1):5–6. 10.1016/S2468-1253(22)00352-1 . Marin JJG, Prete MG, Lamarca A, et al. Correction: Current and novel therapeutic opportunities for systemic therapy in biliary cancer. 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Signal Transduct Target Ther. 2023;8(1):106. 10.1038/s41392-023-01317-7 . Published 2023 Mar 17. Zhu C, Xue J, Wang Y et al. Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer. Front Immunol. 2023;14:1109292. Published 2023 Jan 18. 10.3389/fimmu.2023.1109292 Wang Y, Zhang N, Xue J, et al. Safety and feasibility of toripalimab plus lenvatinib with or without radiotherapy in advanced BTC. Front Immunol. 2023;14:1084843. 10.3389/fimmu.2023.1084843 . Published 2023 Jan 17. Schwartz LH, Seymour L, Litière S, et al. RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 2016;62:138–45. 10.1016/j.ejca.2016.03.082 . Lenvatinib plus pembrolizumab. for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study. Chao J, Wang S, Wang H, et al. Real-world cohort study of PD-1 blockade plus lenvatinib for advanced intrahepatic cholangiocarcinoma: effectiveness, safety, and biomarker analysis. Cancer Immunol Immunother. 2023;72(11):3717–26. 10.1007/s00262-023-03523-2 . Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993–4002. 10.1111/cas.13806 . Fennell DA. Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma. J Thorac Oncol. 2018;13(10):1436–1437. 10.1016/j.jtho.2018.07.007 . PMID: 30244849. Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, DiSilvestro PA, Rubin SC, Martin LP, Davidson SA, Huh WK, O'Malley DM, Boente MP, Michael H, Monk BJ. Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. N Engl J Med. 2016;374(8):738–48. 10.1056/NEJMoa1505067 . PMID: 26933849; PMCID: PMC5081077. Rimini M, Masi G, Lonardi S, Nichetti F, Pressiani T, Lavacchi D, Jessica L, Giordano G, Scartozzi M, Tamburini E, Pastorino A, Rapposelli IG, Daniele B, Martinelli E, Garajova I, Aprile G, Schirripa M, Formica V, Salani F, Winchler C, Bergamo F, Balsano R, Gusmaroli E, Lorenzo A, Landriscina M, Pretta A, Toma I, Pirrone C, Diana A, Leone F, Brunetti O, Brandi G, Garattini SK, Satolli MA, Rossari F, Fornaro L, Niger M, Zanuso V, De Rosa A, Ratti F, Aldrighetti L, De Braud F, Foti S, Rizzato MD, Vivaldi C, Stefano C, Rimassa L, Antonuzzo L, Casadei-Gardini A. Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study. Target Oncol. 2024;19(3):359–70. 10.1007/s11523-024-01060-1 . Epub 2024 May 1. PMID: 38691295. Mitzlaff K, Kirstein MM, Müller C, Venerito M, Olkus A, Dill MT, Weinmann A, Kocheise L, Busch A, Schulze K, Allo G, Waldschmidt DT, Barsch M, Bengsch B, Quante M, Gonzalez-Carmona MA, Himmelsbach V, Finkelmeier F, Kloeckner R, Schirmacher P, Marquardt JU, Zimpel C. Efficacy, safety and differential outcomes of immune-chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort. United Eur Gastroenterol J. 2024;12(9):1230–42. 10.1002/ueg2.12656 . Epub 2024 Sep 20. PMID: 39301763; PMCID: PMC11578849. Matsubara N, de Wit R, Balar AV, Siefker-Radtke AO, Zolnierek J, Csoszi T, Shin SJ, Park SH, Atduev V, Gumus M, Su YL, Karaca SB, Cutuli HJ, Sendur MAN, Shen L, O'Hara K, Okpara CE, Franco S, Moreno BH, Grivas P, Loriot Y. Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Eur Urol. 2024;85(3):229–38. Epub 2023 Sep 29. PMID: 37778952. Chen X, Wu X, Wu H, Gu Y, Shao Y, Shao Q, Zhu F, Li X, Qian X, Hu J, Zhao F, Mao W, Sun J, Wang J, Han G, Li C, Xia Y, Seesaha PK, Zhu D, Li H, Zhang J, Wang G, Wang X, Li X, Shu Y. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase II trial. J Immunother Cancer. 2020;8(2):e001240. 10.1136/jitc-2020-001240 . PMID: 33172881; PMCID: PMC7656907. Fennell DA. Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma. J Thorac Oncol. 2018;13(10):1436–7. 10.1016/j.jtho.2018.07.007 . Zhu C, Li H, Yang X, Wang S, Wang Y, Zhang N, Wang Y, Xue J, Zhang L, Ning C, Yang X, Xun Z, Chao J, Long J, Sang X, Zhu Z, Zhao H. Efficacy, safety, and prognostic factors of PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy as first-line treatment in advanced intrahepatic cholangiocarcinoma: a multicenter real-world study. Cancer Immunol Immunother. 2023;72(9):2949–60. 10.1007/s00262-023-03466-8 . Epub 2023 May 29. PMID: 37247023; PMCID: PMC10412480. Denaro N, Garrone O, Ghidini M, Tomasello G, Hahne JC, Merlano MC, Locati LD. Thrombotic Events during Lenvatinib Treatment: A Single Institution Experience. J Clin Med. 2022;11(24):7312. 10.3390/jcm11247312 . PMID: 36555928; PMCID: PMC9785927. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7101973","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":501904395,"identity":"f2e8aa2e-c01a-47ad-b9df-a199b27d47ba","order_by":0,"name":"Qi Ding","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC, University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Ding","suffix":""},{"id":501904396,"identity":"d79601c4-06a8-47c1-93ed-d12bee8da6e0","order_by":1,"name":"Yongshuai Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC, University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Yongshuai","middleName":"","lastName":"Wang","suffix":""},{"id":501904397,"identity":"1f431826-4b68-4301-9fd8-2b8b603b5da8","order_by":2,"name":"Gang Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC, University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Wang","suffix":""},{"id":501904398,"identity":"673c60f3-3595-41fe-a58f-b3b1ed21b44a","order_by":3,"name":"Ruipeng Song","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC, University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Ruipeng","middleName":"","lastName":"Song","suffix":""},{"id":501904399,"identity":"bef60f09-80a4-47e3-8ee0-3f321ae40776","order_by":4,"name":"Yubei Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYLACxgYGHn4Em1gtkg0Q1cRrYTA4QKwW+Rm5x6R5d9jIGN9If/7gB4ON7IYDzM8e4NNicCMvTZr3TBqP2Y0cw8YehjTjDQfYzA3wapHIMZPmbTsM0sLYzMBwOHHDAR42CfwOA2v5z2M8I/0hUMt/wloYboC1HOAxkEgwBGo5QFiLwZk3xpZzzyTzSJx5YzizxyDZeOZhNjP8DmvPMbzxdoedPX97+oMPPyrsZPuONz/D7zAGBhYkBaCgYiagHqTkA2E1o2AUjIJRMKIBAKSkRpORP5dPAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of USTC, University of Science and Technology of China","correspondingAuthor":true,"prefix":"","firstName":"Yubei","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2025-07-11 13:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7101973/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7101973/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89451055,"identity":"ea297ee1-4793-421f-86d1-09cb2f1514ad","added_by":"auto","created_at":"2025-08-20 06:15:11","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":202553,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart of the study.\u003c/p\u003e\n\u003cp\u003eNote: BTC, biliary tract cancer.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7101973/v1/b5d08d4471de1986e867ce31.jpg"},{"id":89451052,"identity":"04e19c2a-6b83-4bee-935a-492ff16746dd","added_by":"auto","created_at":"2025-08-20 06:15:11","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":602665,"visible":true,"origin":"","legend":"\u003cp\u003ePFSof the intenion-to treat population(A) and subgroups(B).\u003c/p\u003e\n\u003cp\u003eNote: PFS, progression-free survival; ITT, intenion-to treat population.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7101973/v1/ab9b77215e8ec17e46a8bf6a.jpg"},{"id":89451648,"identity":"c69a828d-3691-459c-af0f-0fb48359a1ee","added_by":"auto","created_at":"2025-08-20 06:23:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":582944,"visible":true,"origin":"","legend":"\u003cp\u003eOS of the intenion-to treat population(A) and subgroups(B).\u003c/p\u003e\n\u003cp\u003eNote: OS, overall survival; ITT, intenion-to treat population.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7101973/v1/0f99e9f984d62d2d3473a3ee.jpg"},{"id":92937073,"identity":"754c5ea9-8cfe-4a86-8b9b-1d3486eec7c2","added_by":"auto","created_at":"2025-10-07 10:24:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2198558,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7101973/v1/e504c6e4-94f7-47e1-bef1-7f548ebb828c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer: A retrospective real-world study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBiliary tract cancers (BTCs) are an aggressive and heterogeneous group of malignant tumours that originate from the biliary tree. BTCs can be classified as cholangiocarcinoma (CCA) and gallbladder cancer (GBC), the former of which can be further subdivided into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA)\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Although BTCs account for \u0026lt;\u0026thinsp;1% of all human cancers, the incidence of BTC, especially CCA, has been increasing annually\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Surgical resection is a suitable treatment option for early BTC, but most patients have unresectable tumours or distant metastasis at the time of diagnosis, resulting in a five-year survival rate of only 2%.\u003c/p\u003e\u003cp\u003eAlthough the combination of gemcitabine plus cisplatin (GC) has been the standard palliative chemotherapy for patients with advanced BTC, the objective response rate (ORR) to this treatment is low\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In addition, due to gastrointestinal reactions caused by cisplatin, such as nausea and vomiting, some patients cannot tolerate this regimen. Gemcitabine plus S-1 (GS) reportedly has efficacy that is equal to or better than that of GC along with an acceptable toxicity profile and does not require hydration\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In addition, the combination of gemcitabine plus oxaliplatin (GEMOX) may be a preferred regimen for the treatment of advanced BTC, with a median overall survival (OS) of 9.5 months\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Gemcitabine alone or gemcitabine\u0026ndash;oxaliplatin can be considered for patients who are anticipated to poorly tolerate gemcitabine\u0026ndash;cisplatin\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. However, the overall effect of chemotherapy alone is limited, and few treatment options are available once a patient develops resistance or the disease progresses.\u003c/p\u003e\u003cp\u003eSince its advent, immunotherapy has become the first-line standard treatment for advanced BTC. The TOPAZ-1 study demonstrated improvements in OS, ORR and progression-free survival (PFS) with the addition of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) durvalumab to the cisplatin\u0026ndash;gemcitabine regimen\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Recently, durvalumab plus gemcitabine and cisplatin was proven to be a first-line treatment by the Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN) in the TOPAZ-1 study. However, a subset of patients who do not benefit from the combination of immunotherapy and chemotherapy remains.\u003c/p\u003e\u003cp\u003eIn recent years, targeted combination therapy has also become important in anticancer treatment. Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1\u0026ndash;3, platelet-derived growth factor receptor (PDGFR) alpha, and fibroblast growth factor receptors (FGFRs) 1\u0026ndash;4, and rearranged during transfection (RET)\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Lenvatinib combined with ICIs has been studied in the treatment of various malignant tumours, and this combination has been recommended for patients with endometrial carcinoma who have disease progression after systemic therapy that is not characterized by high microsatellite instability or mismatch repair deficiency and advanced renal cell carcinoma\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Zhou et al. conducted a phase II clinical trial and demonstrated that toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. The median PFS in this study was 10.0 months and the median OS was 22.5 months, with an ORR of 80%\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e In addition, some retrospective studies have proven that lenvatinib combined with programmed cell death protein 1 (PD-1)/PD-L1 inhibitors and GEMOX chemotherapy is an effective and tolerable treatment option in patients with advanced BTC\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Although these studies showed that advanced BTC patients can benefit from immunotherapy combined with targeted therapy and systemic chemotherapy, none of the existing studies have specifically investigated whether adding or omitting lenvatinib to the current standard immunotherapy (durvalumab) and chemotherapy regimen provides incremental clinical benefits.\u003c/p\u003e\u003cp\u003eConsidering that durvalumab, lenvatinib and chemotherapy have different antitumour mechanisms, combining these three compounds may produce a promising synergistic effect on advanced BTC. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib for advanced BTC in the real world.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eStudy population\u003c/p\u003e\u003cp\u003eBetween January 2021 and June 2023, patients with advanced BTC who received either durvalumab and gemcitabine-based chemotherapy with or without lenvatinib at The First Affiliated Hospital of University of Science and Technology of China (USTC), were enrolled in this study. The primary eligibility criteria included histologically confirmed BTC and at least one measurable tumour lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. A total of 40 patients were screened and enrolled, among which 6 patients received only one cycle of combination treatment, and 4 patients were lost to follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Finally, 30 patients were enrolled in the study. All patients signed the informed consent form. The baseline characteristics of the 30 patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Demographics, Eastern Cooperative Oncology Group (ECOG) score, tumour node metastasis classification (TNM) stage, Child‒Pugh score, tumour subtype, cancer antigen 199 (CA19-9) levels, hepatitis B virus (HBV) infection status, site of metastases, differentiated histology and chemotherapy regimens were compiled and recorded. The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (no. 2024-RE-281).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient baseline characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eITT\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003edurvalumab\u0026thinsp;+\u0026thinsp;chemo\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003edurvalumab\u0026thinsp;+\u0026thinsp;lenvatinib+\u003c/p\u003e\u003cp\u003echemo\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge(years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.552\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.696\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (53.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (58.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (46.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (41.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (93.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (93.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNM stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.186\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (40.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (41.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (43.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild-Pugh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (90.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (87.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (56.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (58.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (31.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (35.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCA19\u0026minus;9(U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.232\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (60.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (40.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (43.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (78.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (56.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (87.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetastasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymph node\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (60.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (64.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.654\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (53.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (57.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.696\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (13.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeritoneum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (30.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (31.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.689\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChemotherapy regimens\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.189\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (70.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (75.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (64.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGemcitabine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (13.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGEMOX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Values are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or number (percentage). ITT, intenion-to treat population; ECOG, Eastern Cooperative Oncology Group; TNM, tumour node metastasis classification; ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; CA19\u0026minus;9, cancer antigen 19\u0026minus;9; HBV, hepatitis B virus; GC, gemcitabine/cisplatin; GS, gemcitabine plus S\u0026minus;1; GEMOX, gemcitabine and oxaliplatin.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003cp\u003eDurvalumab is administered via a fixed dose of 1000 mg intravenously (IV) every 3 weeks. Lenvatinib was administered orally at a dose of 12 mg (for patients with a body weight\u0026thinsp;\u0026ge;\u0026thinsp;60 kg) or 8 mg (for patients with a body weight\u0026thinsp;\u0026lt;\u0026thinsp;60 kg) once a day. The gemcitabine-based chemotherapies were repeated every 3 weeks and included gemcitabine and cisplatin (1000 mg/m\u003csup\u003e2\u003c/sup\u003e gemcitabine and 25 mg/m\u003csup\u003e2\u003c/sup\u003e cisplatin were infused on days 1 and 8), gemcitabine and S-1 (1000 mg/m\u003csup\u003e2\u003c/sup\u003e gemcitabine on days 1 and 8 and S-1 administered orally twice a day for 14 consecutive days dosed according to body surface area (BSA) as follows: BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.25 m\u003csup\u003e2\u003c/sup\u003e, 80 mg/m\u003csup\u003e2\u003c/sup\u003e; 1.25 m\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.5 m\u003csup\u003e2\u003c/sup\u003e, 100 mg/day; and BSA\u0026thinsp;\u0026ge;\u0026thinsp;1.5 m\u003csup\u003e2\u003c/sup\u003e, 120 mg/day), and GEMOX (1000 mg/m\u003csup\u003e2\u003c/sup\u003e gemcitabine on days 1 and 8 and 100 mg/m\u003csup\u003e2\u003c/sup\u003e oxaliplatin on day 1). Cisplatin and oxaliplatin were limited to eight cycles; there was no limit to the number of cycles of gemcitabine. Immunotherapy with or without targeted therapy was continued until disease progression or unacceptable toxicity occurred.\u003c/p\u003e\u003cp\u003eOutcome assessment and follow-up\u003c/p\u003e\u003cp\u003eThe clinical objective response was measured using the RECIST v1.1 criteria and evaluated by professional radiologists at the First Affiliated Hospital of USTC\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. To assess the tumour growth rate and treatment response, computed tomography (CT)/magnetic resonance imaging (MRI) or positron emission tomography (PET)-CT imaging was performed regularly. The study endpoints were PFS, OS, ORR, disease control rate (DCR), and safety. Safety assessments and grading were recorded from the electronic medical records of patients or collected by the investigators using the Common Terminology Criteria for Adverse Events (version 5.0) as a reference. Subgroup analyses were also performed. Patient follow-ups occurred every 3 months, with the most recent data from September 23, 2024.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS v27.0 software (IBM, Armonk, NY, USA) and R software (version 4.2.2). In this study, data up to September 23, 2024 were analysed and were used to generate a summary of baseline characteristics, treatment outcomes and adverse events (AEs). The molecular marker analyses included treated patients whose data were available as of September 23, 2024. PFS and OS were estimated using the Kaplan\u0026ndash;Meier method, and the comparisons were performed using the log-rank test. Normally distributed data are expressed as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations, and an independent sample \u003cem\u003et\u003c/em\u003e test was used for comparisons between groups. Count data are presented as the number of cases (percentages), and comparisons between groups were performed by the chi-square test or Fisher\u0026rsquo;s exact test. The hazard ratio (HR) and 95% confidence interval (CI) were calculated. A value of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate a significant difference.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eBaseline characteristics of the 30 patients\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 30 patients with BTC who received durvalumab and gemcitabine-based chemotherapy with or without lenvatinib were included in the study. Fourteen (46.7%) patients had received durvalumab combined with lenvatinib plus chemotherapy. The baseline characteristics and demographics of the 30 patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among the 30 patients with advanced BTC, the ages ranged from 43 to 77 years (mean, 61.5 years), and 53.3% of the patients (16/30) were male. A total of 28 (93.3%) patients had an ECOG performance status of 1, ninety percent of the patients (27/30) had Child‒Pugh stage A disease, and sixty percent (18/30) of the patients had elevated CA19-9 levels (\u0026ge;\u0026thinsp;200 U/mL). Thirteen (43.3%) patients had a history of hepatitis B infection. There were 17 (56.7%) patients with ICC, 3 (10.0%) with extrahepatic cholangiocarcinoma (ECC), and 10 (33.3%) with GBC. In total, 13 (43.3%) patients had TNM stage IV disease. The metastatic distribution among patients was as follows: lymph node metastasis, 18 patients; liver metastasis, 16 patients; bone metastasis, 4 patients; and peritoneal metastasis, 4 patients. Some patients presented with multiple metastatic sites. The patients had received different types of chemotherapy. Among the patients in the durvalumab and lenvatinib groups, 9 patients received gemcitabine and cisplatin, 2 patients received gemcitabine alone, and 3 patients received gemcitabine and S-1. Among patients in the durvalumab group, 12 patients received gemcitabine and cisplatin, 2 patinets received gemcitabine alone, and 2 patients received GEMOX.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment and efficacy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUntil the last follow-up date, only one patient had no disease progression and was still receiving maintenance treatment. All patients underwent complete radiological evaluation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Overall, 17 (56.7%) patients had a decrease in the target tumour size from baseline. Thirteen (43.4%) patients achieved an objective response. Among these 13 patients, 2 (3.5%) achieved a complete response (CR), and 11 (36.7%) achieved a partial response (PR). In total, 10 (33.3%) patients exhibited stable disease (SD), and seven (23.3%) patients exhibited progressive disease (PD). Therefore, the total ORR was 43.4% (95% CI: 25.4\u0026ndash;62.2), and the DCR was 76.7% (95% CI: 60.6\u0026ndash;92.7). The survival outcomes of the enrolled patients were also investigated. For all the patients, the median PFS was 6.23 months (95% CI: 4.6\u0026ndash;8.43) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) and the median OS was 11.82 months (95% CI: 8.76 - NA) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eConfirmed anti-tumour activity (evaluated by RECIST 1.1)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumor response,n(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eITT\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003edurvalumab\u0026thinsp;+\u0026thinsp;chemo\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003edurvalumab\u0026thinsp;+\u0026thinsp;lenvatinib\u0026thinsp;+\u0026thinsp;chemo\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1 (6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11 (36.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (31.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5 (35.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7 (23.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eORR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43.4% (24.5\u0026ndash;62.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e31.2% (5.7\u0026ndash;56.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57.1% (27.5\u0026ndash;86.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.269\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76.7% (60.6\u0026ndash;92.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62.5% (35.9\u0026ndash;89.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e92.9% (77.4\u0026minus;108.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.086\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Values are presented as percentage. RECIST, Response Evaluation Criteria in Solid Tumors; ITT, intenion-to treat population; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response; DCR, disease control rate; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe baseline characteristics of the lenvatinib treatment group compared with the non-lenvatinib treatment group are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and no significant differences in baseline characteristics, except for HBV infection status, were found between the two groups. When patients were stratified by treatment method, Kaplan\u0026ndash;Meier survival curves and log-rank tests revealed that patients who received lenvatinib treatment had longer median PFS (7.42 vs. 4.98 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.875; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) than did those in the non-lenvatinib treatment group; however, the difference was not significant. Nevertheless, the median OS was shorter in patients in the lenvatinib treatment group (10.60 vs. 14.35 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.759; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The ORR and DCR in patients receiving lenvatinib were 57.1% and 92.9%, respectively. However, the ORR and DCR of patients who did not receive lenvatinib were only 31.2% and 62.5%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAEs were reported in all 30 (100%) patients throughout treatment (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Most AEs were mild, well tolerated, and controlled during combination treatment. The most common AEs (of any grade) were anaemia (76.7%), thrombocytopenia (56.6%), and transaminitis (53.3%). The addition of lenvatinib did not increase the risk of AEs. Notably, two patients developed acute cerebral infarction after receiving just one cycle of combination therapy with durvalumab, lenvatinib, and chemotherapy, leading to treatment discontinuation.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of the AEs in patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAEs,n(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eITT\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003edurvalumab+\u003c/p\u003e\u003cp\u003echemo\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003edurvalumab\u0026thinsp;+\u0026thinsp;lenvatinib\u0026thinsp;+\u0026thinsp;chemo(n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (76.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (81.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.675\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (56.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (75.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutropenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (43.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.431\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated ALT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (62.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevates AST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (53.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (62.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6 (42.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.282\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (13.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.602\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (36.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.156\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePruritus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (13.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConstipation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.586\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Values are presented as percentage. AEs, adverse events; ITT, intenion-to treat population; ALT, alanine aminotransferase; AST, aspartate aminotransferase.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBTC is a highly malignant and lethal cancer type with a low response rate and a poor prognosis. This is the first retrospective analysis of the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib in advanced BTC patients and represents a potentially shifting approach to improving the response to immunotherapy. In particular, the combination of durvalumab plus gemcitabine-based chemotherapy with lenvatinib is promising. Patients who received durvalumab plus gemcitabine-based chemotherapy with lenvatinib had longer PFS (7.42 vs. 4.98 months) than patients who received durvalumab plus gemcitabine-based chemotherapy without lenvatinib did. However, no significant improvement in OS was observed with lenvatinib versus without lenvatinib (10.60 vs. 14.35 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.759). In addition, this study demonstrated that durvalumab combined with gemcitabine-based chemotherapy and lenvatinib was well tolerated.\u003c/p\u003e\u003cp\u003eIn this study, the total ORR was 43.4%, which was higher than that reported in the TOPAZ-1 study, with an ORR of 26.7%\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Moreover, patients receiving durvalumab plus lenvatinib with gemcitabine-based chemotherapy achieved an ORR of approximately 57.1% and a DCR of approximately 92.9%. In the Leap-005 study, the ORR of lenvatinib plus pembrolizumab treatment reached only 10%, and the DCR was 68%\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In a real-world cohort study that included 103 patients who received PD-1 blockade plus lenvatinib for advanced intrahepatic cholangiocarcinoma, the ORR was 18.4%, and the DCR was 80.6%\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Recently, a phase II study in which patients received toripalimab combined with lenvatinib and GEMOX for ICC exhibited an ORR of 80.0% and a DCR of 93.3%\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. A growing body of evidence suggests that ICIs can improve treatment efficacy in advanced BTC patients. Moreover, the combination of lenvatinib and ICIs may further improve treatment efficacy.\u003c/p\u003e\u003cp\u003eLenvatinib has been demonstrated to have immunomodulatory activity in in vivo and in vitro studies, and the antitumour activity of lenvatinib and can be enhanced by combination therapy with ICIs\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Targeted therapy can reduce the immunosuppressive effects mediated by vascular endothelial growth factor (VEGF) in tumours and their microenvironments. Reversing VEGF-related immunosuppression and promoting T-cell infiltration into tumours enhances the efficacy of anti-PD-1 and anti-PD-L1 therapies. Lenvatinib can eliminate cancer cells via its direct antitumour activity and by inducing immunogenic cell death while also reducing the number of cells targeted and killed by immune cells, thereby improving immunotherapy effectiveness\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Indeed, lenvatinib strongly inhibits VEGFRs and FGFRs, both of which play crucial immunosuppressive roles in immune responses\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eHowever, the PFS and OS reported in our study were lower than the median PFS and OS reported in the TOPAZ-1 trial\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e and in similar real-world studies\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. The possible reasons for this discrepancy may include the following. First, durvalumab dose reduction: owing to China's earlier drug donation policy, the dose of durvalumab in this study was 1000 mg, which is lower than the approved label dose (1500 mg). Second, in real-world settings in China, patients generally have worse baseline characteristics, with ECOG 1 status accounting for the vast majority (93.3%), whereas in the TOPAZ-1 study\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, only approximately half (50.9%) of patients had an ECOG PS score of 1. Finally, the chemotherapy regimen in our study was less intensive than that in TOPAZ-1\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, with only two-thirds of patients receiving the combination of gemcitabine plus cisplatin. These factors may have collectively contributed to the inferior survival outcomes observed in our study.\u003c/p\u003e\u003cp\u003eMoreover, in our subgroup analysis, the addition of lenvatinib improved only the ORR and DCR and modestly prolonged PFS, but these changes failed to translate into an improvement in OS. This finding aligns with the results of the LEAP-011 trial, which compared pembrolizumab plus lenvatinib with pembrolizumab monotherapy as a first-line treatment for advanced urothelial carcinoma\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. These data suggest that while lenvatinib combination therapy may enhance early efficacy markers (ORR and DCR) and marginally prolong PFS, it does not confer a survival advantage, which is consistent with our real-world findings.\u003c/p\u003e\u003cp\u003eIn our study, although nearly all patients experienced AEs of varying severity, no fatal AEs were observed. Among all patients, the most common adverse reactions were myelosuppression, manifested as anaemia (76.7%), and thrombocytopenia (56.6%), which are likely associated with the chemotherapeutic agents\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. The addition of lenvatinib did not significantly increase treatment-related AEs in patients, which is consistent with findings from other studies\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. However, notably, two patients receiving combination therapy (immunotherapy plus targeted therapy and chemotherapy) developed acute cerebral thrombosis after just one treatment cycle, leading to treatment discontinuation. Although lenvatinib, an antiangiogenic agent, is associated with a relatively low risk of thromboembolic events\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, this combination regimen still requires rigorous screening and close monitoring for thrombosis risk.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, this was a single-centre retrospective study with a small sample size; therefore, the results should be interpreted with caution. Larger scale, multicentre prospective studies are needed to validate these findings in the future. Second, the chemotherapy regimens were not uniform, although all were standard treatments, and dedicated prospective studies are needed to compare outcomes among different drug regimens. Third, our study population exclusively comprised Chinese patients, and the findings may not be directly generalizable to Western cohorts. Despite these limitations, as a real-world study, our findings provide valuable insights for designing future clinical trials and informing treatment strategies in clinical practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eDurvalumab and gemcitabine-based chemotherapy with or without lenvatinib has been shown to be effective and safe in routine practice. However, the addition of lenvatinib may improve only the DCR, ORR, and PFS but may not prolong OS. Hence, larger prospective cohort studies need to be conducted to confirm the necessity and feasibility of adding lenvatinib to ICI and chemotherapy regimens.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBTC, biliary tract cancer; ICIs, immune checkpoint inhibitors; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; DCR, disease control rate; HR, hazard ratio; CI, confidence interval; CCA, cholangiocarcinoma; GBC, gallbladder cancer; ICC, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma; dCCA, distal cholangiocarcinoma; GC, gemcitabine/cisplatin; GS, gemcitabine plus S-1; GEMOX, gemcitabine plus oxaliplatin; PD-L1, programmed death-ligand 1; FDA, Food and Drug Administraion; NCCN, National Comprehensive Cancer Network; VEGFRs, vascular endothelial growth factor receptors; PDGFR, platelet-derived growth factor receptor; FGFRs, fibroblast growth factor receptors; RET, rearranged during transfection; PD-1, programmed cell death protein 1; USTC, University of Science and Technology of China; RECIST, Response Evaluation Criteria in Solid Tumors; ECOG, Eastern Cooperative Oncology Group; TNM, tumor node metastasisclassification; CA19-9, cancer antigen 19-9; IV, intravenously; BSA, body surface area; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; ECC, extrahepatic cholangiocarcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; HBV, hepatitis B virus; AEs, adverse events; VEGF, vascular endothelial growth factor.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (no. 2024-RE-281) and accordance with the Declaration of Helsinki. All patients signed the informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset generated during the present study can be obtained from the corresponding author with a reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no financial interests or personal relationships which may be considered as potential competing interests in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (No. 82272700).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: QD, YS; Administrative support: GW, RS, YS; Provision of study materials or patients: QD; Collection and assembly of data: QD; Data analysis and interpretation: QD, YW; Manuscript writing: All authors; Final approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients and their families for their participation and thank Ms. Shanshan Chen from AstraZeneca medical affairs for her contribution in terms of material support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVogel A, Bridgewater J, Edeline J, et al. 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PMID: 36555928; PMCID: PMC9785927.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"lenvatinib, durvalumab, gemcitabine-based chemotherapy, biliary tract cancer","lastPublishedDoi":"10.21203/rs.3.rs-7101973/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7101973/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eImmunotherapy in combination with gemcitabine-based chemotherapy has become the standard first-line treatment for advanced biliary tract cancer (BTC). Some small sample studies have shown that immune checkpoint inhibitors (ICIs), when used in combination with lenvatinib and chemotherapy as a first-line therapy, exhibit high BTC antitumour activity. However, real-world data showing the efficacy and safety of durvalumab combined with chemotherapy and lenvatinib are lacking. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib for advanced BTC therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective analysis of the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib in advanced BTC cancer patients between January 2021 and June 2023. The study endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThirty patients with advanced BTC were included in this study, among which 14 (46.7%) received durvalumab combined with lenvatinib plus chemotherapy. For all the patients, the median OS was 11.82 months, the median PFS was 6.23 months, the ORR was 43.4%, and the DCR was 76.7%. Patients who received lenvatinib treatment had a longer median PFS (7.42 vs. 4.98 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.875) than did those in the non-lenvatinib group. However, the median OS was shorter in patients in the lenvatinib treatment group (10.60 vs. 14.35 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.759). The ORR and DCR in patients receiving lenvatinib were 57.1% and 92.9%, respectively. However, in patients that did not receive lenvatinib, the ORR and DCR were only 31.2% and 62.5%, respectively. All patients experienced adverse events (AEs), but the inclusion of lenvatinib did not increase the risk of AEs. The data are still being updated.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eDurvalumab and gemcitabine-based chemotherapy with or without lenvatinib has been shown to be effective and safe in routine practice. The addition of lenvatinib may improve only the DCR, ORR, and PFS but may not prolong OS.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer: A retrospective real-world study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 06:15:06","doi":"10.21203/rs.3.rs-7101973/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"919ff5e8-3407-4d42-bbd6-f4ed6c07267d","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-07T10:23:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-20 06:15:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7101973","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7101973","identity":"rs-7101973","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}